endocrinology Flashcards

Question

Development of the adrenal cortex

Answer 1

The cortex originates from mesoderm. The initial primordium of the cortex originates from a group of cells of the coelomic epithelium (mesothelium) in a cleft between the region of the gut (actually the dorsal mesentery, a tissue that connects the gut to the dorsal portion of the embryo) and the urogenital ridge (also called the Wolffian body), see figure below, and recall your kidney embryology of the formation of the mesonephric duct from initial nephrotomes. At about 4 weeks, under induction by the mesonephric (or Wolffian duct), cells in the cleft proliferate and migrate into the mesenchyme just dorsal to it. They multiply and organize into a cup-like structure in roughly the same shape as the cortex of the adrenal. Between 2-3 months, another wave of cells from the coelomic epithelium at the same location enters the mesenchyme and surrounds the outer part of the cup, in another layer. The first early set of cells will become cells of the reticularis of the cortex, whereas the second group of cells that layer on the outside will differentiate into the fasciculata and the glomerulosa. Therefore, the cortical region of the adrenal is entirely mesodermal in origin. Note that after birth, a significant portion of the inner region of the early reticularis regresses.

Answer 2

medulla originates from the ectoderm. Cells in the medullary region come from an entirely different origin. Neural crest cells (ectoderm) migrate to a region that will become the sympathetic ganglia. Early on, these cells are called sympathogonia and some of them continue to migrate into the center of the cup that will become the medullary region of the adrenal (see Fig. above). They happen to stain yellow- brown with chrome salts hence are called chromaffin cells, and are the progenitors of the epinephrine- and norepinephrine-producing cells of the medulla. Development of the adrenal continues after birth, with the layers of the fasciculata and glomerulosa becoming more distinct, the reticularis regressing somewhat and the medulla increasing in relative volume. Vascularization occurs through infiltration of small vessels of mesodermal origin during development with blood flow from vessels entering the outer cortex and blood collecting toward and leaving via the central vein of the medulla.

Answer 3

The classic hormones fall into three categories 1) derivatives of tyrosine, 2) derivatives of cholesterol (steroids), and 3) peptides and proteins.

Answer 4

epinephrine, norepinephrine, dopamine, thyroxine

Answer 5

testosterone, cortisol, estrogens, aldosterone, vit D, progesterone

Answer 6

oxytocin, vasopressin, angiotensin, thyrotropine releasing hormone, gonadotropin releasing hormone

Answer 7

insulin, glucagon, growth hormone, ACTH, prolactin, thyroid stimulating hormone.

Answer 8

The secretion of peptide and protein hormones follows the classical pathway for secretion of protein from cells. After synthesis as a pre-prohormone on ribosomes from their respective mRNAs, the hormone is targeted to the rough endoplasmic reticulum. Here the pre-prohormone is cleaved and the prohormone is transported to the Golgi apparatus where it is further processed and packaged into secretory vesicles. The endocrine organ then secretes the hormone in response to specific signals by vesicular exocytosis, in a calcium-dependent manner. A similar mechanism is used for the secretion of catecholamines like dopamine and epinephrine. Once secreted into the bloodstream, the hormone is then carried to its target organ. Most peptide and protein hormones (the exceptions are growth hormone, prolactin and Insulin-like growth factor) are transported in the blood as free hormones. As the blood contains many proteases, the half-life of these hormones is therefore limited.

Answer 9

The basic precursor for all steroid hormones is cholesterol. Because the names of various steroid hormones derive from the numbering system of cholesterol, it is useful to know how the carbon atoms on a cholesterol molecule are numbered. The outline of the pathway for steroid biosynthesis will be discussed in the lecture on Adrenal gland. As steroid hormones are lipophilic and therefore membrane permeant, it stands to reason that their secretion will not be via the vesicular exocytosis as it is for protein and peptide hormones. The steroid hormones are not stored in the cell they are synthesized in and are therefore immediately released into the blood stream. Another consequence of their hydrophobicity is that they need to be carried by carrier proteins in the blood stream. In the blood, steroid hormones exist in equilibrium between free and bound forms and at any given time only a small fraction of the hormone (1-5%) exists in the free form. However, you must realize that it is the free form of the hormone that is biologically active and thus knowing total hormone levels in the blood might not be very informative. The bound form serves as an essential reservoir of the hormone. Unlike the protein and peptide hormones, steroid hormones linger in the bloodstream for a long time and have half lives in the order of many hours to days.

Answer 10

Measurement of plasma levels of hormones is a primary tool of the clinical endocrinologist. The two major methods for measuring hormone levels are 1) bioassays and 2) immunoassays. Bioassays measure hormone activity and in this case hormone function is measured by using an exogenous system e.g. cell lines, to measure hormone activity. Radio-immunoassays (RIA) and enzyme linked immunosorbent assays (ELISA) measure antibody binding to a specific region of the hormone. They might not be useful if an abnormal form of the hormone is being secreted by the patient.

Answer 11

When protein and peptide hormones (as well as some of the hormones derived from tyrosine, like epinephrine and norepinephrine) reach their target, they bind to specific receptors on the plasma membrane of the target cells. Receptors for some hormones, e.g. epinephrine and norepinephrine, belong to the family of G-protein coupled receptors. Binding of the hormone to these receptors results in changes in the levels of intracellular second messengers like cAMP, diacylglycerol and inositol phosphates. Other hormones like growth hormone and prolactin have receptors that belong to the JAK/STAT family of receptors. Activation of these receptors results in coupling and activation of a tyrosine kinase (Janus kinase or JAK), which then causes the phosphorylation of a group of proteins called signal transducers and activators of transcription (STATs). Yet other receptors for hormones like Insulin and IGF-1 belong to a large family of protein tyrosine kinase receptors. In this case the receptors themselves are tyrosine kinases that can be activated upon hormone binding. Activation of catecholamine, protein and peptide hormones can have rapid consequences, like increased cytosolic calcium, exocytosis, phosphorylation of enzymes and ion channels. In addition, they can have effects that are slower and involve changes in gene expression. We shall discuss individual cases when we talk about individual endocrine glands.

Answer 12

Unlike the peptide hormones, steroid receptors are nuclear in their location. Once steroid hormones reach their target cells, they enter the cell and bind to their receptors in the cytosol or the nucleus. The receptor-hormone complexes then bind to specific hormone responsive elements (HRE) and activate transcription of specific genes.

Answer 13

Levels of various hormones, metabolites, and minerals in the body are very tightly regulated around a specific set point. This is achieved mainly by feedback loops. There are two classes of these feedback loops. One where the hormone level is the regulated variable and the other where the plasma concentration of a metabolite or a mineral acts as the regulated variable. Target hormones regulating their own secretions usually go through negative feedback loops where excess of an end hormone acts to inhibit its own production. Purely positive feedback loops are rare in biology for obvious reasons. A positive loop will lead to an unstable and often cataclysmic process. The only way a positive feedback loop can be terminated is by the exhaustion of the hormone or by an explosive event such as ovulation. An example of a positive feedback loop in endocrinology is the production of oxytocin during the birthing process. The stimulus for oxytocin secretion is the dilation of the uterine cervix. This dilation causes the release of further oxytocin thus creating a positive feedback loop that is terminated by the expulsion of the fetus and relaxation of the uterine muscles. Hormone secretion often occurs in a pulsatile fashion. In addition, the levels of many hormones are regulated by diurnal variation and thus show characteristic circadian rhythms.

Answer 14

The hypothalamus forms the interphase between the brain and the endocrine system. The connection between the anterior pituitary and the hypothalamus consists of a very specialized structure known as the hypothalamo-hypophyseal portal system. Blood enters the median eminence through the superior hypophyseal arteries, which forms a capillary plexus. Nerve terminals of appropriate hypothalamic neurons terminate here, and their neurohormones are released into this capillary bed and then are transported via the portal system vasculature to a second capillary plexus in the anterior lobe. The ability of the plexus to have an easy access to the released hypothalamic hormones is because it lies outside the blood brain barrier. Another consequence of this specialized structure is that hormones secreted by the involved hypothalamic neurons reach the anterior lobe relatively undiluted and thus at higher concentrations than would be achieved if they had been released into the general circulation. Further, hypothalamic hormones act on a local rather than distant target. If the portal system is severed or the anterior pituitary is transplanted elsewhere (where it may even become vascularized), secretion of anterior pituitary hormones will no longer be subject to normal hypothalamic control. Hypothalamic hormones are released into the capillary plexus in the median eminence and travel a relatively short distance, for a hormone, to the anterior pituitary. Here, they regulate the secretion of hormones by the anterior pituitary into the general circulation. The hypothalamic hormones are peptides, except for dopamine (DA), which is a catecholamine, and are usually considered in relation to the anterior pituitary hormone's secretion that they influence.

Answer 15

Hypothalamic hormones are released into the capillary plexus in the median eminence and travel a relatively short distance, for a hormone, to the anterior pituitary. Here, they regulate the secretion of hormones by the anterior pituitary into the general circulation. The hypothalamic hormones are peptides, except for dopamine (DA), which is a catecholamine, and are usually considered in relation to the anterior pituitary hormone's secretion that they influence.

Answer 16

thyrotropin releasing hormone (increases TSH and PRL), gonadotropin releasing hormone (increases LH and FSH), corticotropin releasing hormone (increases POMC and ACTH), growth hormone releasing factor (increases GH), somatostatin (decreases GH and TSH), prolactin inhibiting factor (decreases PRL). Some of these hormones stimulate while others inhibit the secretion of hormones from the anterior pituitary. In some cases, factors have been identified that stimulate and others that inhibit the secretion of the same hormone, e.g., GHRH and somatostatin stimulate and inhibit, respectively, the secretion of GH.

Answer 17

The hypothalamus receives inputs from the thalamus, limbic system including olfactory bulb, hippocampus, habenula and amygdala, the retina, reticular activating substance and the neocortex, information regarding pain, sleep versus wakefulness, emotions, fright, rage, olfactory sensations, light reaches the hypothalamus and can affect the activity of the neurosecretory neurons.

Answer 18

Stimulus-dependent secretion of hypothalamic hormones occurs in a manner similar to neurotransmitter release. In brief, appropriate stimulation of a hypothalamic neuron will result in generation of action potentials, At the nerve terminal, calcium entry through voltage-dependent calcium channels will lead to liberation of hormone (versus neurotransmitter) from secretory vesicles. Thus, just as for neurotransmitter release, hormone secretion from hypothalamic neurons is calcium-dependent.

Answer 19

At a cellular level, the hypothalamic hormones interact with specific receptors on their appropriate target cells in the anterior pituitary. The exact intracellular signaling cascades triggered by receptor activation in the various anterior pituitary cells are the subject of much current investigation. One point of agreement is that extracellular calcium is required for the release. Involvement of calcium release from intracellular stores is still debatable. The hormones bind to their respective receptors, which in turn are coupled to various G-proteins. CRH and GHRH receptors are coupled to Gs and, upon activation, stimulate adenylate cyclase to produce cAMP in corticotrophs and somatotrophs, respectively. In contrast, the interaction of somatostatin with Gi eventually leads to a decrease in cAMP. Similarly, DA leads to a reduction in cAMP levels in lactotrophs. CRH also leads to an increase in the rate of transcription of POMC and formation of ACTH.

Answer 20

Gs. In gonadotrophs, GnRH receptor activation leads to the hydrolysis of membrane phosphatidyl inositol. In somatotrophs and thyrotrophs, the phosphatidylinositol cycle (in addition to adenylate cyclase activation) appears to play a role in signal transduction. For example, TRH induces this pathway in thyrotrophs as well as lactotrophs. The arachidonic acid signaling pathway is receiving attention and evidence is accumulating that implicates it in the release mechanism employed by several pituitary cells.

Answer 21

The role of voltage-dependent calcium and potassium channels in release is currently being examined. One possible mechanism is that the second messengers released upon the activation of receptors for hypothalamic hormones on pituitary cells can alter the states of various membrane ion channels and cause calcium flux from outside to mediate hormonal release from the anterior pituitary. It is also possible in the case of GnRH (and possibly GHRH and TRH) that the production of IP3 upon activation of the receptor (mediated by Gq and phospholipase C) can increase cytosolic calcium from intracellular stores and thus mediate release. In sum, although release of hormone from anterior pituitary cells is dependent upon calcium, evidence exists implicating several intracellular signaling cascades to different degrees in the various pituitary cells. Membrane conductances also appear to play a role. These intracellular cascades are probably also involved in regulating the synthesis of various pituitary hormones.

Answer 22

The pituitary gland acts as an endocrine control center responding to neural signals, and catering to the needs of various target tissues (e.g.,thyroid, gonads, adrenal gland, bone), coordinating and regulating their functions. The gland is attached to a region of the brain (hypothalamus) by a structure known as the pituitary stalk. This anatomical connection is necessary for the functional interactions between the brain and pituitary. The pituitary consists of two major divisions, the anterior (adenohypophysis) and the posterior hypophysis (neurohypophysis). The anterior pituitary is derived from an embryological structure known as Rathke's pouch (pharyngeal epithelium); the intermediate pituitary is also found within the adenohypophysis, but is extremely small in humans and not thought to be of functional significance. The posterior pituitary is derived from neural tissue arising from an embryological evagination of the diencephalon.

Answer 23

The anterior pituitary is comprised of the pars tuberalis, pars intermedia (intermediate lobe) and the pars distalis (anterior lobe). Hormone secretion is under control of the hypothalamic hormones discussed above. TRH acts on cells called thyrotrophs to stimulate the secretion of TSH; GnRH acts on gonadotrophs to stimulate the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH); GHRH and somatostatin act on somatotrophs to stimulate and inhibit, respectively, the secretion of growth hormone (GH); CRH acts on corticotrophs to stimulate the secretion of corticotropin (ACTH) and proopiomelanocortin (POMC); prolactin inhibiting hormone (PIH, thought to be DA) and prolactin releasing factor (PRF, perhaps TRH?) act on mammotrophs to inhibit and stimulate, respectively, the secretion of prolactin (PRL). PRL and GH are polypeptide hormones; TSH, FSH and LH are glycoproteins, each comprised of an identical α-subunit and a unique β-subunit; ACTH is a derivative of a prohormone called POMC, which is cleaved in both the anterior and intermediate lobes of the pituitary to give rise to ACTH, an N-terminal fragment and β-lipotropin; subsequent cleavage of β-lipotropin generates γ-lipotropin and β-endorphin. Β-endorphin contains the sequence of metenkephalin, whereas γ-lipotropin contains the sequence of β- MSH. The post-translational processing of POMC is different in the intermediate lobe where α-MSH is predominantly generated after ACTH is further cleaved.

Answer 24

The release of hormones from the anterior pituitary is not constant over time but instead is quite varied and described as pulsatile. There are periods of higher release followed by periods of diminished release. Thus, the plasma levels show spikes or pulses. It may be that this type of secretion is directed by pulsatile secretion of the stimulating (or inhibiting) hypothalamic hormone. Evidence for this mechanism is strong for LH, FSH (GnRH pulse generator) and ACTH. Pulsatile, rather than continuous, secretion of hypothalamic hormones is the effective signal guaranteeing appropriate stimulation of the anterior pituitary. For example, a pulse of GnRH precedes the pulses of LH that are seen approximately every 90 minutes in an ovariectomized animal, giving rise to the notion of GnRH as a pulse generator for LH. GH is a more complicated case responding to both GHRH and somatostatin pulses. Endogenous pacemakers are thought to be involved in the generation of pulses of some hypothalamic hormones, e.g., GnRH pulses. Gonadal dysfunction (e.g., amenorrhea) produced by hyperprolactinemia is due to inhibition by prolactin of pulsatile secretion of GnRH. A similar mechanism has been described for CRH and corresponding ACTH release. In addition, rhythms that cycle with the period of a day exist (circadian rhythms). For example, GH secretion is elevated shortly after sleep onset, whereas ACTH is highest during the early morning hours.

Answer 25

The posterior pituitary is formed from the evagination of the diencephalon and is thus directly connected to the hypothalamus and brain. It consists of three parts - the median eminence, infundibular stem and the infundibular process (pars nervosa). Posterior pituitary hormones are synthesized in the hypothalamus in two nuclei- the supraoptic nucleus, which and the paraventricular nucleus. These nuclei have two cell types, both of which produce the hormones- 1) the magnocellular neurons, whose processes extend into the posterior pituitary and end in the pars nervosa and 2) the parvocellular neurons, which end at the median eminence close to the endings of hypothalamic neurons that produce the anterior pituitary regulating hormones. Thus, some of the posterior pituitary hormones can reach the anterior lobe where they can have some functions e.g. ADH can act on corticotrophs to increase ACTH production. Cortisol, regulated by ACTH, can in turn, inhibit both ADH function in the kidneys and release at the hypothalamus.

Answer 26

The neurohypophysis secretes two nonapeptides, antidiuretic hormone and oxytocin. Both are synthesized in the cell bodies of large hypothalamic neurons known as magnocellular neurons. They are synthesized as part of a larger prohormone. The prohormone is packaged into secretory vesicles and cleaved into the hormone and a protein called neurophysin (function unknown) as the vesicles travel down the axon of the neuron to the posterior pituitary. The vesicles are released when an action potential invades the terminal, activating calcium channels. Calcium influx occurs, leading to a rise in intracellular calcium and neurosecretion.

Answer 27

ADH is secreted in response to an increase in plasma osmolarity or a decrease in blood pressure. It acts on the cells of the renal tubule and collecting ducts to alter water permeability and conserve water. At high concentrations it is a powerful pressor agent, acting to increase blood pressure; for this reason, it was originally called vasopressin. There are two kinds of ADH receptors: V1 coupled to Gq and the Phospholipase C pathway, mediates the vasopressive action of ADH and V2 coupled to Gs and the cAMP pathway regulates the effects of ADH on glomerular filtration rates in the kidney.

Answer 28

Oxytocin is secreted in three interpersonal situations: 1. During the passage of the infant through the cervix at childbirth. 2. During sexual intercourse. 3. In response to suckling by the infant during breast-feeding. This neuroendocrine reflex can be conditioned. Oxytocin acts on the uterus around the time of birth to cause contraction of the myometrium. In the lactating woman it causes contraction of myoepithelial cells, producing milk ejection.

Answer 29

Prolactin (PRL) and growth hormone (GH) are members of the same family of hormones, and both are ~22-23 kD polypeptides of slightly less than 200 amino acids containing 2-3 disulfide bonds. PRL and GH are ~16% similar at the level of primary sequence. This class of hormones is also referred to as the somatomammotropin family. A third member of this family is placental lactogen (hPL or chorionic somatomammotropin), which has 83% amino acid identity with GH.

Answer 30

This hormone distinguishes itself by the fact that the hypothalamus tonically inhibits the secretion of PRL via PIH, or DA. If the hypothalamic influences to the anterior pituitary are prevented, the adenohypophysis will secrete much larger amounts of PRL, whereas the secretion of the other anterior pituitary hormones will not increase. In some instances of hypersecretion of prolactin, administration of a dopamine agonist, such as bromocriptine, is effective in reducing the excess release of prolactin. DA reduces release and synthesis of PRL, inhibits lactotroph cell division and DNA synthesis and increase destruction of PRL containing secretory granules (crinophagy). Inhibition of cAMP formation appears to be involved in mediating these effects.

Answer 31

The cells that secrete PRL, lactotrophs, comprise 30% of the adenohypophysis. The breast is the principal target of PRL action, where PRL plays a role in the production of milk. In cases where there are prolactin-secreting tumors, there will be inappropriate milk secretion. Reproduction is impaired, because high levels of prolactin inhibit pulsatile secretion of GnRH by hypothalamic neurons. The synthesis of peptide hormones will be discussed below for the case of GH. PRL is transported in the blood unmodified and has a short half-life of 20-30 min.

Answer 32

In females, suckling of the breast is an effective physiological stimulus leading to release of prolactin. In addition, prolactin is released in both males and females in response to stress. Prolactin interacts with specific receptors found in the breast, liver, ovary, testis and prostate; the main site of action is the mammary gland. Prolactin receptors are members of the growth hormone/cytokine receptor families. The long form of PRL receptors and the growth factor receptors are about 620 amino acids in length. . They are single chain proteins crossing the membrane only once. Upon ligand binding, receptors dimerize, leading to the activation of the JAK/STAT pathway. Just as prolactin and growth hormone share structural homology, so do their receptors. Human PRL receptors are well stimulated by GH.

Answer 33

Growth hormone is fundamental for postnatal growth, stimulates somatic growth and regulates metabolism. GH is a peptide hormone as well as a secretory protein. At the level of the genome, the GH gene is organized into exons and introns, and the coding region spans several exons. It is thus possible to generate alternative forms of GH by splicing, and this does occur. The principal and biologically most important form consists of 191 amino acids. Similar to many other hormones, GH is synthesized as part of a prohormone. Once the signal peptide is cleaved, GH is stored in secretory granules of somatotrophs of the adenohypophysis. The synthesis of GH is evidently a major activity of the anterior pituitary, since 10% of the dry weight of the anterior pituitary is contributed by GH! Secretion of GH is under the influence of the hypothalamic hormones GHRH and somatostatin. GHRH and somatostatin stimulation of somatotrophs have opposing actions on cAMP levels; GHRH stimulation increases them, whereas somatostatin decreases them. The majority of GH circulates in an unbound form and has a half-life of 20-45 min. There is some evidence suggesting that a portion of plasma GH is bound specific binding proteins (GHBP), which are cleaved N-terminal peptides of its receptor.

Answer 34

Despite the sequence similarity and the fact that somatomammotropins are evolutionarily conserved genes, human GH is extremely specific for its species. Human or primate GH are the only GH's that are active in humans. Previously, human GH isolated from cadavers was used therapeutically. In 1985, it was noted that several individuals who had been treated with "cadaver" GH acquired Creutzfeld-Jacob disease, a devastating form of spongiform encephalopathy caused by prions. Recombinant GH is now available and has become the sole source of GH replacement therapy.

Answer 35

At a cellular level, GH interacts with GH receptors in the plasma membrane of target cells. Both GH receptors and their signaling mechanisms are similar to that of PRL. In general, GH's effects are anti-insulin like, i.e. glucose uptake will be decreased and plasma glucose levels will rise. Note that the increased plasma FFA is providing an alternate energy source and the increased plasma glucose is reserved for the CNS. Importantly, protein is spared. This contrasts with the actions of cortisol

Answer 36

The net effect is to increase lipolysis and lead to mobilization of lipid and thus an increase in plasma free fatty acids (FFAs). Eventually, the effect of GH on fat metabolism will be evidenced by a loss in subcutaneous fat. In this action GH antagonizes the action of insulin.

Answer 37

GH has a strong anabolic action on muscle. Amino acid transport is increased, and protein synthesis is increased.

Answer 38

Increased RNA, protein and glucose synthesis. Further, IGF-I will be secreted, which mediates the indirect effects. The increase in glucose levels is mainly due to an increase in gluconeogenesis and not due to glycogenolysis.

Answer 39

In addition to its metabolic effects, GH also has effects on muscle and skeletal growth mediated by another hormone-the Insulin-like growth factor (IGF). There are two forms of IGF that have been shown to exist (IGF-I and IGF-II). Of these, IGF-I is the predominant form in postnatal tissues. The production of IGF requires both GH and insulin and occurs in a number of tissues (e.g. liver, bone marrow).

Answer 40

IGF-I is structurally related to proinsulin (hence its name) and has many insulin like actions (especially in adipose tissue and muscle). IGF-I is a powerful mitogen and growth-promoting agent. Elevated IGF-I levels increase slowly from birth until puberty, when there is usually a much more pronounced elevation. Although growth hormone usually promotes secretion of IGF-I production, there are some stimuli that have different effects on GH and IGF-I levels. For example, during fasting, GH levels are elevated, while IGF-I levels are depressed. IGF receptors belong to the EGF/ Insulin receptor family. These receptors contain an inherent tyrosine kinase activity and upon ligand binding can readily phosphorylate themselves (auto phosphorylation) and other proteins of the signal transduction pathway. The major pathway activated by IGF receptors is initiated by the binding of Insulin Receptor Associated proteins 1 and 2 (IRS I&II). IRS in turn can bind to other molecules to activate either the MAP kinase pathway or transduction mediated by PI-3 kinase.

Answer 41

Bone/cartilage - Long bone growth is promoted by the stimulated proliferation of epiphyseal cartilage. After puberty, the epiphyses seal and IGF-I no longer has this effect on linear growth. Muscle - stimulates proliferation, differentiation and protein synthesis. Adipose tissue - stimulates uptake of glucose and inhibits lipolysis. This action of IGF is insulin like and antagonizes that of GH.

Answer 42

Other stimuli include hypoglycemia, amino acids (arginine), low free fatty acid levels, α- adrenergic agonists (clonidine), β-adrenergic antagonists (propranolol) and estrogens. Conversely, hyperglycemia, high free fatty acid levels, obesity, α-adrenergic antagonists, β-adrenergic agonists as well as pharmacological doses of corticosteroids inhibit GH secretion. In assessing GH levels and secretion, it is important to obtain measurements several times over the course of a day. Stimulation of GH secretion by exercise or high doses of arginine is often used to assess GH status. In addition, measurement of IGF-I levels is very helpful, especially since its levels are subject to less diurnal variation.

Answer 43

TSH acts on thyroid gland epithelium. Prolactin has no direct endocrine target, but is important in lactation, menorrhea, libido, and fertility. ACTH stimulates the adrenal cortex, primarily zona fasiculata and zona reticularis. GH acts on receptors in the liver. FSH stimulates testicular Sertoli cells and ovarian granulosa cells. LH stimulates testiscular Leydig cells and ovarian theca cells. MSH acts on melanocytes in the skin and hair.

Answer 44

is counter-regulatory to insulin. It stimulates somatic growth via insulin-like growth factor (IGF-1), which is released by the liver in response to stimulation by GH. IGF-1 increases bone and cartilage growth/mass, increase protein synthesis and muscle mass, increase fat breakdown and TGA levels, and increase salt and H2O retention.

Answer 45

Leads to acromegaly or gigantism. If the excessive GH secretion occurs during childhood (prior to skeletal epiphyseal closure) the disease state that results is gigantism. If the excessive GH secretion occurs during adulthood (after epiphyseal closure) the disease state that results is acromegaly.

Answer 46

Gigantism is characterized by disproportionately long limbs (increased linear bone growth), whereas acromegaly presents as conspicuous growth in the skin and soft tissues, viscera, and bones of the face, hands, and feet. Signs and symptoms of acromegaly include: Coarsening of skin/facial features. Thickening of the hands and feet. Enlargement of the jaw resulting in protrusion (prognathism). Deep voice. Impaired glucose tolerance (insulin resistance). Peripheral neuropathies (due to nerve compression). There are three treatment options for gigantism and acromegaly: Surgery or radiation, Octreotide, a somatostatin analogue that inhibits GH release from the anterior pituitary, and Pegvisomant, a GH receptor antagonist which effectively blocks IGF-1 production.

Answer 47

Diagnosis is made based on increased insulin-like growth factor and MRI/CT imaging of a pituitary neoplasm. A growth hormone suppression test may be performed to determine whether GH production is suppressed by high blood sugar (induced by drinking a glucose solution).

Answer 48

secreted from hypothalamus, targets throtroph causing increased thyroid stimulating hormone

Answer 49

secreted from hypothalamus, targets gonadotroph cells, causing increased release of LH and follicle stimulating hormone

Answer 50

secreted from hypothalamus, targets somatortoph cells, causing increased release of growth hormone

Answer 51

secreted from hypothalamus, targets somatrotroph cells, causing decreased release of growth hormone

Answer 52

secreted from hypothalamus, targets corticotroph cells, causing increased release of ACTH

Answer 53

aka Dopamine, secreted from hypothalamus, targets lactotroph cells, causing decreased release of prolactin

Answer 54

secreted from hypothalamus, targets lactotroph cells, causing increased release of prolactin

Answer 55

Acromegaly is generalized body enlargement due to excessive growth hormone production after the growth plates have fused. Acromegaly is caused by excessive growth hormone production from the pituitary gland. The most common cause is a pituitary adenoma. One key is to differentiate between acromegaly and gigantism. Gigantism occurs before fusion of the epiphyseal plates. Acromegaly occurs after the epiphyseal growth plates have fused. Acromegaly is an insidious process, often presenting after many years. Patients will experience subtle changes such as coarsening of features, changes in glove or hat size, or musculoskeletal complaints such as arthralgias due to tissue overgrowth. As with any pituitary tumor, bitemporal hemianopsia may occur due to compression of the optic chiasm. This mass effect may also cause headaches. The hands, skull, and jaw (macrognathia) are the most affected. Patients may have hyperhidrosis (excessive sweating).

Answer 56

The best initial screening test for patients with suspected acromegaly is quantification of serum IGF-1 levels. The finding of NORMAL IGF-1 levels is sufficient to rule out acromegaly. Oral glucose tolerance test (OGTT) is used to confirm a diagnosis of acromegaly in patients with elevated IGF-1 due to its high level of specificity. An OGTT is considered positive when serum GH concentrations remains > 2 ng/mL (inappropriately elevated) within two hours after ingestion of 75 g glucose (normal value is

Answer 57

Transsphenoidal resection of the pituitary adenoma is the treatment of choice. Radiation therapy may be used if IGF-1 elevations persist after surgery. Somatostatin and Dopamine analogues such as octreotide and bromocriptine, respectively, may be used because of their intrinsic inhibition of GH.

Answer 58

Increased fat deposition; decreased muscle mass, strength and exercise capacity; increased bone loss and fracture risk; increased cholesterol levels; increased inflammatory prothrombotic markers (CRP); impaired energy and mood; decreased quality of life

Answer 59

insulin induced hypoglycemia (contraindicated in elderly, history of seizure disorder). GHRH-arginine is another provocative test. Low IGF-1 levels is also diagnostic.

Answer 60

physiological causes include pregnancy, suckling, sleep, stress. pharmacological reasons include estrogens (OCPs), antipsychotics, antidepressants (TCAs), antiemetics (reglan), opiates. pathological causes include pituitary stalk interruption, hypothyroidism, chronic renal/liver failure, prolactinoma (higher levels, over 150ng/dl).

Answer 61

A benign hyperfunctioning adenoma of the anterior pituitary that secretes the hormone prolactin from the anterior pituitary. A prolactinoma is the most common pituitary tumor, accounting for approximately 30% of all hyperfunctioning pituitary adenomas.

Answer 62

Signs/Symptoms: Female: Galactorrhea and Amenorrhea. Male: Loss of libido, Erectile Dysfunction, and Gynecomastia. Enlargement of the pituitary gland causing compression of optic chiasm causing bitemporal hemianopsia (loss of peripheral vision). Increased Prolactin (>200ng/mL) on labs suggests prolactinoma, but this varies depending on size of tumor. Magnetic Resonance Imaging is used to detect the prolactinoma.

Answer 63

Dopamine agonists bromocriptine or cabergoline. Dopamine inhibits Prolactin release. This also explains why dopamine antagonists (ex: antipsychotics) cause galactorrhea (low dopamine leads to high prolactin). Transsphenoidal surgical resection for large tumors. Radiation therapy in refractory cases.

Answer 64

severe pituitary (lactotrope) destruction. causes include pituitary tumors, infiltrative diseases, infectious diseases infarction, neurosurgery or radiation. presents as failed lactation in post-partum females; no known effect in males. diagnosed based on low basal PRL level

Answer 65

Glucocorticoids (cortisol) are essential for the body to respond to stressful situations (fasting/hypoglycemia, injury etc.) The effects of glucocorticoids (cortisol) can be remembered using the mnemonic "Cortisol tells a BIG FIB”: Blood pressure (increases); Insulin resistance (increases); Gluconeogenesis (increases); Fibroblast activity (decreases); Inflammatory; suppression/Immunosuppression; Bone destruction. Glucocorticoids decrease bone formation through: Inhibition of osteoblast activity; Inhibition of intestinal Ca2+ absorption; Increased renal Ca2+ excretion. Cortisol regulates blood pressure through the upregulation of α1 receptors on arterioles, increasing their sensitivity to norepinephrine (NE). Cortisol excess causes an increase in arterial pressure, while cortisol deficiency causes a decrease in arterial pressure. Glucocorticoids are anti-Inflammatory/Immunosuppressive; they exert these effects through several mechanisms: The induction of synthesis of lipocortin, a phospholipase A2 inhibitor, leads to the inhibition of leukotriene and prostaglandin production . Glucocorticoids inhibit the production of IL-2, which is important for T-cell proliferation. Thus, pharmacologic doses of glucocorticoids prevent the rejection of transplanted organs. Glucocorticoids inhibit leukocyte adhesion, leading to neutrophilia (cells shifted from marginal to circulating pool). Histamine and serotonin release are inhibited by glucocorticoids. Glucocorticoids reduce the number of eosinophils. Cortisol increases insulin resistance, leading to a diabetogenic effect. Glucocorticoids increase gluconeogenesis, as well as lipolysis and protein catabolism. Cortisol decreases fibroblast activity, which plays a role in the development of striae characteristically found in Cushing syndrome.

Answer 66

Weight gain; Fat redistribution (notably moon facies, buffalo hump, truncal obesity); Hypertension; Hyperglycemia (secondary in insulin resistance); Osteoporosis; Immune suppression; Amenorrhea; Impotence; Skin changes (thinning, striae)

Answer 67

Cushing disease represents 70% of endogenous causes of excess cortisol. It is caused by an ACTH-secreting pituitary adenoma which results in increased cortisol levels. Only a primary pituitary adenoma is referred to as Cushing disease, while other etiologies of high cortisol are collectively referred to as a Cushing syndrome.

Answer 68

Adrenal hyperplasia or adrenal neoplasias (adenoma or carcinoma) are responsible for 15% of patients with endogenous Cushing syndrome. ACTH levels are decreased due to negative feedback of cortisol on the pituitary gland. The uninvolved adrenal gland may exhibit atrophy. Adrenal hyperplasia, adenoma, or carcinoma may also present as primary aldosteronism (Conn syndrome).

Answer 69

Ectopic ACTH production, as seen in paraneoplastic syndromes, are responsible for 15% of endogenous hypercortisolemia. Important examples of paraneoplastic ACTH secretion include: Small cell carcinoma of the lung; Renal cell carcinoma; Bronchial carcinoids; Neural tumors. Bilateral adrenal hyperplasia, specifically of the zona fasciculata and zona reticularis, result from the elevated levels of ACTH.

Answer 70

Increased cortisol may be due to exogenous iatrogenic corticosteroid use, or a variety of endogenous causes including: An ACTH-secreting pituitary adenoma Adrenal hyperplasia Adrenal neoplasias Paraneoplastic syndromes (e.g. renal cell carcinoma) To determine the specific etiology of Cushing syndrome, measure ACTH levels: If suppressed, perform an MRI to confirm an adrenal tumor If elevated, perform a dexamethosone suppression test and CRH-stimulation test to identify the source of ACTH Exogenous (iatrogenic) steroids are the #1 cause of Cushing syndrome. Therapeutic treatment with cortisol causes decrease pituitary secretion (negative feedback) of adrenocorticotropic hormone (ACTH). The decreased ACTH levels can lead to bilateral adrenal atrophy.

Answer 71

If Cushing syndrome is due to a tumor, the treatment will involve excision with postoperative glucocorticoid replacement. Drug therapies, including mitotane and ketoconazole, may also be used. Mitotane is an antineoplastic agent used in the treatment of Cushing syndrome because it selectively inhibits the adrenal cortex. Ketoconazole is an antifungal which inhibits cholesterol desmolase preventing steroid hormone (cortisol) synthesis. Furthermore, it inhibits P450 enzymes.

Answer 72

episodic ACTH/ cortisol secretions daily. Major ACTH/ cortisol burst in the early morning (before awakening). Cortisol Nadir 11-12pm (assuming a normal sleep wake cycle)

Answer 73

most cortisol is bound to transcortin (cortisol binding globulin- CBG). 10%-15% bound to albumin (less tightly). 5% unbound (free cortisol)

Answer 74

Disrupted circadian rhythm can be identified from midnight salivary or serum cortisol. Increased filtered cortisol load seen in 24 hr urine free cortisol. Attenuated negative feedback seen with low dose dexamethasone suppression test.

Answer 75

Adrenal insufficiency (hypofunction) is a deficiency of adrenal hormones secondary to adrenal or hypothalamic disease. The adrenal cortex secretes: Aldosterone (Mineralocorticoid); Cortisol (Glucocorticoid); Androgens (Sex Steroids); Adrenal insufficiency may present with symptoms of all three. Causes include: Adrenal atrophy or autoimmune destruction (most common); Granulomatous infection (eg, tuberculosis) of the adrenal gland; Infarction of the adrenal gland; HIV (human immunodeficiency virus); Waterhouse-Friderichsen syndrome (due to adrenal hemorrhage secondary to severe bacterial infection, most commonly Neisseria Meningitidis); DIC (disseminated intravascular coagulation)

Answer 76

Addison's Disease (Primary adrenal insufficiency) is failure of the adrenal cortex most commonly by autoimmune destruction. Because it is autoimmune to the cortex only, ACTH levels will be significantly elevated due to no negative feedback from cortisol. Due to destruction of the adrenal gland patients will present with decreased Aldosterone and Cortisol.Important Recall: Aldosterone normally functions to reabsorb Sodium and excrete Potassium and Hydrogen Ions; Cortisol normally functions to increase Glucose. Therefore, if there is a deficiency of Aldosterone and Cortisol the patient will present with: Hyponatremia (volume contraction —> HYPOtension); Hyperkalemia; Metabolic acidosis; Hypoglycemia; Skin Pigmentation (MSH shares same precursor as ACTH and Primary Adrenal Insufficiency is a hyper-ACTH state). Other symptoms may include constipation, diarrhea, fatigue. Hyponatremia and hyperkalemia can be suggestive of primary adrenal insufficiency. The diagnosis can be made by a low morning cortisol level. Less than 5 mcg/dL is confirmatory for the diagnosis. Other causes include: Infection (fungal or bacterial); Hemorrhage; Sarcoidosis; Hemochromatosis; Lymphoma; Metastatic cancer (commonly carcinomas); Infiltrative disorders such as tuberculosis or histoplasmosis are common infective causes. Also a high infective rate in AIDS patients. Hemorrhagic adrenal infarction is common post-operatively, in sepsis (frequently in cases of meningococcal sepsis), or in any hypercoagulable state.

Answer 77

Secondary adrenal insufficiency is decreased ACTH from the pituitary due to failure of the hypothalamic-pituitary axis, leading to decreased activity of the zona fasciculata and zona reticularis. Pituitary adenomas are a common cause of suppressed ACTH. Following long-term suppression of the hypothalamic-pituitary axis with exogenous glucocorticoid therapy (i.e. prednisone), ACTH production is minimal and the adrenal cortex stops producing much endogenous cortisol. Secondary adrenal insufficiency may develop, particularly if the steroids are abruptly stopped. Metabolism in the zona glomerulosa of the adrenal cortex is NOT controlled by ACTH (it is stimulated by high potassium), so aldosterone is largely unaffected. Patients will present with profound hypoglycemia (zona fasciculata) and low testosterone (zona reticularis). There is no hyperpigmentation in secondary adrenal insufficiency because ACTH is not being produced. Pro-opiomelanocortin (POMC) is the gene that produces ACTH and melanocyte-stimulating hormone (MSH).

Answer 78

Tertiary adrenal insufficiency is due to decreased Corticotropin-releasing hormone (CRH) from the hypothalamus. The most common cause is iatrogenicly induced by chronic corticosteroid use.

Answer 79

The cosyntropin stimulation test is used to differentiate primary and secondary adrenal insufficiency. Cosyntropin is a synthetic analog of ACTH. Plasma cortisol levels of greater than 20 mcg/dL are indicative of normal adrenal function and indicate hypothalamic-pituitary disease, while levels lower than this indicate non-responsiveness of the adrenals to ACTH and primary adrenal failure. Metyrapone inhibits 11-β-hydroxylase, a key enzyme on the synthetic pathway of cholesterol to cortisol. Administration of metyrapone will result in decreased synthesis of cortisol and increases in 11-deoxycortisol. The anterior pituitary will attempt to compensate by increasing ACTH production. The ACTH increase will further increase levels of 11-deoxycortisol. In adrenal insufficiency, there will be no increase in 11-deoxycortisol, as adrenal synthetic function is absent. In primary adrenal insufficiency, ACTH will increase in response to metyrapone administration, as the pituitary tries to compensate for the further reduction in cortisol synthesis. In secondary adrenal insufficiency, ACTH will not increase in response to metyrapone, as pituitary ACTH production is impaired. Shock is the most severe complication of adrenal insufficiency. This is known as adrenal crisis, and should be treated emergently in cases of high clinical suspicion. May be precipitated by stress, such as surgery or sepsis. Suspect it in a patient with chronic illness or known adrenal insufficiency who has refractory hypotension, hyponatremia, and hyperkalemia. Presents with fever, altered mental status, weakness, and vascular collapse.

Answer 80

Treatment requires repletion of adrenal hormones. Patients in adrenal crisis should receive IV glucose and corticosteroids (hydrocortisone or dexamethasone) until the shock is reversed. Vasopressors may also be used. Maintenance therapy in primary or secondary adrenal insufficiency is 5 mg prednisone every morning. Stress dosing (increased doses) of steroids are given in cases of increased stress, such as infection or surgery. Patients with primary adrenal insufficiency also require replacement of aldosterone with the aldosterone analog fludrocortisone.

Answer 81

low FSH/LH due to hypothalamic/ pituitary diseases. Causes include macroadenomas, prolactinomas, isolated GnRH deficiency (Kallman's vs idiopathic), hemochromatosis, functional deficiency due to critical illness, OSA, starvation, meds-opiates, gluccorticoids.

Answer 82

high FSH/LH. causes include congenital anorchia, klinefelter's syndrome, testicular injury, autoimmune testicular disease, glycoprotein tumor.

Answer 83

In females: anoculatory cycles (oligo/ amenorrhea, infertility), vagina dryness, dyspareunia, hot flashes, decreased libido, breast atrophy, reduced bone mineral density. In males: reduced libido, erectile dysfunction, oligospermia or azoospermia, infertility, decreased muscle mass, testicular atrophy and decrease bond mineral density, hot flashes with acute and severe onset of hypogonadism.

Answer 84

The majority of FSH/LH tumors are clinically silent (?inefficient intact LH/FSH hormone synthesis or secretion). Rare presentation (from functionally-intact FSH/LH molecules) include: ovarian hyper-stimulation syndrome (females) or macro-orchidism (males). Middle-aged patients (males >females) with macroadenomas and related mass effects (i.e., headaches, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies).

Answer 85

Blood tests usually showing low FSH/LH, T/E2. Pituitary MRI. Immunohistochemical analyses (+FSH, LH, or ASU staining) of the resected tumor

Answer 86

Secondary causes include thyrotropic secreting pituitary tumor- very rare (less than 1% of pituitary tumors) and thyroid hormone resistance (generalized or pituitary- specific, rare conditions).

Answer 87

similar clinical presentation to primary hyperthyroidism (i.e., goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also with associated mass effects (i.e., headaches, vision loss, loss of pituitary gland function) from macroadenoma. Diagnosis based on elevated free T4 and a non-suppressed TSH and pituitary MRI.

Answer 88

causes include pituitary/ hypothalamic disease and/or their treatments, critical illness/ starvation- euthyroid sick syndrome, congenital defects (TSH-beta mutations, PROP1 POUF1 mutations), drug induced supraphysiologic steroids, dopamine, rexinoids. Clinical presentation is similar to primary hypothyroidism (e.g. fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses). Possible mass effects. Diagnosis is made based on low free T4 levels in the setting of a low or normal TSH.

Answer 89

deficiency of 1 or more pituitary hormones. Panhypopituitarism is loss of all pituitary hormones. Causes includes congenital- genetic diseases (transcription factor mutations) and acquired pituitary lesions and or their treatments (macroadenomas, pituitary surgery, radiation therapy, infiltrative, infectious, granulomatous disease, traumatic brain injury, subarchnoid hemorrhage, apoplexy. There is predictable loss of the anterior pituitary: GH, LH/FSH-> TSH, ACTH-> PRL. Clinical presentation depends on the severity of the pituitary hormone deficiencies and their rate of development. Generally similar presentation to target gland hormone deficiency with some exceptions: primary adrenal insufficiency also presents with hyperkalemia from mineralcorticoid deficiency and hyperpigmentation from ACTH. Diagnosis is based on basal and dynamic testing. Treatment involves end organ hormone replacement.

Answer 90

Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland. Occurs in 10-15% of pituitary adenomas; sub-clinical disease is more common. Diagnosis based on MRI or CT. Treatment includes emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes. Stress dose steroids for adrenal insufficiency.

Answer 91

The syndrome of inappropriate anti-diuretic hormone (SIADH) is a condition of excess anti-diuretic hormone (ADH) leading to impaired water excretion and excessive water retention. SIADH should be suspected in any patient with hyponatremia, serum hypoosmolality, and urine osmolality > 100 mOsmol/kg. Patients may experience cognitive slowing and confusion, anorexia, ataxia with muscle weakness causing falls, and generalized seizures or coma. Note: these symptoms are typically only seen with severe or acute-onset hyponatremia. Physical exam is most often normal, with no evidence of fluid overload or volume depletion (normal blood pressure, skin turgor, etc.). Complications of SIADH are typically neurologic issues such as seizure or coma, due to hyponatremia.

Answer 92

Ectopic production of ADH, most commonly from small-cell lung carcinoma. CNS disorder or trauma, such as stroke, hemorrhage, infection, or psychosis. Pulmonary disease, particularly pneumonia. Surgery, especially transsphenoidal pituitary surgery. Drugs: cyclophosphamide, carbamazepine, SSRIs

Answer 93

Diagnosis is made using both the clinical appearance of euvolemia and the laboratory results described below. When SIADH is suspected, the following labs should be ordered, and these results are consistent with SIADH: Serum electrolytes (sodium, potassium, bicarbonate): low sodium, normal potassium and bicarbonate; Serum osmolality: low; Urine osmolality: submaximally dilute (> 100 mOsmol/L); Urinary sodium excretion: normal, not reduced as one would expect in the setting of hyponatremia; Anion gap: reduced; Serum blood urea nitrogen (BUN): low (less then 10 mg/dL); Serum uric acid: low (less then 4 mg/dL); Blood glucose: normal value rules out hyperglycemia as cause of hyponatremia; Serum cortisol: normal value rules out adrenal insufficiency as cause of hyponatremia; Thyroid-stimulating hormone: normal value rules out hypothyroidism as cause of hyponatremia. Correction of hyponatremia after fluid restriction is indicative of SIADH. Imaging is used to find the cause of the SIADH, rather than to come to the initial diagnosis of SIADH. Chest X-ray may show small-cell lung carcinoma producing exogenous ADH. Head CT or MRI may show a brain tumor or other CNS disorder causing excessive ADH production. It may also show cerebral edema, a complication of SIADH.

Answer 94

Treatment focuses on correcting the hyponatremia. First-line therapy in emergent situations is infusion of 3% hypertonic saline. Do not correct sodium levels too quickly, as rapid normalization of sodium levels can lead to central pontine myelinolysis! The goal is to raise serum sodium levels by 0.5-1 mEq/hour. Sodium levels should not be raised more than 10-12 mEq in the first 24 hours. Maximum sodium level is 125-130 mEq/L. In non-emergent situations, use fluid restriction and/or V2 receptor antagonists. Fluid restriction limits water intake, forcing the kidneys to excrete free water from plasma to maintain the fixed osmolality dictated by ADH secretion. V2 (vasopressin) receptor antagonists, the –vaptans, reduce aquaporin channels in the renal collecting ducts, thereby decreasing permeability of the duct to water and reducing the amount of water reabsorbed into the body in the collecting duct. Furosemide and other loop diuretics can also be used to increase free water excretion, but should be used in conjuction with infusion of hypertonic saline to avoid net sodium loss. Demeclocycline, an older tetracycline, can induce diabetes insipidus by interfering with the action of ADH on the collecting duct. This drug is no longer commonly used, because its onset of action can take over a week, it can be nephrotoxic in patients with liver disease, and it is no longer available in most countries. Aside from correcting the hyponatremia, further care centers on finding and treating the cause of the SIADH. This may involve surgery or chemotherapy for small-cell lung carcinoma, antibiotics for pneumonia, neurology or cardiology intervention for CNS disorder, or medication management for drug-induced SIADH.

Answer 95

Diabetes insipidus (DI) is the inability of the body to retain water, which is normally done by reabsorbing it from the urine. There are two types: central and nephrogenic.

Answer 96

Central diabetes insipidus is caused by decreased ADH synthesis from the hypothalamus or decreased release from the posterior pituitary. Causes of central DI include: Idiopathic: Destruction of the ADH-secreting cells in the hypothalamus; Trauma; Tumors; Anorexia nervosa

Answer 97

Nephrogenic diabetes insipidus is caused by renal resistance to antidiuretic hormone. Causes include: Hereditary renal diseases; Drugs; Hypokalemia; Hypercalcemia. Drugs that cause nephrogenic diabetes insipidus include: Lithium; Demeclocycline (tetracycline antibiotic); Cidofovir (antiviral); Foscarnet (antiviral); Amphotericin (antifungal). Patients classically present with polyuria, polydipsia, and new-onset nocturia. In adults, onset of symptoms is usually abrupt in central DI, but more gradual in nephrogenic DI.

Answer 98

The first step of workup is urinalysis and serum metabolic panel. Urine will be inappropriately dilute, meaning the urine osmolality will be less than the serum osmolality. Look for urine specific gravity 290 mOsm/L. Low urine and serum osmolality is characteristic of psychogenic polydipsia, not diabetes insipidus. If urine osmolality is low and serum osmolality is high, the next step is a water deprivation test. In normal physiology, decreased water intake leads to higher serum osmolality, provoking release of ADH and consequent water resorption from the urine, resulting in increased urine osmolality. No change in urine osmolality after water deprivation is diagnostic of diabetes insipidus. Once the diagnosis of diabetes insipidus is established with the water deprivation test, the next step is a DDAVP test to distinguish central DI from nephrogenic DI. DDAVP (a.k.a. desmopressin) is a synthetic form of ADH/vasopressin. In central DI, administration of DDAVP will result in increased urine osmolality, because the absent vasopressin is replaced by a synthetic analogue. In nephrogenic DI, there will be no change in urine osmolality with administration of DDAVP, since the problem is renal resistance to ADH.

Answer 99

The key treatmenr in central DI is desmopressin, which can be administered IV, SQ, PO, or intranasally. Surgery may be appropriate if the condition is caused by a pituitary or hypothalamic tumor. For nephrogenic DI, the key is to treat the underlying disorder, if present. The following are helpful in symptomatic management: Hydrochlorothiazide, due to sodium excretion in the distal convoluted tubule, mild hypovolemia, and compensatory increased sodium and water reabsorption in the proximal tubule. indomethacin, an NSAID that functions by similar mechanism as hydrochlorothiazide. Amiloride in lithium-induced DI. Amiloride is a potassium-sparing diuretic that blocks lithium entry through the epithelial sodium channels in principal cells

Answer 100

The two most common pituitary adenomas are prolactinoma and GH-secreting adenoma. Synaptophysin and reticulin are markers.

Answer 101

85%+ of sellar region masses are pituitary adenomas, which although not formally graded, are equivalent to WHO grade I; almost all the other non-pituitary adenoma sellar region masses are also WHO grade I and treated by surgical resection except in instances where medical therapies are available. Some pituitary adenomas are hyperfunctioning and produce physiologically-unregulated excess of endocrine hormone(s); many are clinically non functioning and produce mass effect or visual disturbances due to compression of critical nearby anatomical structures. Most uncommon (Rathke cleft cyst), or rare, sellar region masses (pituicytoma, spindle cell oncocytoma, hypophysitis) closely mimic pituitary adenomas on neuroimaging and clinically mimic clinically non functioning pituitary adenomas in that they present with mass effects or visual disturbance. All except craniopharyngioma predominantly affect middle age adults; craniopharyngioma has two age peaks, pediatric (5-15 yrs) and middle age (45-60 yrs) adults.

Answer 102

Pituitary blastoma related to DICER1 mutation, almost always ACTH IHC(+). Pediatric/young adults occasionally get pituitary adenomas and this population is enriched for syndromic examples; very rare infantile pituitary masses are a different entity: pituitary blastoma. Almost all other pituitary adenomas SPORADIC. 85% of usual ACTH adenomas are microadenomas, most prolactinomas in premenopausal women are microadenomas. Gonadotroph are the most common type of clinically non functioning adenoma, most common adenoma type to come to surgery.

Answer 103

growth hormone factor of corticotroph tumors

Answer 104

transcription factor of somatotroph tumors

Answer 105

steroidogenic factor of gonadotroph tumors

Answer 106

A prolactinoma is the most common pituitary adenoma, which overproduces the hormone prolactin. Signs and symptoms of prolactinoma include: Impotence; Amenorrhea; Gynecomastia; Galactorrhea; Low libido; Infertility; Headache. Enlargement of the pituitary gland may also lead to compression of the optic chiasm. This results in a loss of peripheral vision known as bitemporal hemianopsia. Since prolactin provides feedback-inhibition to gonadotropin releasing hormone (GnRH), high levels of prolactin secretion in prolactinomas can suppress GnRH secretion. Prolactin inhibits its own secretion by directly increasing the release of dopamine from the hypothalamus (dopamine subsequently inhibits further prolactin secretion). Because of the physiological action of dopamine (suppressing prolactin), dopamine antagonists (notably antipsychotics) can cause galactorrhea from this loss of inhibition. The treatment for prolactinoma includes bromocriptine or cabergoline, both of which are dopamine agonists. Dopamine normally inhibits prolactin release. Bromocriptine can also be used in the treatment of Parkinson disease. Transsphenoidal surgical resection may be indicated for large tumors.

Answer 107

inappropriately secretes growth hormone (GH), leading to acromegaly or gigantism. If the excessive GH secretion occurs during childhood (prior to skeletal epiphyseal closure) the disease state that results is gigantism. If the excessive GH secretion occurs during adulthood (after epiphyseal closure) the disease state that results is acromegaly. Gigantism is characterized by disproportionately long limbs (increased linear bone growth), whereas acromegaly presents as conspicuous growth in the skin and soft tissues, viscera, and bones of the face, hands, and feet. Signs and symptoms of acromegaly include: Coarsening of skin/facial features; Thickening of the hands and feet; Enlargement of the jaw resulting in protrusion (prognathism); Deep voice; Impaired glucose tolerance (insulin resistance); Peripheral neuropathies (due to nerve compression). Diagnosis is made based on increased insulin-like growth factor and MRI/CT imaging of a pituitary neoplasm. A growth hormone suppression test may be performed to determine whether GH production is suppressed by high blood sugar (induced by drinking a glucose solution). There are three treatment options for gigantism and acromegaly: Surgery or radiation; Octreotide, a somatostatin analogue that inhibits GH release from the anterior pituitary and; Pegvisomant, a GH receptor antagonist which effectively blocks IGF-1 production.

Answer 108

A Rathke's cleft cyst is a benign growth found on the pituitary gland in the brain, specifically a fluid-filled cyst in the posterior portion of the anterior pituitary gland. It occurs when the Rathke's pouch does not develop properly and ranges in size from 2 to 40mm in diameter. Asymptomatic cysts are commonly detected during autopsies in 2 to 26 percent of individuals who have died of unrelated causes. Females are twice as likely as males to develop a cyst. If a cyst adds pressure to the optic chiasm, it may cause visual disturbances, pituitary dysfunction, and headaches. The majority of pituitary patients with chronic headaches have Rathke's Cleft Cysts. This is believed to be caused by the constant change in volume and the drastic changes in vasopressure from fluctuations in gonadotrophs and ADH. Symptoms vary greatly between individuals. RCCs can be non-functioning, functioning, or both. Besides headaches, neurocognitive deficits are almost always present, but have high rate of immediate reversal if cyst is properly treated by being drained. They will eventually rupture if not addressed. Patients report attacks of violent headache radiating down the back of their neck. Cortisol will drop due to impact of ACTH production form apoplexy. The treatment of choice for symptomatic cysts is drainage and taking a biopsy. Radical excision is more dangerous because of the potential of damaging the patient's pituitary function e.g. ADH storage and lowering growth hormone production.

Answer 109

Craniopharyngiomas are relatively benign (WHO grade I) neoplasms that typically arise in the sellar/suprasellar region. They account for ~1-5% of primary brain tumours, and can occur anywhere along the infundibulum (from the floor of the third ventricle, to the pituitary gland). There are two pathological types, which are said to differ not only in appearances, but also in prognosis and epidemiology. Whether or not they represent distinct entities or a spectrum of morphology remains a little controversial. They are: adamantinomatous (paediatric); papillary (adult); mixed: ~15%, but share imaging and prognosis similar to adamantinomatous. Craniopharyngiomas are believed to derive from Rathke cleft rather than squamous cell rests along the craniopharyngeal duct as was previously thought 3. This histological appearance of the two subtypes are different, accounting for the various imaging features.

Answer 110

Clinical presentation is variable on account of the variable location and size of the tumour. Presenting complaints include: headaches and raised ICP, visual symptoms (20% of children and 80% adults), hormonal imbalances, short stature and delayed puberty in children, decreased libido, amenorrhoea, diabetes insipidus, behavioural change due to frontal or temporal extension

Answer 111

This type is seen predominantly in children. It consists of reticular epithelial cells that have appearances reminiscent of the enamel pulp of developing teeth. There may be single or multiple cysts filled with thick oily fluid high in protein, blood products, and/or cholesterol, creating the so-called "machinery oil". "Wet keratin nodules" are a characteristic histological feature. Calcification is usually present: ~90%. Adamantinomatous craniopharyngiomas is the most common form ~ 90%, and typically have a lobulated contour as a result of usually multiple cystic lesions. Solid components are present, but often form a relatively minor part of the mass, and enhance vividly on both CT and MRI. Overall, calcification is very common, but this is only true of the adamantinomatous subtype (~90% are calcified). These tumours have a predilection to be large, extending superiorly into the third ventricle, and encasing vessels, and even being adherent to adjacent structures

Answer 112

The papillary subtype is seen almost exclusively in adults and is formed of masses of metaplastic squamous cells. "Wet keratin" is absent. Cysts do form, but these are less of a feature, and the tumour is more solid. Calcification is uncommon or even rare. Papillary craniopharyngiomas tend to be more spherical in outline and usually lack the prominent cystic component; most are either solid or contain a few smaller cysts. Calcification is uncommon or even rare in the papillary subtype, a fact often forgotten

Answer 113

Surgery is generally the first line of treatment for all pituitary tumors except for tumors that secrete prolactin. Tumors that secrete both prolactin and growth hormone generally are candidates for surgical intervention

Answer 114

The major classes of steroid hormones are glucocortocoids, mineralocorticoids, and sex steroids. The three major classes of sex steroids are progestins, androgens, and estrogens. The conversion of cholesterol into the three major classes of sex steroids follows a progressive reduction in the number of carbon atoms the molecules contain. Principle sources of sex steroids include the gonads, the adrenal cortex, and the placenta. Peripheral tissues such as the skin, liver and adipose tissues play key roles in the conversion and metabolism of sex steroids. The total amounts, relative amounts, and physiologic sources of circulating sex steroids differ between males and females. The amounts of circulating estrogen and progesterone in women of reproductive age follow a monthly pattern, producing the changes in the endometrial lining of the uterus which lead to menstruation

Answer 115

These include the glucocortocoids such as cortisol (C-21), the mineralocorticoids such as aldosterone (C-21), and the sex steroids which include progestins (C-21), androgens (C-19), and estrogens (C-18). Like the bile salts and Vitamin D, all three major classes of steroid hormones have cholesterol as their precursor. Cholesterol is a 27-carbon steroid molecule, with all 27 carbon atoms derived from acetyl-CoA in a series of steps beyond the scope of this session. The biochemical relationships among the three major classes of steroid hormones is also addressed elsewhere. Specific gonadal cells can synthesis cholesterol de novo from co-enzyme A or derive cholesterol from low-density lipoproteins (LDL's) in the circulation. Sex steroids can be produced in the gonads as well as in extra-gonadal tissues such as the adrenal cortex, the skin, and adipose tissue. By a process which includes a reduction in the size of the hydrocarbon side-chain and hydroxylation of the 4-ring steroid nucleus, the cholesterol molecule is converted into the steroid hormones. The initial and rate-limiting step in these reactions is catalyzed by the cholesterol side chain cleavage enzyme located in the mitochondrial membrane. This enzyme is also known as 20, 22 desmolase. The resulting structure is a 21-carbon compound known as pregnenolone. Pregnenolone is then converted into all other sex steroids.

Answer 116

Progestins are the 21-carbon sex steroids derived from cholesterol. The progestins synthesized in the human body include pregnenolone, 17-alpha-hydroxy-pregnenolone, progesterone, and 17- alpha-hydroxy-progesterone (17-OH-P). In addition to being sex steroids, progestins are also precursors for the production of aldosterone and cortisol by the adrenal gland. Like progesterone, cortisol and aldosterone also have 21 carbons. The major circulating progestins are progesterone and 17-hydroxy-progesterone, with the former present in higher concentrations in females. Clinically, 17-hydroxy-progesterone is an excellent marker for late-onset congenital adrenal hyperplasia. Progestins affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts. Key functions of progesterone include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation. Progesterone levels fluctuate during the normal menstrual cycle. Within the context of the hypothalamic – pituitary – ovarian axis, progesterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.

Answer 117

Androgens are the 19-carbon sex steroids derived from cholesterol via pregnenolone. The major androgens synthesized in the human body include testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), and androstenedione. Approximately 95% of the testosterone which circulates in the male is produced in the testes. The other major source of androgens is the adrenal cortex. The majority of DHEA and conjugated DHEA-S is produced in the adrenal cortex and serves as an excellent marker of adrenal androgen activity. Physiologic levels of adrenal androgens do not appear to have significant effects on the growth of the reproductive system. Within the ovary, androstenedione from the theca calls is the precursor for ovarian estradiol production by the granulosa cells. Androstenedione is also a precursor for extraglandular estrogen formation in the liver and adipose tissues.

Answer 118

5-alpha-reductase is the enzyme which converts testosterone to dihydrotestosterone (DHT) in target cells such as those located in the prostate and skin. The biologic activity of dihydrotestosterone (DHT) is 30 to 50 times higher than that of testosterone. Dihydrotestosterone cannot be converted to estrogens.

Answer 119

Testosterone affects almost all tissues in the body. The effects are classified into two major categories: androgenic and anabolic. Androgenic impacts include the growth and development of the internal and external genitalia, the development and maintenance of secondary sex characteristics, spermatogenesis, and sexual fantasies and libido. Sebum production is an androgen dependent process. Anabolic effects can be summarized as the growth-promoting effects on somatic tissues such as bone and muscle. Within the hypothalamic – pituitary – testicular axis, testosterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary. The levels of circulating testosterone in men are relatively stable throughout most of adulthood.

Answer 120

Estrogens are the 18-carbon sex steroids derived from cholesterol via pregnenolone. Pregnenolone is converted into other progestins, and then into the androgens. Androgens are converted into the estrogens via an enzyme known as aromatase. Aromatase is present in the gonads and in various peripheral tissues including adipose tissue, liver, ands the CNS. The estrogens synthesized in the human body include estrone (E1), estradiol (E2) and estriol (E3). They have one, two, and three hydroxyl groups, respectively. Of these, estradiol is the most potent and estriol is the least. Estradiol is the major circulating estrogen and is produced by the granulosa cells of the ovary in females and by the Sertoli cells of the testes in males. Estrone is derived from androstenedione in adipose tissue. Estriol is an important placental product. Estrogens affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts. Key functions of estradiol include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation. Estradiol levels fluctuate during the normal menstrual cycle. Within the context of the hypothalamic – pituitary – ovarian axis, estradiol acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.

Answer 121

Sex steroids are hydrophobic and therefore carried in the bloodstream predominantly bound to plasma proteins. These proteins include albumin, sex hormone binding globulin (SHBG), and corticosteroid binding globulin (CBG). SHBG is produced in the liver. Orally administered exogenous estrogens stimulate hepatic synthesis of SHBG. Sex steroid molecules enter target cells via passive diffusion. Testosterone and estradiol act on their target cells by binding to receptors located within the nucleus. The gene encoding for the androgen receptor is located on the X chromosome. These activated sex steroid / receptor complexes then bind to nuclear chromatin, increasing the transcription of target proteins.

Answer 122

The hypothalamus releases a compound called gonadotropin releasing hormone (GnRH) into the portal circulation, which delivers GnRH to the anterior pituitary gland. Most of the GnRH originates in neurons of the arcuate nucleus and preoptic area of the hypothalamus. GnRH is released into the portal circulation in a pulsatile fashion. Pulsatility is key to the physiologic stimulation of the anterior pituitary as constant administration of GnRH actually suppresses the pituitary response. In adult males, approximately 8-14 pulses are released every 24 hours. In adult females, patterns of GnRH, FSH, and LH secretion vary throughout the menstrual cycle. Within the anterior pituitary, GnRH stimulates responsive cells in the anterior pituitary to release Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). Though named for their functions in the female, LH and FSH are the primary regulators of gonadal function in both sexes. Biochemically, they are related to TSH and Human Chorionic Gonadotropin (hCG). The alpha subunits of LH, FSH, hCG and TSH are identical. The beta subunits are distinct and confer specific functional and immunologic characteristics to the intact molecule. Patterns of FSH and LH secretion change over the life cycle. In ovulatory women, the levels of FSH and LH also vary throughout the menstrual cycle, reaching their peaks shortly before ovulation. The levels of circulating estradiol and progesterone produced in response to the FSH and LH also fluctuate in a cyclic pattern. The endometrial cells which form the uterine lining responds to these fluctuations in a predictable pattern which culminates in menstrual blood flow. To stimulate FSH and LH secretion by the pituitary gonadotrophs, GnRH binds to receptors on the cell surface. LH and FSH are then released into the circulation and stimulate the production of sex steroids and inhibin. The sex steroids exert negative feedback control on the reproductive axis at both the hypothalamic and pituitary levels. Inhibin exerts negative feedback control on the reproductive axis exclusively at the level of the pituitary. At midcycle in ovulatory women, ovarian estradiol also exerts positive feedback on the pituitary gland, leading to a surge in FSH and LH.

Answer 123

In both sexes, gonadal sex steroid production and gametogenesis involve 2 distinct cell types working synergistically. In the testis, these are the Leydig and Sertoli cells. In the ovary, they are the theca and the granulosa cells. The theca and granulosa cells are located at the surface of the ovary in a layer known as the ovarian cortex. Both cell types are required to metabolize cholesterol into estradiol, which is the principle gonadal estrogen. The male Leydig and female theca cells are interstitial cells and have many features in common. These include the presence of LH receptors, the ability to make androgens, and the inability to make estrogens due to the absence of aromatase. The male Sertoli and female granulosa cells are immediately adjacent to the developing gametes and also have many features in common. These include the presence of FSH receptors, the ability to make inhibin, and the ability to convert androgens into estrogens due to the presence of aromatase.

Answer 124

The Leydig cells occupy the interstitial layer surrounding the seminiferous tubules. In response to LH, Leydig cells produce around 95% of the testosterone in males. LH stimulates the rate-limiting conversion of cholesterol into pregnenolone in two ways: by increasing the amount of desmolase and by enhancing the affinity of desmolase for cholesterol. The resulting testosterone which acts on the Sertoli cells to support spermatogenesis. This testosterone also exerts negative feedback on the hypothalamic – pituitary – testicular axis at both the hypothalamic and pituitary levels.

Answer 125

The Sertoli cells in the male are in direct contact with the developing spermatozoa and are regarded as the as the support or nurse cells of the developing spermatozoa. Spermatogenesis requires LH, FSH, Leydig cells, Sertoli cells, and testosterone. The Sertoli cells are organized into a tubular epithelium known as the seminiferous tubule. This general structure is supported by the presence of tight gap junctions between adjacent Sertoli cells. Maturing spermatogonia are located between adjacent Sertoli Cells. Gap junctions between Sertoli cells and the adjacent spermatozoa are responsible for the maturation of those gametes. FSH binding to Sertoli cells has several effects. These include increased production of androgen binding protein, enhanced conversion of testosterone from the Leydig cells into estradiol, and the production of inhibin. The Sertoli cells are the primary source of inhibin in males. Inhibin plays an important role in the negative feedback arm of the hypothalamic-pituitary-testicular axis.

Answer 126

The theca cells are located in the ovarian stroma surrounding the follicles and are similar to the Leydig cells in the male. In response to LH secretion, theca cells produce progesterone and androgens. Theca cells lack aromatase and therefore the capacity to produce estrogens. Androstenedione from the theca cells must therefore diffuse into nearby granulosa cells for estrogen to be produced.

Answer 127

The ovarian granulosa cells are in direct contact with the oogonia and are similar to the Sertoli cells in the male. The gametes and their surrounding granulosa cells are called primordial follicles. In reproductive age women, one follicle, called the dominant follicle, matures each month. Oogenesis and ovulation require LH, FSH, granulosa cells, theca cells, testosterone and estradiol. Granulosa cells lack the enzyme which converts progesterone into androgens. Progesterone from the granulosa cells must therefore diffuse to the theca cells where it is converted into androstenedione. Theca cells lack aromatase, so the resulting androstenedione diffuses back to the granulosa cells for conversion to estradiol.

Answer 128

Release of hypothalamic hormones (releasing factors) under CNS control via neurotransmitters (NE, DA, GABA, 5HT, ACh). Release of anterior pituitary hormones (trophic hormones) is controlled by hypothalamic hormones (either releasing or inhibiting factors) that are synthesized in and released from peptidergic neurons. They are then delivered via portal circulation to the pituitary gland for release into the systemic circulation where they act on endocrine glands to regulate production of hormones that perform ultimate regulatory functions

Answer 129

Synthesized in peptidergic neurons in the hypothalamus and then transported to the neuronal terminal in the posterior lobe of pituitary. Neuronally released into the systemic circulation and act directly on target tissues to perform regulatory functions

Answer 130

Diagnostic tools: Testing for site of disorder along hypothalamic-pituitary-target organ axis in hypo- or hyperfunctional endocrine states. Often use hypothalamic releasing factors or pituitary trophic factors. Management of hypofunction: Hormone replacement (physiologic) therapy for deficiency states. Management of hyperfunction: Suppression of hormone synthesis or effect (nonhormonal agents). Alteration of normal endocrine states: Interference with normal function in order to achieve desired state, e.g., oral contraceptives or anabolic steroids (supraphysiologic doses). Control of nonendocrine disorders: Drug therapy for variety of diseases using pharmacologic doses of hormones, e.g., glucocorticoids for inflammatory diseases

Answer 131

191 amino acid peptide with 2 sulfhydryl bridges. Produced with recombinant DNA technology: Somatropin (Humatrope, Serostim, Genotropin, Nutropin, Saizen, Norditropin) matches native GH amino acid sequence. Somatrem (Protropin), which was formerly available, has additional methionine AA. Circulating t1/2 of 25 min. Can be given IM, peak levels in 2-4 hrs, active levels persist 36 hrs

Answer 132

Release increased by GHRH, exercise, hypoglycemia, dopamine, l-DOPA, arginine. Decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly. Produces anabolic and metabolic effects: Positive nitrogen balance, stimulation of lipolysis, increased free fatty acids and blood glucose. At pharmacologic doses GH works indirectly to stimulate synthesis of insulin-like growth factors (IGF-1, IGF-2 in growth plate cartilage and liver) promoting linear and skeletal muscle growth

Answer 133

Recombinant human growth hormone now available; until 1985 only source was human cadaver, use was discontinued due to possible prion contamination [Creutzfeldt-Jakob disease]. Replacement therapy in children with deficiency. Given daily at bed time via SC injection (more effective, mimics natural release pattern) or 3 times a week IM - SR preparations for weekly SC injection are in development. Yearly cost $10,000-50,000 depending on patient's weight. Use in children with idiopathic short stature is controversial. Response to GH is highly variable with responders showing only modest growth increase. Scant evidence that short stature is substantial psychosocial burden to most short children. Any psychosocial benefit must be weighed against cost (∼ $50,000 per inch) and possible adverse effects. If growth hormone insensitive (receptor mutation - Laron dwarf) can treat with recombinant IGF-1 (Mecasermin-Increlex); concern with hypoglycemia, so carb intake prior to injection. Treatment of poor growth due to Turner’s syndrome, Prader-Willi syndrome, and chronic renal insufficiency. Growth hormone deficiency in adults (most commonly due to pituitary tumor or consequences of its treatment - surgery and/or radiation). Treatment of wasting or cachexia in AIDS patients. Patients with short bowel syndrome dependent on total parenteral nutrition

Answer 134

Use by athletes to increase muscle mass and improve performance despite lack of controlled studies and in violation of regulations (banned by IOC / MLB) and standard medical practice NOTE: Many oral preparations containing “stacked” amino acids that reportedly stimulate GH release have been marketed as nutritional supplements. Again, validation in controlled trials is lacking, but they are part of multibillion dollar anti-aging and performance-enhancing programs. Use by healthy elderly for “anti-aging” effects. General consensus from limited studies suggests GH use is associated with small changes in body composition and increased rates of adverse events (edema, joint pain, muscle pain, carpal tunnel syndrome, skin numbness and tingling - may also increase growth of pre-existing malignant cells and increase the possibility of developing diabetes). Cannot be recommended

Answer 135

Generally safe when used for replacement in children. Insulin resistance and glucose intolerance may occur. Slight increased risk for idiopathic intracranial hypertension (pseudotumor cerebri)  Rarely pancreatitis, gynecomastia, nevus growth. Misuse in athletes: Acromegaly, arthropathy, visceromegaly, extremity enlargement

Answer 136

Linear peptide - 44 amino acids. Synthetic analogs [GHRH44, GHRH40, and GHRH29] are easier to synthesize and cheaper - available for investigational use

Answer 137

Rapidly stimulates GH synthesis and secretion via binding to GPCR coupled to Gs -> increasing cAMP and Ca++ levels in somatotrophs - no receptor down-regulation with continuous stimulation. Ghrelin is a 28 AA peptide that also stimulates GH release via a different GPCR. It is secreted predominantly by endocrine cells in stomach and also stimulates appetite and increases food intake. Acts in complex manner to integrate functions of GI tract, hypothalamus, and pituitary. Dominant inhibitory regulator is somatostatin. Growth hormone also acts as own feedback inhibitor. Effective given intravenously, intranasally, subcutaneously. Adverse effects rare, facial flushing (IV), antibody formation with continued use

Answer 138

Sermorelin (Geref)-GHRH29 withdrawn from US market in 2008. Diagnostic evaluation of patients with idiopathic GH deficiency. Potential use in GH-deficient children (preserves feedback at pituitary level - smaller molecule than GH, less expensive); potentially fewer side effects. However, synthetic human growth hormone is now usually used for treatment of GH deficiency. For approximately two-thirds of GH deficient children, the deficiency may be secondary to inadequate GHRH release. Tesamorelin (Egrifta) is a GHRH analog available for use in HIV patients with lipodystrophy secondary to use of highly active retroviral therapy (HAART) - reduces excess abdominal fat

Answer 139

Present in hypothalamus, nervous system, gut, endocrine and exocrine glands - function varies. Inhibits GH release via GPCR coupled to Gi decreasing cAMP levels and activating K+ channels. Decreases secretion of gastric enzymes and acid - decreased GI motility - suppresses release of serotonin and gastroenteropancreatic peptides. Reduces insulin and glucagon release - complex effects on blood glucose. Interferes with TRH ability to release TSH

Answer 140

Somatostatin: T1/2 following exogenous administration only 3-4 min limiting therapeutic usefulness - kidney has significant role in clearance. Octreotide (Sandostatin): plasma t1/2 ∼ 90 min (duration ∼ 12 hrs); given SC every 6-12 hours. Octreotide (Sandostatin LAR depot) given intramuscularly every 4 weeks Lanreotide (Somatuline depot) given subcutaneously every 4 weeks

Answer 141

Treats excess of growth hormone. Acromegaly (adults - rare, most commonly due to pituitary somatotroph adenoma) and gigantism (children - extremely rare). Surgical resection preferred unless adenoma does not appear fully resectable, patient has high surgery risk, or does not choose surgery. Long-acting somatostatin analog is preferred pharmacotherapy - utilized after response seen to SC octreotide. Dopamine agonists may inhibit GH secretion in some patients, but not as effective as SST analogs. Cabergoline is preferred agent for adjuvant management of acromegaly with advantage of oral administration. GH receptor antagonist: Pegvisomant (Somavert) is a mutated GH molecule with polymers attached to extend its half-life. Binds to receptor, blocking GH access, but does activate signaling transduction. Single daily dose administered subcutaneously.

Answer 142

Control of bleeding from esophageal varices and GI hemorrhage - direct action on vascular smooth muscle to constrict splanchnic arterioles. Fewer side effects than vasopressin. Carcinoid tumors, VIP-secreting tumors, glucagonoma, gastrinoma. Symptoms of WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria)

Answer 143

Transient deterioration in glucose tolerance (hyperglycemia) then subsequent improvement. Abdominal cramps, loose stools. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%)

Answer 144

Prolactin release is under inhibitory control by hypothalamic dopamine at D2 receptors. Main stimulus for release is suckling - causes 10-100-fold increase within 30 min. Stimulates milk production if appropriate levels of insulin, estrogens, progestins, and corticosteroids are present. Stimulates proliferation and differentiation of mammary tissue during pregnancy. Inhibits gonadotropin (FSH/LH) release and/or ovarian response to these hormones - related to lack of ovulation during breastfeeding

Answer 145

Hypoprolactinemia - No preparation available for prolactin deficiency. Hyperprolactinemia (prolactinomas) - These pituitary adenomas are the most amenable to pharmacotherapy because of the availability of dopamine agonists that both decrease secretion and reduce tumor size. All available as oral preparations. Bromocriptine [Parlodel] - prototype agent of long-standing use. Ergot derivative that also activates D1 receptors. Frequent side effects include nausea-vomiting, headache, and postural hypotension; less frequently can see psychosis or insomnia. Cabergoline [Dostinex] - has become preferred agent for hyperprolactinemia. More selective for D2 receptor and more effective in reducing prolactin secretion. Better tolerated, less nausea, but may cause hypotension and dizziness. Concern with higher doses and valvular heart disease (agonist action at 5HT2B receptors). Quinagolide - non ergot D2 agonist not approved for use in US

Answer 146

Critical role in control of water content throughout body via actions on cells in distal nephron and collecting tubules in kidney. Released from supraoptic nuclei of hypothalamus. Main stimulus for release is rising blood osmolality. Also released in response to a decrease in circulating blood volume  Recall that release can be inhibited by alcohol. Renal actions are mediated by V2 receptors (GPCRs coupled to Gs). Main effect is to increase the rate of insertion of water channels (aquaporins) into luminal membraneincrease water permeabilityleading to an antidiuretic effect. Also activates urea transporters and increases Na+ transport in distal nephron. Non-renal V2 actions include release of coagulation factor VIII and von Willebrand’s factor. ADH-vasopressin actions at V1 receptors (GPCRs coupled to Gq). Mediates vasoconstriction of vascular smooth muscle. BUT pressor responses occur in vivo only at much higher concentrations than those that produce maximal antidiuresis

Answer 147

ADH analog that is more stable to degradation, t1/2 ∼ 1.5-2.5 hrs

Answer 148

Central Diabetes Insipidus - can result from head injury (trauma or surgery), pituitary tumors, cerebral aneurysm, or ischemiainadequate ADH secretion from posterior pituitary  Desmopressin is treatment of choice. Nasally 1-2/day individualized to response. ADRs: may cause nasal irritation. Orally 2-3/day (bioavailability 5-10%), particularly useful in patients with sinusitis from nasal preps. ADRs: GI symptoms, asthenia, mild elevation of live enzymes. ADRs: Headache, nausea, abdominal cramps, allergic reactions, water intoxication. Chlorpropamide (1st generation sulfonylurea). Potentiates action of small or residual amounts of ADH - mechanism not clear. Option for patients intolerant (side effects-allergy) to desmopressin. Other drug options: Carbamazepine, clofibrate (not in US), thiazides, NSAIDs. Nephrogenic Diabetes Insipidus - can be congenital or drug-inducedinadequate ADH actions. Congenital: Diverse receptor and aquaporin mutations are known. Drug-induced: Lithium: reduces V2-receptor mediated stimulation of adenylyl cyclase. As many as 1/3 of patients treated with Li+ may develop nephrogenic diabetes insipidus. Demeclocyline (tetracycline antibiotic): mechanism not completely understood but possibly acts via block of ADH binding to receptor. Treatment: Low salt, low protein diet. Thiazide diuretics: Paradoxically reduce the polyuria of patients with DI. Mechanism not completely understood but antidiuretic effect parallels ability to cause natriuresis - used in doses that mobilize edema fluid. NSAIDs: Since prostaglandins attenuate ADH-induced antidiuresis, inhibition of PG synthesis by indomethacin may relate to the antidiuretic response seen. Indomethacin has greatest efficacy among NSAIDs. Thiazides and indomethacin are also used as combined therapy

Answer 149

Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) - incomplete suppression of ADH secretion under hypoosmolar conditions. Produced by multitude of disorders including malignancies, pulmonary diseases, CNS trauma- infections-tumors. Drug classes most commonly implicated. Psychotropic agents: SSRIs, haloperidol, tricyclic antidepressant. Sulfonylureas (chlorpropamide). Vinca alkaloids chemotherapy. Methylenedioxy methamphetamine (MDMA). Treatment of hyponatremia. Restriction of free water intake is initial conservative approach. Demeclocyline inhibits ADH effect on distal tubule and has been preferred drug in patients with inadequate response to conservative measures. V2 receptor antagonist - potential therapeutic advance for hyponatremia (also tried in HF). Tolvaptan (Samsca®) - oral route, but use limited by cost, increase in thirst. Conivaptan (Vaprisol®) - IV infusion (useful in hospitalized SIADH patients) - if severe symptomatic hyponatremia present, conivaptan can be given with hypertonic saline (3%), permitting a more rapid initial correction. BUT: Warning against too rapid correction of hyponatremia  cerebellar pontine myelinolysisserious consequences and fatalities. Both are eliminated by CYP3A4 and associated with variety of drug-drug interactions

Answer 150

Attenuates pressure and bleeding in esophageal varices via vasoconstriction of splanchnic arterioles - octreotide better tolerated and now preferred if drug used ± endoscopy. Used as a vasopressor for treatment of patients with severe septic shock. Alternative to epinephrine in ACLS protocol for shock-refractory ventricular tachycardia / fibrillation (long duration of action may have adverse effects on survival)

Answer 151

Option in nocturnal enuresis - oral desmopressin [DDAVP]: 30% of children are full responders and 40% have a partial response. Von Willebrand’s disease (elevates von Willebrand factor) and moderate hemophilia A (elevates factor VIII) - IV desmopressin

Answer 152

Growth Hormone (recombinant)

Answer 153

Insulin-like Growth Factor-1 (recombinant IGF-1)

Answer 154

Somatostatin Analogs

Answer 155

Somatostatin Analogs

Answer 156

Dopamine Agonists

Answer 157

Dopamine Agonists

Answer 158

GH Receptor Antagonist

Answer 159

Dopamine Agonists

Answer 160

Dopamine Agonists

Answer 161

ADH analog

Answer 162

ADH analog. Like other sulfonylureas, chlorpropamide acts to increase the secretion of insulin, so it is only effective in patients who have some pancreatic beta cell function.

Answer 163

Thiazide diuretics

Answer 164

It is officially indicated for the treatment of various types of bacterial infections. It is used as an antibiotic in the treatment of Lyme disease, acne, and bronchitis. Resistance, though, is gradually becoming more common, and demeclocycline is now rarely used for infections. It is widely used (though off-label in many countries) in the treatment of hyponatremia (low blood sodium concentration) due to the syndrome of inappropriate antidiuretic hormone (SIADH) when fluid restriction alone has been ineffective. Physiologically, this works by reducing the responsiveness of the collecting tubule cells to ADH. The use in SIADH actually relies on a side effect; demeclocycline induces nephrogenic diabetes insipidus (dehydration due to the inability to concentrate urine)

Answer 165

ADH-V2 receptor antagonists

Answer 166

ADH-V2 receptor antagonists

Answer 167

Lithium, demeclocycline

Answer 168

SSRIs, haloperidol, TCADs

Answer 169

The cortex secretes steroid hormones that are referred to as mineralocorticoids, glucocorticoids and sex steroids. We will primarily focus on the steroid hormones that are glucocorticoids, which are essential for life and necessary for responding to both acute and chronic stress. Mineralocorticoids, mainly aldosterone, act in the maintenance of salt balance. The most important sex steroids secreted by the adrenals are weak androgens (e.g., dehydroepiandrosterone-sulfate, DHEA-S). The cortex is organized anatomically in three distinct zones but functionally as two. The outer most is the Zona glomerulosa, which produces aldosterone. The middle one is the Zona fasciculata, which is the major producer of cortisol (the most important glucocorticoid made by the adrenals in humans). The inner most one is the Zona reticularis which is the major producer of adrenal androgens. The latter two zones function more as a unit. In the fetus, the gland is proportionally much larger than it is in the adult. Further, the three zones described above are found in an outer subcapsular area. An additional region or fetal zone is found in a large inner zone. During fetal life, it is an important source of precursor for estrogen synthesis by the placenta. The fetal zone disappears rapidly after birth.

Answer 170

Cholesterol is the precursor of the adrenal hormones. It is mostly derived from circulating LDL (low-density lipoproteins) which bind to plasma membrane receptors and are then internalized by endocytosis. LDLs are rich in cholesterol. Once inside the cell the cholesterol is removed, esterified and stored in this form in lipid droplets. The cortex also has the ability to synthesize cholesterol from acetyl-CoA, but this is not the major source of cholesterol. Thus, the most common first step in steroid hormone synthesis is the release of cholesterol from lipid droplets by removal of the esters. The subsequent steps in steroid hormone synthesis occur within either the mitochondria or endoplasmic reticulum. The rate-limiting step requires mitochondrial enzymes - the cytochrome P-450 enzymes or 20, 22 desmolase. Pregnenolone is the product of this reaction.

Answer 171

After all, the rate-limiting reaction is the formation of pregnenolone, which occurs throughout the cortex. However, other biosynthetic enzymes involved in steroid hormone synthesis have different activities in each zone. For example, the Zona glomerulosa lacks the enzyme 17α- hydroxylase and hence cannot make glucocorticoids or the sex steroids. Likewise, in the inner zone, critical enzymes (e.g., 11β-hydroxylase) required for cortisol synthesis have high activity. Congenital deficiencies (complete and partial) of several adrenal enzymes exist. Normal biosynthetic pathways are suppressed and precursors build up or other products are produced in excess. The most common defect involves the enzyme, 21-hydroxylase, which is required for the conversion of 17-hydroxyprogesterone and progesterone to the precursors of cortisol and aldosterone, 11-deoxycortisol and 11-deoxycorticosterone, respectively. Defects in other biosynthetic enzymes exist but are less common. When 21-hydroxylase is defective, neither cortisol nor ALDO are synthesized; levels of adrenal androgens are increased. Some of the consequences of this deficiency are due to effects of ACTH regulation of cortical function as well as to ACTH itself.

Answer 172

The most important glucocorticoid, cortisol, has ketones at carbons 3 and 20 and hydroxyls on carbons 11, 17 and 21 (See Figure in Introductory Lecture Handout). Cortisol is secreted at a rate of 8-25 mg/day and has a plasma concentration of 40-180 μg/100 ml. Just as with most hormones, the plasma levels of cortisol vary with the time of day and in response to various stimuli. Cortisol circulates primarily (90%) bound to proteins. Only 10% circulates in a free form. Of the 90% that is bound, 75% is bound to cortisol binding globulin (CBG) and 15% is bound to albumin. As discussed previously, the free form of hormones is the active form, although it is in equilibrium with the bound form. Protein binding increases the plasma concentration of hormone, prevents its excretion by the kidney, prolongs its half-life and serves as a reservoir of extra hormone. If the binding protein is elevated, the total concentration of hormone in the plasma is elevated but the biological activity of the hormone is unchanged, because it is the concentration of free hormone (set point) that is regulated.

Answer 173

At physiological levels, important actions of glucocorticoids involve glucose mobilization. Two mechanisms are involved: a stimulation of gluconeogenesis in the liver and increased proteolysis in muscle and other soft tissues providing amino acid substrates for gluconeogenesis. Cortisol is of great significance in maintaining or elevating blood glucose in times of stress. However, its strong catabolic actions mean that glucocorticoids have severe detrimental effects in situations where they are maintained at high levels for prolonged periods. Muscle weakness is a hallmark of this condition. Other consequences of cortisol's catabolic actions include thinning of the skin and increased capillary fragility leading to easy bruising. High concentrations of cortisol appear to interfere with calcium absorption and/or bone formation, so that osteoporosis and bone fractures are a common side effect of cortisol excess. Although the direct actions of glucocorticoids seem to facilitate lipolysis, their overall effects on lipid metabolism are complex. High doses lead to deposition of adipose tissue on the trunk, abdomen, face, and mobilization from the extremities. Other effects of glucocorticoids are facilitation of excretion of a water load (this occurs due to cortisol's ability to inhibit ADH function) and increased gastric acid secretion. In addition, cortisol has a paracrine effect on the adrenal medulla and stimulates the synthesis and activity of phenyl-N-methyl Transferase (PNMT) thus increasing the production of epinephrine from norepinephrine. High doses of glucocorticoids have significant anti-inflammatory effects and they are used as treatment when the inflammatory process is life threatening. At these doses, they also act as immunosuppressants and induce all of the phenotypic, metabolic sequelae of hypercortisolism (Cushing's disease). Synthetic glucocorticoids used clinically include the powerful dexamethasone, and milder prednisone and triamcinolone. Hydrocortisone and prednisone also have considerable mineralocorticoid potency and can be used in cases of Addison's disease where both gluococorticoid and mineralocorticoid secretions are compromised.

Answer 174

Cortisol secretion is regulated by a negative feedback loop through the hypothalamo- pituitary axis. The hypothalamus secretes CRH, which acts on the anterior pituitary to stimulate the release of ACTH. CRH binds to receptors on corticotrophs, thereby activating adenylate cyclase. Secretion of ACTH occurs in a calcium-dependent manner; POMC gene transcription is also activated. ACTH in turn interacts with receptors on the cells of the Zona fasciculata and reticularis to promote secretion of cortisol. ACTH has several actions, which lead to increased cortisol secretion. In the cortex, ACTH leads to elevated cAMP levels, which in turn increase the rate of synthesis of pregnenolone. LDL uptake is also enhanced, as is hydrolysis of stored cholesterol esters and transport of cholesterol into mitochondria. Plasma free cortisol feeds back on the hypothalamus and the pituitary to inhibit CRH and ACTH secretion, completing the negative feedback loop. There is also evidence that ACTH can inhibit its own secretion. This entire mechanism is subject to considerable variation. In particular, there is a daily rhythm or diurnal variation in cortisol secretion that results in cortisol being elevated about the time of waking in the morning and falling to a low level at about the onset of sleep. This rhythm may be entrained by light and dark cycles, but tends to vary in individuals who habitually work at night and sleep during the day. It takes some time to alter the cycles, which may explain the sensation of "jet lag". The negative feed-back can be overridden by the effects of stress, which can produce up to a 40-fold increase in cortisol secretion. Individuals who are not able to respond to stress with increased cortisol secretion have increased morbidity. Stress of various forms stimulates secretion of CRH and thus ACTH and cortisol. Stress can be physical in nature such as pain, trauma or cold exposure. Emotional stress is another stimulant. Stress due to exposure to specific chemicals is also effective.

Answer 175

Adrenal androgens generally vary with the secretion of cortisol and appear to be stimulated by ACTH. However, there is a large increase in adrenal androgen secretion at puberty (adrenarche). This increase occurs in both females and males. Adrenal androgens are less potent than ones made in the male gonads. However, in females, adrenal secretion of androgens is the major source of hormone with androgen like activity. Thus, in females, they are important for libido and growth of pubertal hair, processes that require androgens.

Answer 176

Regulation of aldosterone secretion: Aldosterone is regulated by the renin-angiotensin system. It is only minimally influenced by ACTH. Renin is secreted by the juxtaglomerular apparatus of the kidney in response to a decrease in plasma volume or sodium. It also responds to diminished blood pressure, receiving signals from the sympathetic nervous system. Renin converts circulating angiotensinogen to angiotensin I, which in turn is degraded to angiotensin II. Angiotensin II is the major stimulus for aldosterone secretion.

Answer 177

Angiotensin II is also a powerful pressor agent. The adrenal also responds to high plasma potassium with an increase in aldosterone secretion. Long-term elevation of angiotensin may lead to hypertrophy of the glomerulosa region of the adrenal cortex.

Answer 178

The major action of aldosterone is to stimulate sodium absorption, potassium, and hydrogen ion excretion in the renal tubule. It has similar effects on sweat glands, sparing sodium in chronically hot, humid environments. These actions maintain or increase blood volume.

Answer 179

Cortisol has a plasma half-life of 60-70 minutes, while aldosterone is metabolized more quickly, having a half-life of ~ 20 minutes. Important points about degradation of steroid hormones include that they undergo reactions in the liver that tend to both reduce their activity and increase their water solubility. The metabolites are then excreted in the urine providing a convenient medium for assessing their secretion.

Answer 180

This rare condition results from an infectious process (e.g., tuberculosis, fungal disorders, autoimmune response) that wipes out the entire adrenal cortex. It is life threatening and both mineralocorticoid and glucocorticoid secretion is deficient. Symptoms include weakness, weight loss, hyponatremia, hyperkalemia, GI problems. ACTH is not subjected to negative feedback and it is elevated leading to hyperpigmentation. Glucocorticoid and mineralocorticoid activities must be replaced.

Answer 181

This disorder results from ACTH insufficiency and does not have the symptoms related to mineralocorticoid loss or excess ACTH. Only glucocorticoids need to be replaced. It usually occurs as a general defect in the anterior pituitary (panhypopituitarism).

Answer 182

Increased plasma aldosterone can result from a tumor of the adrenal cortex (primary) or inappropriately high activity of the renin-angiotensin system (secondary). Symptoms include hypertension in the case of primary hyperaldosteronism, hypokalemia, and alkalosis.

Answer 183

Congenital defects in the 21-hydroxylase or 11β- hydroxylase pathways of steroidogenesis decrease the synthesis of adrenal corticoids so that the negative feedback pathway controlling ACTH release is defective. The resultant increased ACTH stimulates steroidogenesis and precursors accumulate as well as hormones whose synthesis is not affected (e.g. adrenal androgens in some cases). In females, a common symptom is masculinization.

Answer 184

Excessive secretion or levels of cortisol leads to Cushing's Syndrome. Several features are associated with Cushing's Syndrome. Patients tend to have a characteristic obesity that is central, but deposits on the face (moon facies), dorsocervical region (buffalo hump) and supraclavicular region are common. Females often present with hirsutism. Thinning of the skin is very common, leading to "purple" striae, easy bruising and slow wound healing. Glucocorticoids have catabolic actions and in excess lead to muscle weakness. Osteoporosis is another frequent symptom associated with Cushing's due to decalcification of bone. Cortisol has CNS effects and, predictably, a wide range of psychological disturbances are found in Cushing's patients: emotional lability, insomnia, poor memory, euphoria, mild depression; in extreme cases, psychosis and severe depression may be present.

Answer 185

Unlike the cortex, the adrenal medulla is derived from the neural crest. At about 7 weeks of gestation, neuroectodermal cells of the neural crest invade the primitive cortex and develop into the cells of the medulla. The medulla is essentially a specialized sympathetic ganglion. The cells of medulla are known as the adrenal chromaffin cells because they bind chromium dyes. These cells are stimulated by nerve endings of cholinergic preganglionic fibers of the sympathetic nervous system. Acetylcholine, released from the acts on cholinergic receptors on chromaffin cells to release the catecholamine hormone epinephrine, and to a lesser extent, norepinephrine (NE). The release occurs from secretory granules of chromaffin cell by calcium-dependent exocytosis. The rate-limiting enzyme in the synthesis of epinephrine and norepinephrine in chromaffin cells is tyrosine hydroxylase, a cytosolic enzyme that converts tyrosine to dihydroxyphenylalanine. This compound in turn is converted to dopamine in the cytosol. Dopamine is then taken up in the secretory granules where it is converted to norepinephrine and then epinephrine.

Answer 186

Both epinephrine and norepinephrine mediate their actions via the activation of a class of G-protein coupled receptors. There are two classes of adrenergic receptors α (with α1 and α2 receptor subtypes) and β (with β1, β2 and β3 subtypes). β-adrenergic receptors stimulate adenylate cyclase and thus cAMP is the second messenger that mediates their effects. The α2-adrenergic receptor is coupled to the G-protein Gi and inhibits cAMP production. On the other hand, the α1 adrenergic receptors activate the Phospholipase C signaling pathway. Among the two hormones, epinephrine activates the β-adrenergic receptors with greater efficacy while norepinephrine activates the α- adrenergic receptors better.

Answer 187

Perception or even anticipation of danger, trauma, pain, and other physiological stressors like hypovolemia, hypotension, hypoglycemia, and exercise all trigger the rapid secretion of epinephrine. Responses are initiated at the hypothalamus and brainstem. The final common pathway is the activation of the cholinergic fibers in the greater splanchnic nerve. When these fibers are stimulated, acetylcholine is released from nerve terminals on to the chromaffin cells. The major mediator of cholinergic control is via the activation of nicotinic acetylcholine receptors (nAChRs) though calcium increases by the activation of muscarinic acetylcholine receptors (mAChRs) might also play a role. The adrenal medulla is often activated along with the rest of the sympathetic nervous system thought there might be instances (e.g. hypoglycemia) where the medulla is activated selectively. Activation of nAChRs leads to cation flux into the chromaffin cell leading to depolarization and activation of calcium influx through voltage-gated calcium channels. Recent evidence suggests that calcium flux through nAChRs might also be significant. Changes in intracellular calcium lead to release of catecholamines via calcium-dependent exocytosis.

Answer 188

Stress is perceived by many areas of the brain. Major stressors activate CRH, ADH and NE neurons in the hypothalamus. NE release in the brain acts as a molecular switch for mediating arousal, aggressiveness and sharpening a number of sensory behaviors. CRH activates the ACTH-cortisol axis. At the same time, stimulation of sympathetic neurons in the hypothalamus leads to stimulation of the splanchnic nerve and release of epinephrine from the adrenal medulla. Both epinephrine and cortisol lead to rapid energy mobilization and redistribution as well as changes in cardiac responsiveness. At the same time, these hormones lead to inhibition of a number of non-essential (as far as stress response is concerned) physiological responses leading to rapid mobilization of resources towards combating stress.

Answer 189

A rare neuroendocrine tumor of adrenal medulla chromaffin cells that secretes catecholamines. Remember the rule of 10s: 10% malignant; 10% found extraadrenal; 10% are bilateral Associated with Von Hippel-Lindau, Neurofibromatosis 1 and MEN (multiple endocrine neoplasia) IIa and IIb; 10% in children; 10% familial (although it's thought to be up to 25%!); 10% calcify.

Answer 190

The classic presentation for a pheochromocytoma is episodic hypertension that is resistant to treatment. Patients may also experience “paroxysms”, which can be remembered with the 5 P’s: Pressure (hypertension); Pain (headache); Perspiration; Palpitations (tachycardia); Pallor. Long-standing undiagnosed pheochromocytoma can cause a cardiomyopathy (catecholamine cardiomyopathy)

Answer 191

The evaluation for a pheochromocytoma is first established clinically and biochemically before any imaging is done. Labs: Increased plasma-free metanephrines and normetanephrines (97-100% Sensitive and 82-85% Specific). Increased 24 hour urinary catecholamines and metanephrines (98% Specific and 97% Sensitive). Increased 24 hour urinary vanillylmandelic acid (VMA) (Often limited due to sensitivity/specificity issues). Radiology: CT scans may show an adrenal adenoma. (Iodine-131-meta-iodobenzylguanidine) aka MIBG scans use this radioactive tracer to directly target certain tumor cells and can be used to diagnose a pheochromocytoma that is not on the adrenal gland and is frequently used before surgery. (Remember: 10% are extra-adrenal and 10% are multiple). MIBG is also used to diagnose neuroblastomas.

Answer 192

A "Pheo Crisis" is rare, but is the most feared complication in a patient with a pheochromocytoma; mortality rates approach 85%. It results in an adrenergic hypertensive crisis leading to multiple system organ failure. Conditions that may induce a Pheo Crisis Include: Anesthesia induction agents; Drugs (Corticosteroids, metoclopramine, morphine, glucagon, chemotherapeutic drugs, sympathomimetics, and TCAs); Emotional stress; IV urographic contrast.

Answer 193

The treatment approach to a pheochromocytoma is accomplished with the following, in this order: Irreversible α-blockade (accomplished with phenoxybenzamine); β-blockade; Surgical resection. A β-blocker may be added for rate control AFTER α-blockade is established. (If used before the alpha blockade, ß-blockade can lead to unopposed α-stimulation from catecholamines, causing a hypertensive crisis.) Alpha blockade prevents catecholamine surge during surgical resection of the tumor, which would be dangerous for the patient under anesthesia. Medical management of hypertension is achieved with an irreversible, non-competitive, non-selective α-blocker such as phenoxybenzamine. Prazosin and Terazosin may also be used with similar effect. Note: Do not confuse phenoxybenzamine (irreversible α-blocker) with phentolamine (reversible α-blocker).

Answer 194

There are two important tumors that can arise in the adrenal cortex: adrenocortical adenomas and adrenocortical carcinomas.

Answer 195

Adrenocortical adenomas are benign neoplasms of the adrenal cortex, which are most often discovered incidentally (and thus also called incidentalomas) upon abdominal imaging or post-mortem. Most adrenocortical adenomas are non-functional (do not secrete hormones), but some may produce mineralocorticoids (aldosterone), glucocorticoids (cortisol), or sex steroids. If an adrenocortical adenoma is functional (that is, if it secretes hormones), patients may present with the signs, symptoms and laboratory findings of hormone excess (i.e. Cushing syndrome, Conn syndrome, or hyperandrogenic disorders).

Answer 196

The imaging modalities that most commonly find adrenocortical adenomas are either abdominal CT or MRI. Imaging shows lipid-rich tumors of less than 4 cm in diameter.

Answer 197

Surgical treatment for adrenocortical adenomas is usually reserved for hormone-secreting tumors, and involves unilateral adrenalectomy. Another option is pharmacologic treatment with agents such as ketoconazole (inhibits excess cortisol synthesis).

Answer 198

Adrenocortical carcinomas are rare, aggressive neoplasms of adrenal cortex cells. Most adrenocortical carcinomas are functional (hormone secreting), secreting any of the adrenal cortex hormones: glucocorticoids (most common), mineralocorticoids, or androgens. This functionality leads to the physiologic consequences of the neoplasm. Adrenocortical carcinomas are found in a bimodal age distribution, affecting patients under 5 years old and those in their 4th and 5th decades. Women and girls are typically affected more often than men and boys. Most adrenocortical carcinomas arise sporadically, but they may be associated with hereditary cancer syndromes, such as Li-Fraumeni syndrome. Most patients with adrenocortical carcinomas will present with advanced disease. Those with functional tumors most commonly present with Cushing-like symptoms (weight gain, weakness, insomnia). Those with non-functional tumors may complain of abdominal or flank pain or mass, and possibly constitutional symptoms (weight loss, fevers, fatigue, chills, night sweats). Adrenocortical carcinomas are locally very invasive. They often invade the renal veins, or inferior vena cava. They also metastasize through the lymph, most commonly to liver, lungs, lymph nodes, and bone.

Answer 199

Laboratory findings in a patient with adrenocortical carcinoma include: No decrease in cortisol levels with a 1 mg. Dexamethasone suppression test. Increased 24 hour urine cortisol levels. Increased aldosterone to renin ratio. High serum androgen levels. Imaging for adrenocortical carcinomas includes CT and MRI (more sensitive to vascular invasion). PET scan using fluorodeoxyglucose is also an option.

Answer 200

The treatment of choice for adrenocortical carcinomas is total surgical resection of the adrenal gland(s). This is also the only treatment option with potential curative outcomes. Other treatments include treating syndromes of hormone excess, chemotherapy (especially Mitotane) and radiation.

Answer 201

Glucocorticoids. Principally involved in carbohydrate and protein metabolism and anti-inflammatory response. Cortisol is prototype hormone. Mineralocorticoids. Principally involved in Na+ retention. Aldosterone is prototype hormone. Adrenal Androgens. Increased release occurs in concert with cortisol, but not aldosterone. Dihydroandrostenedione (DHEA) and androstenedione have weak androgenic activity, but some DHEA is converted to testosterone and estradiol outside of the adrenal gland.

Answer 202

Pituitary adrenocorticotropic hormone (ACTH) release is controlled by corticotropin-releasing factor. (CRF) from the hypothalamus. Synthesis and secretion of glucocorticoids and androgens is controlled by actions of ACTH at the adrenal cortex. NOTE: The renin-angiotensin system is the primary regulator of mineralocorticoid (aldosterone) synthesis and release.

Answer 203

1. Diurnal rhythm of basal steroidogenesis, entrained by higher neuronal centers that release CRH from hypothalamus in response to sleep-wake cycles -> ACTH release -> cortisol release. 2. Negative feedback regulation by circulating corticosteroids (both endogenous hormones and exogenous agents used in therapy) at the hypothalamus and pituitary decreases ACTH release and steroidogenesis. NOTE: Chronic use of pharmacologic doses of glucocorticoids can suppress the HPA axis and result in adrenal atrophy and insufficient adrenal response to environmental stressors adrenal crisis3. . Stress (injury, hemorrhage, severe infection, surgery, hypoglycemia, cold, pain, fear) can override negative feedback and produce

Answer 204

Glucocorticoid pathway is a substrate-limited system with synthetic enzymes in excess that provides for rapid responsiveness. Rate-limiting step is conversion of cholesterol to pregnenolone. ACTH stimulates this step and at several levels in zona fasiculata and in the zona reticularis (androgens). Synthesis is inhibited by metyrapone and mitotane (also inhibited by ketoconazole).

Answer 205

Mineralocorticoid pathway in zona glomerulosa has 18-OH-steroid dehydrogenase enzyme that converts corticosterone to aldosterone. Renin-angiotensin system (via angiotensin II) stimulates conversion of cholesterol to pregnenolone and corticosterone to aldosterone (independent of ACTH).

Answer 206

Most actions mediated by widely distributed glucocorticoid receptors. Steroid [S] binds to intracellular receptors [R] in cytosol -> Forms [S-R] complex that is transported to nucleus -> Binds to Glucocorticoid Response Element [GRE] on DNA. [plus other transcription factors that regulate growth factors and proinflammatory cytokines]. -> Activates or inhibits transcription of target genesincrease or decrease in protein synthesis. -> Alteration of cellular function – onset of effects in hours or more. NOTE: The resulting effects on protein synthesis bring about the final hormone response – delayed onset of response, occurring in hours or greater. BUT some actions of GCs can occur within minutes (e.g.,  ACTH release) and can’t be explained by above pathway. Proposed mechanisms include interactions with membrane receptors.

Answer 207

Metabolic effects (physiologic levels of glucocorticoids) lead to some of the serious adverse effects of chronic glucocorticoid use. Carbohydrate: Stimulate gluconeogenesis (in fasting state) causing an increase in blood glucose (leading to increase insulin release). Stimulates gluconeogenesis and glycogen synthase activity leading to increase in liver glycogen deposition. [In excess, can lead to diabetes-like state.] Protein: Increase AA uptake into liver and kidney, decreased protein synthesis (except liver) and net transfer of AA from muscle / bone to liver (into glucose). [In excess, can lead to muscle wasting, while catabolic effects in skin and connective tissue result in atrophy.]. Lipid: Inhibit uptake of glucose by fat cells, which stimulatse lipolysis (but net effect is lipogenesis due to increased insulin release). Greater lipogenic effect in central tissues. [In excess, can see as centripetal obesity (buffalo hump, increased abdominal fat).] Net Physiologic Result: Maintenance of glucose supply to brain (insulin antagonism)

Answer 208

Responses that occur to appreciable extent only in presence of glucocorticoids, but which are not further stimulated with increased amounts of glucocorticoids. Vascular (vasoconstriction) and bronchial (bronchodilation) response to catecholamines. Fat cell lipolytic response to catecholamines, ACTH, Growth Hormone. Required for normal cardiac output

Answer 209

Aldosterone binds to cytosolic receptor that migrates to nucleus where it induces formation of mRNA to direct synthesis of specific proteins (Na+-K+-ATPase, Na+ and K+ channels). Insertion of protein in membrane induces increased reabsorption of Na+ from renal distal tubules that is loosely coupled to increased secretion of H+ and K+.

Answer 210

Structure Activity Relationships. All natural steroids have both glucocorticoid (GCC) and mineralocorticoid (MCC) activity, except 11-deoxycorticosterone. Intensive investigation of synthetic analogs has demonstrated that GCC and MCC effects can be separated but NOTE that metabolic (GCC) effects can NOT be separated from anti-inflammatory effects and anti- inflammatory effects can NOT be separated from immunosuppressive effects. Changes in structure can also be made that affect specificity, potency, absorption, protein binding, rate of metabolism/excretion, membrane permeability

Answer 211

Necessary for intrinsic glucocorticoid activity

Answer 212

Compounds are inactive until liver enzyme 11-hydroxysteroid dehydrogenase type I (11-HSD I) reduces compound to 11-hydroxyl congener. NOTE: Skin does not have this enzyme, thus drugs in Panel B cannot be used in topical glucocorticoid preparations.

Answer 213

Increases anti-inflammatory effects 4-5 fold (prednisolone vs cortisol).

Answer 214

Increases anti-inflammatory effects 5-6 fold (methylprednisolone vs cortisol).

Answer 215

Enhances glucocorticoid and especially mineralocorticoid activity. Fludrocortisone is the drug of choice for mineralocorticoid effects.

Answer 216

Increases anti-inflammatory effects 18 fold and essentially eliminates mineralocorticoid activity (dexamethasone vs cortisol).

Answer 217

Liver inactivates by reduction of double bonds and conjugation to glucuronic acid, makes cortisol more water soluble. Two forms of major metabolic enzyme - 11-hydroxysteroid dehydrogenase (11HSD). Liver: 11-HSD1 converts cortisone back to cortisol (or prednisone to prednisolone) – activating step. Kidney: 11-HSD2 converts cortisol to cortisone - inactivating step (“protects” kidney from MC activity of cortisol). Fetus: Placental 11-HSD2 (inactivating form) is active, but not 11HSD1 as fetal liver is not functional. Can treat mother with glucocorticoids without effect on fetus because placental enzyme can convert active drug back to prodrug (e.g., prednisolone to prednisone). To treat fetus with glucocorticoids (e.g., lung development prior to premature delivery) can use agent that is poor substrate for 11HSD2 (e.g., betamethasone).

Answer 218

Plasma Protein Binding via corticosteroid binding globulin (CBG) and albumin. 90% of circulating cortisol is bound, only unbound is bioavailable (able to diffuse into cells). Most analogs bind to CBG with low affinity, approximately 2/3 binds to albumin, rest is free (free is metabolized).

Answer 219

promotes partitioning into adipose tissue, extending half-life.

Answer 220

Mineralocorticoid activity refers to salt (Na+)-retaining actions at the kidney. Glucocorticoid activity refers to metabolic effects (hyperglycemia, protein wasting, lipid redistribution). Since it is not possible to design a molecule that has anti-inflammatory activity without glucocorticoid activity, these activities are interchangeable. The natural glucocorticoid molecule, cortisol (aka hydrocortisone), possesses equal amounts of glucocorticoid and mineralocorticoid activity. The natural mineralocorticoid molecule, aldosterone, possesses essentially all mineralocorticoid activity.

Answer 221

a longer-acting analog of aldosterone is used in replacement therapy for adrenocortical insufficiency; used at dosages sufficient for salt-retaining activity without glucocorticoid or anti-inflammatory activity.

Answer 222

When using these agents in physiologic replacement regimens (e.g., Addison’s disease), it is necessary to use an agent with both glucocorticoid and mineralocorticoid activity such as cortisol. Agents such as dexamethasone or triamcinolone would be inappropriate. When using these agents in pharmacologic doses for their anti-inflammatory or immunosuppressive actions, it is desirable to select an agent with minimal or no mineralocorticoid activity (e.g., dexamethasone). Ideally, one would desire to also select an anti-inflammatory steroid without glucocorticoid activity, but that is not possible at the present time. Thus, any time these adrenocorticosteroids are used to treat inflammatory conditions, the possibility of glucocorticoid metabolic side effects must be considered.

Answer 223

20-30 mg/day cortisol (often 15-20 mg AM, 5-10 mg PM). Dose should be increased dose by 2-4 fold during periods of stress. Unless mild disease, fludrocortisone is usually required for sufficient salt-retaining effect. DHEA may have benefits in some patients.

Answer 224

Life-threatening, so immediate treatment needed. Large amounts IV cortisol (100 mg q 6-8 hrs) until stable; must correct fluid/electrolyte abnormalities. Fludrocortisone may be required in some patients after switch to lower oral maintenance doses of cortisol (hydrocortisone).

Answer 225

Used to treat cushings syndrome. Divided into agents affecting early (broad effects) or later (more specific effects) steps in steroid biosynthesis.

Answer 226

early glucocorticoid synthesis inhibitor. Inhibits cholesterol to pregnenolone step (+ androgen synthesis)

Answer 227

Glucocorticoid receptor antagonist, anti-progestational drug that blocks glucocorticoid receptors at higher doses. Not first-line agent - approved to control hyperglycemia secondary to hypercortisolism. Can increase cortisol secretion via block of negative feedback at pituitary. Contraindicated for use during pregnancy - women of child- bearing age should use contraception.

Answer 228

Cortisol synthesis and secretion is diminished because of congenital enzyme defects in biosynthetic pathway resulting in increased ACTH and adrenal hyperplasia (due to lack of cortisol to suppress ACTH secretion, thus overstimulation of adrenal gland). Can be accompanied by excess or deficient levels of adrenal mineralocorticoids and androgens. The goal of therapy is to replace deficient steroids while minimizing adrenal sex hormone (overproduction) and glucocorticoid excess (via overtreatment). Hydrocortisone is used in children while longer acting agents (prednisone or dexamethasone) are preferred in adults. Fludrocortisone can be used if mineralocorticoid replacement is necessary.

Answer 229

No cortisol synthesis leads to increased ACTH causing excess androgens, leading to virilizing. No desoxycorticosterone or aldosterone synthesis, which leads to decreased smooth muscle contraction and hypotension.

Answer 230

No adrenal androgen synthesis, therefore it is non-virilizing. No cortisol synthesis leading to increased ACTH. There is also increased desoxycorticosterone leading to increased smooth muscle contraction and hypertension.

Answer 231

no cortisol synthesis leads to increased secretion of ACTH, leading to excess androgens and virilization. No cortisol synthesis also increases desoxycorticosterone causing increased smooth muscle contraction and hypertension

Answer 232

The signs and symptoms of pheochromocytoma are related to the pathophysiology of excess catecholamine secretion. Treatment is achieved by surgical removal of the tumor after appropriate pre-operative alpha-adrenergic receptor blockade to avoid a hypertensive crisis during surgery.

Answer 233

Aimed at controlling hypertension along with volume expansion to counter catecholamine-induced volume contraction. Phenoxybenzamine, an irreversible α1-α2 receptor antagonist, is given twice daily with upward dose titration every 3 days until blood pressure controlled. Beta-blockade (e.g., metoprolol) - after adequate alpha-adrenergic receptor blockade has been achieved - can be employed 2-3 days preoperatively to control tachycardia and other arrhythmias. NOTE: Block of beta-2 receptors (i.e., block of beta-2 mediated vasodilation) with non-selective beta blockers (e.g., propranolol [2] or labetalol [α1-1-2]) prior to alpha-1 block may result in severe hypertension due to effects of epinephrine on alpha-1 receptors mediating unopposed vasoconstriction. Calcium channel blockers (nifedipine) can be used to supplement alpha-and beta-blockade if blood pressure control is inadequate or side effects of alpha-blockade with phenoxybenzamine are not tolerated. Metyrosine, a competitive inhibitor of catecholamine synthesis, can be added to antihypertensive regimen to reduce catecholamine synthesis for inoperable or metastatic tumors

Answer 234

Glucocorticoids act by suppressing T-cell activation, suppressing cytokine production, and preventing mast cells and eosinophils from releasing various chemical mediators of inflammation [histamine, prostaglandins, leukotrienes and other substances] that cause tissue damage, vasodilation and edema. Over all effects are a reduction in chronic inflammation and autoimmune reactions BUT decreased healing and diminution of the protective aspects of the immune system.

Answer 235

educed vasodilation, decreased fluid exudation

Answer 236

overall decrease in accumulation and activation of cells. Areas of acute inflammation: Decrease number / activity of leukocytes (move to lymphoid tissues); neutrophils increase in circulation as movement to peripheral tissues is decreased. Areas of chronic inflammation: Decreased activity of monocytes and lymphocytes (T and B), decreased proliferation of blood vessels, less fibrosis. Lymphoid areas: Decreased clonal expansion of T and B cells, decreased action of cytokine secreting cells, but little effect on antibody formation at moderate doses.

Answer 237

decrease in synthesis. Decreased production and action of cytokines (IL-1 to IL-6, IL-8, TNF, GM-CSF) [not shown below].  Reduced generation of leukotrienes [LT] and prostaglandins [PG] via: Decreased expression of inducible COX-2 (decreased PG formation) in inflammatory cells. Inhibition of phospholipase A2 (decreased PG and LT formation) via lipocortin

Answer 238

GCs penetrate blood-brain barrier, increasing brain excitability. [Excessive use in therapy can lead to insomnia and/or behavioral disturbances (often euphoria, but also see depression or psychotic reactions, especially on withdrawal).]

Answer 239

Antagonize vitamin D effect on Ca++ absorption [Excessive use in therapy can lead to osteoporosis.] Stimulate excessive acid / pepsin production. [Excessive use in therapy can predispose to ulcers in very large doses.]

Answer 240

Common use in physiologic doses for replacement therapy and emergencies; glucocorticoid and mineralocorticoid actions [1:1]; administered orally and parenterally.

Answer 241

Most commonly used oral agent when steroid burst therapy desired; glucocorticoid and mineralocorticoid actions [5:1]; activated to prednisolone in liver.

Answer 242

Used if parenteral administration desired for steroid burst (no better than oral prednisone in acute exacerbations of asthma); minimal mineralocorticoid action. Oral (Medrol) and parenteral (Solu-Medrol).

Answer 243

Most potent anti-inflammatory agent, used in cerebral edema, chemotherapy-induced vomiting; minimal mineralocorticoid action, greatest suppression of ACTH secretion at pituitary.

Answer 244

Potent systemic agent with excellent topical activity; no mineralocorticoid action.

Answer 245

Allergic reactions: Asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis, serum sickness, urticaria. Collagen-vascular: Giant cell arteritis, lupus erythematosus, connective tissue syndromes, rheumatoid arthritis. Eye diseases: Acute uveitis, allergic conjunctivitis, optic neuritis. GI diseases: Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis. Hematologic disorders: Hemolytic anemia, idiopathic thrombocytopenic purpura, leukemia, multiple myeloma, Neurologic disorders: Cerebral edema (post-op brain surgery), multiple sclerosis. Pulmonary diseases: Aspiration pneumonia, bronchial asthma, respiratory distress syndrome, sarcoidosis. Skin diseases: Atopic dermatitis, lichen simplex, mycosis fungoides, pemphigus, seborrheic dermatitis. Miscellaneous: Hypercalcemia, mountain sickness

Answer 246

Pharmacodynamics: Stimulates secretion of ACTH and β-endorphin from pituitary (activation of receptor associated with increase in cAMP as second messenger). Clinical Uses: Used only for diagnostic purposes: Cushing's disease vs ectopic ACTH secretion and psychiatric depression (hypocortisolism) vs Cushing's disease. Side Effects: Transient facial flushing or dyspnea (10%); higher doses can produce bradycardia or hypotension.

Answer 247

The thyroid gland is located below the larynx, and there are two lobes on each side of the trachea. A narrow band of the gland known as the isthmus connects the two lobes. The blood supply to the gland is provided by the superior thyroid artery (from the external carotid) and the inferior thyroid artery (from the thyrocervical trunk of the subclavian artery). Of all the endocrine organs, the thyroid receives the highest blood flow. The functional unit of the gland is the follicle, consisting of a layer of cells surrounding a lumen filled with a substance known as colloid. Thyroglobulin (TG) is the primary constituent of colloid. Blood vessels flow between the follicles. The parafollicular cells (C cells) are also found in between the follicles; these secrete calcitonin and will be discussed more in the lecture about control of calcium and phosphate. Nerves terminate on the blood vessels as well as the follicular cells raising the possibility of direct neural control of the gland.

Answer 248

Iodide and the amino acid tyrosine are the ingredients for thyroid hormone (TH) synthesis.

Answer 249

Thyronine is the backbone of the THs. The 3, 5, 3' and 5' positions can be iodinated.

Answer 250

3, 5, 3', 5' tetraiodothyronine is the hormone T4, also known as thyroxine. 3, 5, 3' triiodothyronine is the hormone T3. TH synthesis involves iodination of tyrosine residues, followed by the coupling of iodotyrosines to form the iodothyronines.

Answer 251

Iodide is acquired from the dietary intake of iodine. 70-80 μg of iodide is lost daily from the thyroid primarily in the form of hormone; the typical daily intake of a U.S. resident is ~ 500 μg. Ingested iodine is mostly absorbed from the gut in the form of iodide to enter an extracellular iodide pool. Iodide exits this pool from the blood into the follicular cells of the thyroid gland. The mechanism for iodide transport into the gland is also called the "iodide trap" mechanism. The term "trap" refers to the fact that a membrane pump on the basal side of the follicular cell promotes accumulation of a concentration of iodide in the thyroid typically 30-40 times that in the serum. Iodide is concentrated in the gland against an electrical as well as this chemical gradient. Certain anions, notably perchlorate (ClO4), are transported by the same mechanism and thus act as competitive inhibitors of iodide uptake. Once inside the follicular cell, iodide diffuses from the basolateral (closest to the blood) to the apical (closest to follicular lumen) side. Iodide is moving with its electrical and chemical gradients when it exits the follicular cell at its apical side. Colloid is found outside the follicular cell near the apical membrane. Organification of iodide (incorporation of iodide into tyrosyl residues on thyroglobulin) occurs at the follicular cell-colloid interface. Iodide has to be oxidized before it can participate in tyrosyl iodination; the nature of the iodide intermediate is not understood. The enzyme that catalyzes iodination of thyroglobulin, thyroperoxidase, is a membrane bound glycoprotein, and immunohistochemical studies suggest it is present in the microvilli of the apical membrane.

Answer 252

Thyroglobulin (TG) is a glycoprotein of 660 kD composed of two identical polypeptides. TG is synthesized on the rough endoplasmic reticulum within the follicular cell and transported to the Golgi apparatus, where it is glycosylated and packaged into secretory vesicles. The secretory vesicles are released from the apical side of the follicular cell into the lumen and thus TG enters the colloid. All the iodination and coupling reactions of TH synthesis occur on tyrosyl residues of TG.

Answer 253

In the first step, thyroperoxidase catalyzes the iodination of tyrosyl moieties on TG. In this way mono- (MIT) and diiodotyrosine (DIT) are formed on TG. Certain compounds act as inhibitors of iodination. These decrease TH synthesis and secretion, ultimately leading to elevated levels of TSH and hypertrophy of the gland, a condition known as a goiter. These inhibitory compounds are thiourea drugs (e.g., propylthiouracil-PTU, and methimazole) and since they lead to enlarged thyroid glands (goiters), they are also termed goitrogens. Next, 2 DITs or 1 DIT and 1 MIT couple to form iodothyronines. The coupling reaction is thought to be catalyzed by thyroperoxidase as well, and thus probably occurs near the apical membrane.

Answer 254

The prequel to secretion is the endocytosis of TG from the lumen (colloid) into the follicular cells. Drops of colloid move into the follicular cell and coalesce with lysosomes; the lysosomal enzymes act on TG to cleave T4 and T3 from it. Under normal conditions, the amount of T4 removed is in excess (~20X) of the amount of T3 removed and thus released. It is not clear how release of the hormone occurs. It may be facilitated by specific carrier proteins. Note that the proteolytic action of the lysosomal enzymes will cleave iodotyrosines (MIT and DIT) from TG as well. These are de-iodinated, and the tyrosine and iodide are both reincorporated into TG.

Answer 255

Once in the blood, the majority of THs exist either in a protein bound form (up to 99.97% under normal conditions) or in free form (a minor part, ~0.03% T4 and 0.4% T3). The free from is the active form. TH binding proteins include thyroid binding globulin (TBG), thyroid binding pre-albumin (TBPA) and albumin. Under normal conditions, only about 30% of the binding sites on these proteins are occupied by TH; the majority is available. Measurements of TH levels are complicated by the fact that the majority is not free but bound to proteins. However, it is the free form that is important for evaluation of thyroid function. Thus, measurements of plasma TH levels must include values for the bound or free form in addition to the total TH in the blood. This is particularly important, because certain physiological states, such as pregnancy, increase TBG and TBPA. In sum, TG in the colloid serves as an extracellular reservoir of TH. Further, in the blood, the protein bound TH acts to delay, buffer and prolong the effects of TH action. This latter mechanism is more pronounced for T4 than for T3, in part because proportionally more (~10X) T4 is protein bound due to the higher affinity of TBG for T4. The half-lives of T4 and T3 are 7 days and 1 day, respectively. The lower affinity for T3 can in part explain the more rapid onset of action of T3 and its shorter half life in the serum. T3 is considered to be the active form of TH, because the affinity of the TH receptor is 10 fold greater for T3 than for T4. T3 and T4 both enter cells by active transport. T4 is converted to T3 by 5'-deiodinase (T4 is often considered to be a prohormone). T3 enters the nucleus where it interacts with nuclear receptors (TRs); there are several isoforms of thyroid hormone receptors, The T3-receptor complexes then act on DNA to direct transcription of specific mRNAs. One species of mRNA that has received particular attention is the Na-K ATPase, also known as the Na-K pump; the transcription of respiratory enzymes of the mitochondria is also stimulated.

Answer 256

1) THs are the major regulators of metabolic rate. A clinical measurement that has fallen into disuse, basal metabolic rate or BMR, was used to evaluate thyroid function. This measurement indicated the basal heat production of an individual in units of kcal/hr/M2 surface area. Typical values for females and males are 36 and 40 kcal/hr/M2, respectively. Although BMR is not in significant use now, it is important to note that in the absence of THs, the BMR decreases dramatically. This aspect of TH action-heat production- is referred to as a calorigenic effect. A large part of the calorigenic effect is due to Na pumping. Oxygen consumption is also increased. The calorigenic effect is evident in most tissues with the prominent exceptions of spleen, brain and testis. The calorigenic effect of TH occurs after a delay, and is blocked by inhibition of protein synthesis. 2) TH is necessary for normal fetal and neonatal brain development. They regulate proliferation, differentiation, myelinogenesis, neurite outgrowth, and synapse formation. Thus congenital hypothyroidism can lead to severe and irreversible mental retardation. Neonatal screening for TH levels is thus very important. Even in adults, TH levels can regulate behavioral functions as we shall see under dysregulation of thyroid function. 3) Both TH and growth hormone are essential for normal growth. Children with low TH levels can show severely stunted growth. This is due to the many developmental effects of TH. In addition when TH levels are low, growth hormone levels also decline. 4) Thyroid hormones enhance the response to catecholamines and thus mimic the effects of sympathetic nervous system activation. There is evidence suggesting that the number of β-adrenergic receptors increases in response to a hyperthyroid status. In fact, hyperthyroidism is often treated with β-blockers. 5) Thyroid hormones have effects on metabolism, some of which are consequences of the calorigenic actions, while others are independent effects. These actions are time and dose dependent. In general, low to moderate doses of TH tend to be anabolic, while high doses are catabolic. High doses of TH lead to increased fuel consumption, protein breakdown and muscle wasting. Lipolysis is the net result of the actions of TH on lipid metabolism. Low to moderate doses of TH promote the conversion of glucose to glycogen, while high doses enhance glycogenolysis.

Answer 257

In response to stimulation by TRH, TSH is released from thyrotrophs in the anterior pituitary. TRH interacts with a membrane receptor, and thereby leads to increases in cAMP and hydrolysis of membrane phosphatidyl inositol. Free T3 and T4 can influence the response of the anterior pituitary to TRH; high free T3 and T4 levels reduce the response, whereas low free T3 and T4 levels sensitize the response. TSH is carried by the blood to the thyroid gland. At a cellular level, TSH interacts with a membrane receptor. Eventually, the steps of thyroid hormone synthesis are stimulated. For example, TSH stimulates the iodide pump, thyroperoxidase and endocytosis of colloid. (Asterisks in Figure 1 designate steps that are stimulated by TSH.) TSH increases iodide transport with a latency (TSH also increases I- efflux, but its net effect is to increase transport into the follicular cells). This effect is seen with a latency. TSH also increases iodide Organification, the coupling of iodotyrosines, TG synthesis and its proteolysis following endocytosis from the colloid. All of these actions lead to an increase in TH secretion. These actions are thought to be mediated by cAMP; TSH activates adenylate cyclase by binding to its receptor on the follicular cell membrane. There is increasing evidence that other second messengers (e.g., diacylglycerol, Ca- calmodulin and IP3) may also participate in mediating TSH stimulation. TSH also affects the morphology of the gland. The follicular cells proliferate as well as enlarge and elongate; there are compensatory changes in the amount of colloid.

Answer 258

Iodine deficient diets will eventually lead to decreased TH synthesis and secretion. There is also an unexpected effect of high doses of iodine; in the short term, elevated iodide will also lead to a decrease in TH release, known as the Wolff-Chaikoff effect. The underlying mechanism involves decreases in incorporation of iodide into TG and consequent TH synthesis. In addition, high iodide will diminish the response to TSH. High iodine intake is sometimes used to prepare patients for thyroid surgery. However, high iodine intake is not used for chronic management of hyperthyroidism, because its effects are transient. As the iodide transporter has a higher affinity for perchlorate and thiocyanate (found in cabbages and cassava), presence of these ions can inhibit iodide uptake from the blood. Additionally drugs like thioureas, propylthiouracil and methimazole can block the activity of TPO and thus the incorporation of iodide to form TH. They also block the conversion of T4 to T3 in the target cells of the thyroid.

Answer 259

TSH is secreted by the anterior pituitary in response to stimulation by the hypothalamic hormone TRH. Stimuli such as cold, fasting and stress alter hypothalamic release of TRH. TH's enter into a negative feedback in this system by inhibiting the secretion of TSH by the anterior pituitary; it is not clear if they also inhibit secretion of TRH by the hypothalamus. Due to the difficulties in accurately assessing free TH levels, it is common to use TSH levels as an index of thyroid function.

Answer 260

Conditions include Graves' Disease (autoimmune), tumors of pituitary or thyroid, excess TH administration. Signs and symptoms include BMR, Nervousness, Pretibial Myxedema (Graves), Heat intolerance, Muscle weakness, Goiter, Palpitations, Exopthalmos (Graves), Lid retraction (Graves), Tachycardia

Answer 261

Conditions include Hashimoto's thyroiditis, iodine deficient diet; Deficiency in child leads to cretinism, characterized by severe mental and growth retardation. Signs and symptoms include BMR, Lethargy, Weakness, Myxedema, Cold intolerance, Slow speech, Goiter, Hoarseness, Mental Slowness, Psychosis, Bradycardia

Answer 262

Thyrotoxicosis describes all forms of excess thyroid hormone, including both endogenous and exogenous causes. Hyperthyroidism refers to excessive thyroid hormone production, while thyroiditis describes thyroid hormone release from a damaged thyroid gland. Increased levels of T4 and T3 lead to a hypermetabolic state (e.g., increased Na/K ATPase activity). The most common cause of hyperthyroidism is Graves disease.

Answer 263

Jod-Basedow phenomenon describes iodine-induced hyperthyroidism. It arises in two settings: Administration of iodine to a patient with an iodine deficiency goiter (e.g. patient with endemic goiter relocates to iodine-abundant geographical location). Ingestion (diet) or injection (contrast medium) of iodine by a patient with toxic multinodular goiter, hot nodule, or Graves disease

Answer 264

Hyperthyroidism results in signs and symptoms that reflect the abnormal function of many organ systems. These include: Cardiovascular, CNS, Opthalmologic, Gastrointestinal, Endocrine. In addition, metabolic changes ares seen with hyperthryoidism. In general, these symptoms are opposite of those observed with hypothyroidism. Cardiovascular signs and symptoms of hyperthyroidism include: Peripheral vasodilation to get rid of heat which leads to warm, flushed skin; Increased synthesis of cardiac β1 receptors which leads to: Increased heart rate (sinus tachycardia), Increased contractility and, increased stroke volume (increased pulse pressure), Increased cardiac output; Cardiomegaly, systolic hypertension, high-output heart failure; Hypercalcemia-induced EKG changes (due to increased bone turnover); Arrhythmias (especially atrial fibrillation) secondary to increased heart rate and/or cardiomegaly. The effects of hyperthyroidism on the nervous system include an increased sympathetic nervous system tone. This leads to: Fine tremor (hands), Anxiety, Insomnia, Emotional lability, Inability to concentrate, Brisk deep tendon reflexes. Ophthalmologic signs and symptoms of hyperthyroidism are secondary to the increase of sympathetic nervous system tone. Overstimulation of the superior tarsal muscle (a muscle which receives SNS innervation from the internal carotid plexus & contracts reflexively to elevate the upper eyelid) leads to a wide-eyed staring gaze and lid lag. NOTE that true thyroid ophthalmopathy with exophthalmos (proptosis) is only seen in Graves disease. Hyperthyroidism affects the gastrointestinal system by increasing GI motility, which leads to malabsorption and diarrhea. Effects of hyperthyroidism on the endocrine system include: Increased bone turnover, leading to osteoporosis and an increased risk of fractures; Oligomenorrhea. Metabolic signs and symptoms of hyperthyroidism include: Increased basal metabolic rate, resulting in increased O2 consumption which effectively increases respiratory rate (tachypnea); Weight loss, despite an increased appetite; Negative nitrogen balance (catabolic), which can lead to thyroid myopathy (proximal muscle weakness and decreased muscle mass); Increased heat production and sweating, leading to heat intolerance.

Answer 265

Lab findings used in diagnosis of hyperthyroidism include serum thyroid stimulating hormone (TSH), as well as total T4 and free T4. When hyperthyroidism is clinically suspected, serum TSH is usually the most sensitive test. Serum TSH varies based on etiology: In primary hyperthyroidism, TSH levels are decreased; In secondary hyperthyroidism, TSH levels are increased; In the rare case that a patient has secondary hyperthyroidism due to a TSH-secreting pituitary adenoma, inject TRH and look for an increase in TSH. An increase in the levels of total T4 and free T4 is seen in hyperthyroidism. Up to 5% of patients may exhibit T3 toxicosis, an increase in serum T3 with low or normal serum T4. T3 toxicosis can be seen in any condition that causes hyperthyroidism, and the treatment is the same as for hyperthyroidism. After confirming thyrotoxicosis with TSH and free thyroid hormone level assays, 123I uptake may help determine the etiology of the thyrotoxicosis. In Graves disease, 123I uptake is diffusely increased throughout the whole thyroid gland. With a toxic multinodular goiter, uneven 123I uptake is seen, with an occasional autonomous “hot” nodules demonstrating increase 123I uptake. In thyroiditis, a decrease in 123I uptake will be observed. If the hyperthyroidism is due to exogenous thyroid hormone intake, a decreased 123I uptake will be observed. In iatrogenic hyperthyroidism, patients with hypothyroidism may take too much of their prescribed thyroid hormone replacement medication. In surreptitious hyperthyroidism, patients take thyroid hormone for secondary gain. In both cases, excess thyroid hormone negatively feeds back on the pituitary, leading to decreased TSH. This decrease in thyroid activity manifests as decreased 123I uptake, with thyroid gland atrophy. Other lab findings consistent with thyrotoxicosis include: increased bone turnover, and therefore an increase in serum calcium (hypercalcemia), increased glycogenolysis, and therefore an increase in serum glucose (hyperglycemia), and increased low densitiy lipoprotein (LDL) receptor synthesis, and therefore a decrease in serum cholesterol (hypocholesterolemia).

Answer 266

Treatment of hyperthyroidism includes: β-blockers; Thioamides; High-dose iodide; Radioactive iodine (131I). β-blockers are indicated to control the symptoms of increased sympathetic nervous system tone. Furthermore, propranolol decreases peripheral conversion of T4 to T3 by interfering with the activity of 5'-deiodinase, producing a net decrease in thyroid hormone actions at target tissues. Thioamides (e.g., propylthiouracil and methimazole) may induce remission by blocking new thyroid hormone production via inhibition of the organification and coupling steps of thyroid hormone synthesis. In addition, PTU (but not methimazole) also inhibits peripheral conversion of T4 to T3. High-dose iodide blocks the release of T4 and T3 into circulation. High-dose radioactive iodine 131I (versus the 123I used in imaging studies) becomes concentrated in the thyroid gland. This leads to ablation of follicular cells, and decreases thyroid function.

Answer 267

Hypothyroidism describes a condition in which the thyroid gland does not produce enough thyroid hormone. Primary hypothyroidism accounts for >95% of cases, and describes a group of abnormalities related to the thyroid gland itself.

Answer 268

Hypothyroidism results in signs and symptoms that reflect the abnormal function of many organ systems. These include: Cardiovascular; CNS; Dermatologic; Gastrointestinal; Endocrine. In addition, metabolic changes are seen with hypothyroidism. In general, these symptoms are opposite of those observed with hyperthyroidism. Cardiovascular signs and symptoms of hypothyroidism include: Peripheral vasoconstriction to maintain body heat, which leads to cool, pale, dry skin; Decreased synthesis of cardiac β1 receptors, which leads to Bradycardia, Decreased contractility and decreased stroke volume (decreased pulse pressure), Decreased cardiac output, which decreases exercise capacity and dyspnea on exertion; Blunted EKG voltages; Accelerated atherogenesis, due to increased total cholesterol and LDL levels (LDL receptor expression regulated by thyroid hormone). Central nervous system signs and symptoms of hypothyroidism include: Slow deep tendon reflexes, with a prolonged relaxation phase; Fatigue and lethargy; Mental slowness; Perinatal mental retardation. Dermatologic signs and symptoms of hypothyroidism include: Coarse, brittle hair and nails; Yellow/orange, dry skin; Facial and periorbital myxedema- swelling of the skin and underlying tissue gives the skin a 'waxy' appearance. The term myxedema coma denotes severe hypothyroidism, while myxedema may refer to two different dermatologic conditions: Pretibial myxedema is a localized dermopathy characterized by thickening of skin overlying non-pitting edema, which may occur in hyperthyroid states (notably Graves disease). Myxedema is a non-pitting edema due to interstitial accumulation of osmotically active mucopolysaccharides in the dermis, which may occur in severe, long-standing hypothyroid states. The edema is generally facial or periorbital. Gastrointestinal signs and symptoms of hypothyroidism include decreased GI motility, which manifests as constipation. Endocrine signs and symptoms of hypothyroidism include hyperprolactinemia (if primary or secondary hypothyroidism). The decrease in T3 and T4 production increases TRH, which stimulates prolactin release. Metabolic signs and symptoms of hypothyroidism include: Decreased basal metabolic rate, resulting in a decreased O2 consumption which effectively reduces respiratory rate; Positive nitrogen balance (anabolic), which leads to weight gain; Decreased heat production, which decreases sweating and results in cold intolerance; Growth retardation

Answer 269

A serious complication of hypothyroidism is myxedema coma, which generally occurs in patients with long-standing hypothyroidism that have not been properly treated. Myxedema coma is the only emergent hypothyroid condition. Myxedema coma can have a spontaneous onset, or it can be precipitated by: Cold exposure; Infections; Drugs (CNS depressants); Hypoxia. Symptoms include: Hypothermic stupor/coma; Hypoventilation with CO2 retention; Hypotension. Treatment for myxedema coma include: Respiratory support; Intravenous levothyroxine; Cortisol. The use of T4 alone, combined T4 and T3, or T3 alone is controversial. Deiodinase conversion of T4 to the active hormone T3 is often reduced in these patients, advising T3 administration. However, T3's more immediate action and short half-life may be more likely to cause arrhythmias (particularly with compromised myocardial function).

Answer 270

Major etiologies of primary hypothyroidism include: Iodine deficiency; Hashimoto thyroiditis (chronic autoimmune thyroiditis); Surgical thyroid removal or thyroid ablation (surgical or I-131 radiation); Drugs (notably lithium, amiodarone or sulfonamides); Other types of thyroiditis (subacute lymphocytic, subacute granulomatous, Riedel's etc). In contrast secondary hypothyroidism is caused by pituitary hypofunction, and tertiary hypothyroidism is caused by hypothalamic hypofunction. Endemic dietary iodine deficiency is the most common cause of hypothyroidism worldwide. The most common cause of hypothyroidism in iodine-sufficient regions is Hashimoto thyroiditis.

Answer 271

Congenital hypothyroidism (cretinism) is most commonly caused by thyroid dysgenesis in the US. It may be caused by maternal hypothyroidism, thyroid agenesis, iodine deficiency and dyshormonogenic goiter. Cretinism is the term used to describe arrested physical and mental development due to congenital hypothyroidism. Testing of all newborns for hypothyroidism (elevated TSH) is standard of care, because mental retardation can be minimized when thyroid hormone is administered during the neonatal period. The 6 P's of congenital hypothyroidism (cretinism) include: Poor brain development; Pot-bellied; Pale; Puffy-faced; Protruding umbilicus; Protuberant tongue. Congenital hypothyroidism may present with a hoarse cry, weak cough, and slow respiratory effort. A protuberant abdomen, or "potbelly" with an umbilical hernia may be a symptom of congenital hypothyroidism. Prolonged neonatal (physiologic) jaundice may result from congenital hypothyroidism. Macroglossia, or a protruding tongue, is characteristic of congenital hypothyroidism. The arrest of physical development associated with congenital hypothyroidism may result in enlarged fontanelles, delayed dentition and retarded bone age. An infant with congenital hypothyroidism may have dry skin and scarce lanugo (unpigmented downy hair), as well as a pale body with mottled cool extremities. Coarse facial features, including wide-set eyes and a broad flat nose may be present in an infant with congenital hypothyroidism. Infants are also described as having a characteristic "puffy face".

Answer 272

The laboratory value of a serum TSH test will differed among primary, secondary and tertiary etiologies of hypothyroidism: In primary hypothyroidism (caused by thyroid hypofunction), TSH levels will be increased. In secondary hypothyroidism (caused by pituitary hypofunction), TSH levels will be decreased. In tertiary hypothyroidism (caused by hypothalamic hypofunction), TSH levels will be normal/low-normal, but in rare cases may be elevated. For this reason, TSH and free thyroxine are examined concurrently when central hypothyroidism is expected. When hypothyroidism is clinically suspected, serum TSH is usually the most sensitive test. Total T4 and free T4, as well as T3 resin uptake, will generally be decreased.

Answer 273

Graves disease is the most common cause of endogenous hyperthyroidism (85% of cases). Females are affected 10x more frequently than males, with a peak incidence between age 20-40. Graves disease is caused by a type II hypersensitivity reaction. A decrease in self-tolerance to thyroid auto-antigens leads to the production of autoantibodies. Thyroid-stimulating immunoglobulin (TSI) is an IgG that binds and activates TSH receptor, mimicking the action of TSH. TSI is relatively specific for Graves disease. Anti-thyroglobulin and anti-thyroid peroxidase antibodies are often present. TSI & other autoantibodies cross-react with and stimulate several tissues in the body containing TSH receptors, including: Thyroid; Retro-orbital fibroblasts; Dermal fibroblasts. Graves disease is associated with HLA-DR3 and HLA-B8. Graves disease is accompanied by a triad of clinical findings, which result from IgG autoantibodies stimulating TSH receptors throughout the body. Hyperthyroidism results from continuous stimulation of the thyroid gland by IgG autoantibodies. This stimulation leads to diffuse, symmetrical, nontender and hyperfunctional enlargement of the thyroid (aka diffuse goiter). Graves disease is treated similarly to other causes of hyperthyroidism, the most commonly used therapy being radioactive iodine.

Answer 274

Infiltrative ophthalmopathy is characterized by exophthalmos (proptosis) and impairment of the extraocular muscles. When stimulated, TSH receptors on orbital pre-adipocyte fibroblasts synthesize hydrophilic glycosaminoglycans (notably hyaluronic acid and chondroitin sulfate). The accumulation of glycosaminoglycans, infiltration of fat and T cells in the retro-orbital space, and edema of the extraocular muscles all lead to exophthalmos (proptosis). This occurs in ~50% of patients. Infiltrative dermopathy, most commonly manifesting as pretibial myxedema (a scaly thickening and induration of the skin overlying the shins with nonpitting edema), results from TSH receptor stimulation on dermal fibroblasts. This only occurs in 1-2% of patients.

Answer 275

Diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells results in abundant tall columnar cells lining the follicles. Colloid appears pale with scalloped (moth-eaten) margins due to increased colloid absorption. Lymphocytic infiltrate leads to germinal centers in the thyroid (more commonly seen in Hashimoto thyroiditis). Germinal centers are found in normal lymph nodes and should NOT be in the thyroid.

Answer 276

Thyroid storm is a severe complication of Graves disease. It describes an abrupt-onset of severe thyrotoxicosis. Thyroid storm is most likely induced by an acute elevation in catecholamine levels, as seen in situations of acute stress including: Infection; Surgery; Trauma. Thyroid storm is most commonly seen in patients with Graves disease, as well as other hyperthyroid disorders. Patients will present with: Agitation; Delirium; High fever (hyperpyrexia); Tachycardia (out of proportion to fever); Diarrhea; Vomiting; Coma. Thyroid storm is treated with propranolol, propylthiouracil (PTU), and prednisone, all of which decrease peripheral conversion of T4 to T3. Additionally: Propranolol (β- blocker) controls tachycardia and prevents tachyarrhythmias. PTU interferes with the function of thyroid peroxidase, decreasing thyroid hormone synthesis. Iodide compounds may be administered, as high levels of iodide inhibit the release of thyroid hormone. Complications of thyroid storm include: Tachyarrhythmias (notably atrial fibrillation and ventricular fibrillation) which are the most common cause of death in patients with thyroid storm. Shock (heart failure, diarrhea/vomiting-induced volume depletion). Coma

Answer 277

Hashimoto thyroiditis (chronic autoimmune thyroiditis) is the most common cause of hypothyroidism in developed countries. Hashimoto thyroiditis is caused by autoimmune-mediated destruction of the thyroid gland. Thyroid cell death results from a failure of self-tolerance to thyroid auto-antigens: CD8+ T-cell mediated cell death; Activated TH1 cells release IFN-γ that recruits and activates macrophages, which release inflammatory mediators that inflict follicle damage; Anti-thyroid autoantibodies (anti-Tg and anti-TPO) lead to complement activation and antibody-dependent cell-mediated cytotoxicity. Anti-thyroid antibodies include anti-thyroglobulin antibodies and anti-thyroid peroxidase (TPO) antibodies. Note that TPO was formerly known as microsomal antigen. Hashimoto thyroiditis presents as a nontender thyroid, which often becomes diffusely enlarged. The development of hypothyroidism (and resultant symptoms) is insidious, most commonly in women age 30-50. Early in the course of Hashimoto thyroidis, hyperthyroidism may occur as thyroid follicules rupture. A patient with Hashimoto thyroiditis is at an increased risk of developing: Other autoimmune diseases, for example: Type 1 Diabetes Mellitus; Systemic Lupus Erythematosus; Sjögren’s syndrome; Myasthenia Gravis; Pernicious anemia; Primary thyroid lymphoma, particularly B-cell non-Hodgkin lymphomas (extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue [MALT] type). The treatment for hypothyroidism associated with Hashimoto thyroiditis is levothyroxine.

Answer 278

Lymphocytic infiltrate. Prominent germinal follicles. Atrophic thyroid follices lined by Hürthle cells (epithelial cells with abundant, granular, deeply eosinophilic cytoplasm). Because thyroid follicles are normally lined by low cuboidal epithelium, this is also known as Hürthle cell metaplasia.

Answer 279

A goiter is an enlarged thyroid gland, which has undergone hyperplasia in response to excessive stimulation of TSH receptors. There are three types of goiters: Simple; Multinodular; Dyshormonogenic. A goitrogen is a substance that interferes with iodine uptake, which suppresses the function of the thyroid gland and results in the enlargement of the thyroid (a goiter). Many cruciferous vegetables are goitrogens (broccoli, brussel sprouts). A fixed, painless and hard (rock-like) goiter is found in Riedel thyroiditis. Autoantibodies stimulate TSH receptors in Graves disease, resulting in the formation of a diffuse goiter. A simple goiter occurs when the body is unable to produce sufficient thyroid hormone, and the thyroid gland undergoes hyperplasia in response. In many cases the etiology is unknown, but it may be caused by a lack of dietary iodine or intrinsic thyroid hormone production defects. Patients with iodine deficiency goiters are most commonly euthyroid. Goitrous hypo- and hyperthyroidism may also be seen, but this is less common.

Answer 280

A multinodular goiter describes an enlarged thyroid gland with multiple nodules, typically due to relative iodine deficiency. Patients are usually euthyroid. In contrast, a toxic multinodular goiter contains focal patches of hyperfunctioning follicular cells that function independently of thyroid stimulating hormone (TSH) due to a mutation of the TSH receptor. The term 'toxic' does not mean malignancy, rather it refers to the hyperthyroidism (thyrotoxicosis) that results from these self-sufficient nodules. As a result of the autonomously functioning thyroid nodules in a patient with a toxic multinodular goiter, the release of T3 and T4 is increased resulting in hyperthyroidism.

Answer 281

Dyshormonogenetic goiter is a genetically-determined thyroid hyperplasia that result from enzyme defects in thyroid hormone synthesis, most commonly thyroid peroxidase. These deficiencies are a cause of congenital hypothyroidism (cretinism).

Answer 282

Thyroid adenomas are benign, typically small nodules of the thyroid gland. Most thyroid adenomas are derived from follicular epithelium. Although both are derived from follicular epithelium and surrounded by a capsule, follicular carcinomas invade through the surrounding capsule while follicular adenomas do not.

Answer 283

Parathyroid nodules commonly cause primary hyperparathyroidism. There are three main causes of a parathyroid mass: Solitary adenoma (85-95%); Hyperplasia (5-10%); Carcinoma (1%). Parathyroid hyperplasia is commonly associated with MEN 1 and MEN 2A syndromes.

Answer 284

There are four subtypes of thyroid carcinoma: Papillary, Follicular, Medullary, Anaplastic

Answer 285

Thyroglobulin is a marker for papillary and follicular thyroid cancer, but is not used for medullary or anaplastic thyroid cancer.

Answer 286

Papillary carcinoma is the most common (85%) type of thyroid cancer. It is well-differentiated, and it has an excellent prognosis. Patients at a higher risk for thyroid papillary carcinoma include women in their 30s, as well as patients with prior exposure to ionizing radiation. Patients with RET and BRAF mutations are at an increased likelihood of developing papillary carcinoma of the thyroid. Papillary carcinoma has a propensity for lymphatic spread, and thus can present with lymphadenopathy. Characteristic histological findings on light microscopy include: "Orphan Annie eye" nuclear inclusions (nuclei with uniform staining, which appear empty); Psammoma bodies (round, concentric collections of calcium); Nuclear grooves

Answer 287

Follicular carcinomas account for 5-15% of thyroid cancers. They generally have a good prognosis. Follicular carcinomas consist of uniform thyroid follicles which invade the thyroid capsule. This distinguishes it from a follicular adenoma which does not invade the capsule. Follicular carcinomas have a propensity for hematogenous spread, and thus can present with distant metastasis (liver, bone, lungs). Note: this is an exception to the general rule- carcinomas typically spread via the lymphatics.

Answer 288

Medullary thyroid carcinomas originate from parafollicular C cells of the thyroid, which are neuroendocrine cells that secrete calcitonin. Calcitonin produced by the tumor may produce hypocalcemia at high levels, and often deposits within the tumor as amyloid. Calcitonin can serve as a tumor marker for medullary carcinoma of the thyroid. Histologically, this tumor appears as solid sheets of cells in an amyloid stroma. Amyloid deposition in medullary thyroid carcinomas stains with Congo Red and shows apple-green birefringence under polarized light. Medullary thyroid carcinomas are associated with MEN 2A and 2B.

Answer 289

Anaplastic carcinomas account for less than 5% of thyroid cancer cases. Anaplastic carcinomas are most common in patients older that 65. Anaplastic carcinomas have the worst prognosis of all thyroid cancers. They are poorly differentiated and invade local structures.

Answer 290

The clinical presentation of thyroid cancer can vary, but is generally highlighted by painless enlargement of the thyroid gland. Diagnostic tests include ultrasound, FNA (fine needle aspiration) and radioactive iodide uptake scans (scintigrams). FNA cannot distinguish between follicular adenoma and follicular carcinoma of the thyroid because it is examining cells, not the capsule. Thyroid carcinomas generally present as cold nodules on scintigrams (no uptake of 123I). More advanced lesions may present with signs of local invasion including: Hoarseness (from recurrent laryngeal nerve involvement); Dysphagia; Cough. Thyroidectomy is the major treatment option for thyroid cancers. Complications of thyroidectomy include: Hoarseness, due to recurrent laryngeal nerve damage; Hypocalcemia, due to removal of the parathyroid glands. Transection of recurrent and superior laryngeal nerves during ligation of the inferior thyroid artery and superior laryngeal artery, respectively.

Answer 291

Thyroid imaging with radioiodine demonstrates the distribution of functioning thyroid tissue, including ectopic tissue, since thyroid tissue is the only tissue that concentrates large amounts of iodine. Must discontinue iodine containing preparation and medications that could potentially affect the ability of thyroid tissue to accumulate iodide. I 123 scan- To evaluate function of the thyroid gland and thyroid nodule in patient with abnormal thyroid function. Half life of I-123 is 13 hrs. I131 scan- Diagnostic and therapeutic role. Half life of I-131 is 8 days. Detect local and distant thyroid cancer metastasis. Treatment of hyperthyroidism as well as for well differentiated thyroid cancer.

Answer 292

Congenital hypothyroidism is the presence of hypothyroidism at birth, and is most often caused by thyroid dysgenesis. Other etiologies of congenital hypothyroidism include: Resistance to TSH; Disorders of thyroid hormone synthesis, secretion, transport, or metabolism; Resistance to thyroid hormone; Central hypothyroidism (hypothalamic or pituitary). A transient congenital hypothyroidism can be caused by: Anti-thyroid drugs (given to mothers); Iodine exposure; Large hepatic hemangiomas; Mutations in the dual oxidase gene. The incidence of congenital hypothyroidism varies by location and by ethnicity, but occurs more often in females than in males. In most cases, congenital hypothyroidism caused by thyroid dysgenesis arises sporadically, though there are some cases in which a familial/hereditary component has been identified. In contrast, congenital hypothyroidism caused by defects in thyroid hormone synthesis and secretion are uniformly hereditary and autosomal recessive. The vast majority of infants with congenital hypothyroidism are asymptomatic at birth.

Answer 293

Congenital hypothyroidism presents with few clinical manifestations both because some maternal T4 crosses the placenta, and because many affected infants have some (but not enough) functioning thyroid tissue. If congenital hypothyroidism is left untreated for the first two to three years of life, permanent neurological sequelae will occur. A “classic” (though, as noted above, uncommon) history for an infant with a congenital hypothyroidism is an infant with: Prolonged jaundice; Poor feeding; Lethargy; Constipation. Clinical manifestations of congenital hypothyroidism include: Hoarse cry, weak cough, slow respiratory effort; Abdominal distention (protuberant abdomen), potbelly with umbilical hernia; Prolonged neonatal (physiologic) jaundice; Poor feeding, neonatal hypotonia; Macroglossia (protruding tongue); Enlarged fontanelles, delayed dentition, retarded bone age; Coarse facial features, widely set eyes, broad flat nose, dry skin with scarce lanugo, pale body with mottled cool extremities. Physical exam findings in infants with congenital hypothyroidism are most commonly normal. For testing purposes, the “classic” congenital hypothyroidism physical findings including large anterior and posterior fontanelles, protruding tongue, umbilical hernia, myxedema, mottled skin, hypothermia, delayed neurodevelopment, and poor growth.

Answer 294

Classic signs and symptoms of congenital hypothyroidism are now rarely seen because we are better at detecting the disease early. Today, congenital hypothyroidism is most commonly detected through newborn screening programs that measure either T4 or TSH in all newborns. As in adults, infants with congenital hypothyroidism will have low serum total or free T4 and elevated TSH. Subclinical hypothyroidism is diagnosed in infants with elevated TSH but normal free or total T4 levels. The rare infant with central congenital hypothyroidism will have low serum total and free T4 in addition to low TSH. Imaging is not routinely used for infants with congenital hypothyroidism. However, imaging might be useful in infants with minor abnormalities in thyroid function (to determine whether treatment is necessary), in infants in whom an enzymatic defect in thyroid synthesis is suspected (to confirm and allow for counseling about risk in future children), and to confirm a diagnosis of transient hypothyroidism (by locating normally functioning thyroid tissue). If imaging of an infant’s thyroid is indicated, it is recommended to begin with thyroid ultrasonography, followed by thyroid radionuclide uptake and scan if the ultrasound is inconclusive. Hypothyroidism is typically diagnosed with the following laboratory findings: Increased TSH; Decreased FT4, TT4, T3. Imaging studies that can be used in the diagnostic process include: Radionuclide imaging of the thyroid can be used to help evaluate the cause of hypothyroidism; Thyroid ultrasound is also used

Answer 295

The overall treatment goal for congenital hypothyroidism is to rapidly restore serum T4 to normal range and to maintain euthyroid status from that point on. Patients with congenital hypothyroidism are treated with oral levothyroxine (L-T4). TSH and free T4 levels are followed closely and adjustments made as necessary. Adequately treated infants with congenital hypothyroidism generally grow and develop normally. Some severely affected infants (treated appropriately), as well as those who are treated inadequately have IQs below those of normal children.

Answer 296

Initiation of thyroid cell differentiation, maintenance of the differentiated state, and essential for thyroid cell proliferation. Autosomal dominant pattern of inheritance. Phenotypes vary from mild to severe hypoplasia associated with compensated or overt hypothyroidism, ectopy, normal glands at birth. Few cases assoc w/ renal agenesis

Answer 297

Migration of thyroid precursor cells and transcriptional control of the TG (thyroglobulin) and the TPO (thyroid peroxidase) gene promoters in thyroid development. Homozygous mutations result in Bamforth-Lazarus syndrome: CH, cleft palate, spiky hair, and variably bifid epiglottis and choanal atresia.

Answer 298

A homeobox domain transcription factor. Development of the gland and in transcriptional control of the TG, TPO, and TSH receptor genes. Also expressed in the lung, the forebrain, and the pituitary gland. Humans with heterozygous mutations associated with various combinations of CH, respiratory distress and neurological disorders

Answer 299

The TSH receptor gene (TSHR) encodes a transmembrane receptor present on the surface of follicular cells which mediates the effects of TSH and is critical for the development and function of the thyroid gland. Heterozygous loss-of-function mutations – partial resistance with normal size gland and TSH elevation. Homozygous TSHR mutations usually cause CH with hypoplastic gland and decreased T4 synthesis

Answer 300

NIS (sodium/iodide symporter) -iodide transport from the blood into thyroid cell (basal membrane). Rate-limiting step in thyroid hormone synthesis. Mutations cause hypothyroidism of variable severity and goiter is not always present -individuals with a higher dietary iodine intake are less likely to have severe hypothyroidism than those with iodine deficient diets

Answer 301

Encodes pendrin which is important for efflux of iodide at the apical membrane of thyroid follicular cells. Mutations cause Pendred’s syndrome, an autosomal recessive disorder associated with sensorineural congenital deafness and goiter. Rarely present with CH; the majority of individuals are euthyroid, at least under conditions of normal iodine intake

Answer 302

Hypothalamic-pituitary-thyroid axis can be activated by circadian rhythms, prolonged cold exposure or acute psychosis; severe stress can suppress activation. Pituitary release of TSH stimulated by hypothalamic TRH and inhibited by somatostatin, dopamine and glucocorticoids

Answer 303

Unique, complex, grossly inefficient process - controlled at all steps by TSH. Major regulated step: Uptake of I- (iodide ion) into thyroid gland is stimulated by TSH via a G-protein coupled receptor (increase in cAMP levels). This process can be blocked by anions of similar size such as SCN-, ClO4-, and I- itself (high concentrations greater than 6 mg, autoregulatory action via decreased expression of transporter). The generation of cAMP is inhibited by lithium ions and can result in symptoms of hypothyroidism when lithium is used as anti-manic therapy. Iodide organification. I- oxidized and incorporated into tyrosine residues on thyroglobulin [Tg] molecules (mono-[MIT] and di-iodinated [DIT] tyrosine) via thyroid peroxidase. Coupling of precursors occurs on Tg (T4 / T3 ratio of 5:1 on thyroglobulin molecule); also mediated via thyroid peroxidase. MIT + DIT -> T3 and DIT + DIT -> T4. Retrieved from storage in lumen (large capacity) by pinocytosis; slowly released from gland by proteolysis (in T4/T3 ratio of 12-14:1)

Answer 304

Structure / Pharmacokinetics: Tripeptide; administered IV, t1/2 about 4-5 min. Pharmacodynamics. Activation of phospholipase C -> increase IP3 -> increase intracellular Ca++. Stimulates pituitary production of TSH (and prolactin) -> stimulates thyroid to produce T4  TRH stimulation of TSH blocked by T3 (and somatostatin), potentiated by lack of T3. Uses: Test for pituitary reserve of TSH in suspected hypothyroidism and for hyperthyroidism; Unlabelled: Antisedative effect (CNS action) for phenobarbital, diazepam, ethanol overdose situations; high- dose TRH may improve outcome of spinal cord injuries; Orphan drug for prevention of infant respiratory distress syndrome in premature infants. Side Effects. Duration only a few minutes: urge to urinate, metallic taste, nausea, light-headedness

Answer 305

Structure / Pharmacokinetics: Glycoprotein, consists of alpha and beta subunits. MW: 28,000-30,000. Therapeutic TSH prepared from bovine source. Administered IM or SC; t1/2 about 1 hr. Pharmacodynamics: Stimulates cAMP production (via activation of adenylyl cyclase) resulting in increased uptake of iodine and production of thyroid hormones. Lithium blocks this action of TSH. Uses. Role in therapy of metastatic thyroid carcinoma (enhances uptake of radioactive 131I into thyroid gland, which is subsequently destroyed). Side Effects: Nausea / vomiting, thyroid tenderness, allergic symptoms, hyperthyroid symptoms

Answer 306

Free T4 and T3 enter cell via active transport (T4 converted to T3 in cells), T3 then enters nucleus and binds to receptor. Most of thyroid hormone effects mediated by subsequent increase in RNA and then protein synthesis: increased formation of Na+-K+-ATPase -> increases ATP turnover and O2 consumption -> calorigenic effect; also increases in myosin ATPase and sarcoplasmic reticulum Ca++-ATPase. Metabolic actions include increased fat / carbohydrate / protein consumption and metabolism.

Answer 307

Responsible for optimal growth (via control of protein synthesis), development, function, and maintenance of all body tissue. Critical for development of nervous (myelination), skeletal (ossification in epiphyses), and reproductive tissues. Thyroid deprivation results in irreversible mental retardation and dwarfism. Thyroid hormones influence secretion and degradation rates of virtually all other hormones (including cortisol, estrogen, testosterone, insulin, catecholamines). Sympathetic nervous system activity increased via thyroid hyperactivity, especially cardiovascular system (increased number of β-adrenergic receptors and adenylyl cyclase activity)

Answer 308

Responsible for optimal growth (via control of protein synthesis), development, function, and maintenance of all body tissue. Critical for development of nervous (myelination), skeletal (ossification in epiphyses), and reproductive tissues. Thyroid deprivation results in irreversible mental retardation and dwarfism. Thyroid hormones influence secretion and degradation rates of virtually all other hormones (including cortisol, estrogen, testosterone, insulin, catecholamines). Sympathetic nervous system activity increased via thyroid hyperactivity, especially cardiovascular system (increased number of β-adrenergic receptors and adenylyl cyclase activity)

Answer 309

Presents as a multisystem disorder of reduced metabolic rate. Manifested by reversible slowing of all body functions in adults and striking retardation of growth and development in children. Common clinical findings include: weight gain, lethargy / weakness / fatigue, goiter, pale and puffy dry skin, bradycardia, decreased appetite, fluid retention, cold intolerance, constipation, hyperlipidemia, depression

Answer 310

Replacement therapy is appropriate; use of levothyroxine (T4) most satisfactory. For adults, generally start with 50-100 mcg, working up to 1.6-1.8 mcg/kg/day. Infants / children require more T4 / kg (∼10 mcg/kg) - should be monitored for normal growth and development as well as TSH and free thyroxine index. Greater urgency to achieve full thyroid replacement, increase at weekly intervals. For elderly patients the optimum dose may be as low as 0.5 mcg/kg. Resolution of symptoms begins within 2-3 weeks of initiating therapy, but requires 6-8 weeks after starting with given dose to reach steady-state plasma levels. Thyroid function tests (TSH levels) should be assessed 6-8 weeks after dosage adjustments are made and then every 6-12 months after euthyroid state obtained. Pregnancy may require increased dose due to increased levels of TBG (via elevated estrogen) and increased placental metabolism of T4-T3. Check levels upon pregnancy confirmation to guide potential dose change, monitor every 1-3 months  Average dose increase about 25%. Use caution in initiating therapy if underlying cardiac disease exists (smaller initial doses: 12.5-25 mcg, increase every 4-6 weeks) or in elderly patients who might have clinically silent cardiac disease. Myxedema coma (end state of untreated hypothyroidism) is an acute medical emergency (hyponatremia, hypoglycemia, hypothermia, shock, death possible). Large doses required with IV loading dose of T4 followed by daily IV dosing (oral absorption is poor). May also be treated with both T4 and T3 or T3 alone. Hydrocortisone may be required to prevent adrenal crisis as thyroid hormone may increase its metabolism

Answer 311

Preparations are of synthetic or animal origin, containing T4 only, T3 only, or combinations of T4 and T3. NOTE: Levothyroxine, the drug of choice for thyroid hormone replacement therapy, has a narrow therapeutic index. Thus, its pharmacokinetics and drug-drug interactions take on added importance.

Answer 312

Best in ileum and colon (bioavailability - T4: 65-85%, T3: 95%). Modified by binding-proteins (T4), food, intestinal flora; absorption may be impaired in severe myxedema (requiring use of parenteral formulation). Levothyroxine should be taken alone on an empty stomach, with a full glass of water, at least 30 minutes before breakfast. Drugs that can impair absorption of levothyroxine include: metal ions (antacids-Ca++-Fe++), ciprofloxacin, bile acid sequestrants, raloxifene, sucralfate, dietary fiber, soy. Managed by spacing levothyroxine dose 2 hours before or 4-6 hours after interacting drug.

Answer 313

Reversibly bound in plasma to thyroid-binding globulin (TBG) (free T4 = 0.04%, free T3 = 0.4%). Only the unbound hormone has metabolic activity. Thus, changes in either the concentrations of binding proteins OR binding affinity of hormone for protein will have major effects on TOTAL serum hormone levels. Drug effects on protein binding: Increase binding: estrogens/ SERMs/ Tamoxifen, methadone, clofibrate, 5-fluorouracil, heroin. Decrease binding: glucocorticoids, andorgens, salicylates, antiseizures meds (phenytoin, carbamazepine), furosemide. NOTE: Laboratory tests that measure only TOTAL hormone levels can be misleading since the pituitary gland responds to and regulates only circulating FREE hormone levels. I.e., levels of free hormone are minimally changed when total levels of hormone are altered by changes in binding to proteins, IF the hypothalamic-pituitary-thyroid axis is intact.

Answer 314

Activating step: T3 is the biologically active thyroid hormone. Most circulating T3 (80%) that is utilized by peripheral tissues is derived from deiodination of T4 in the liver via 5'-deiodinase. T3 in brain and pituitary is derived locally. The activity of this activating enzyme can be inhibited by various drugs and conditions. Drugs: glucocorticoids, beta antagonists, amiodarone, propylthiouracil. Conditions: acute and chronic illness, caloric deprivation, malnutrition, fetal/ neonatal period. Inactivating reactions: Include deiodination to reverse T3, deamination, decarboxylation, and conjugation to glucuronide or sulfate. Metabolic clearance rates may be increased in hyperthyroidism and with P450 enzyme induction [carbamazepine, digoxin, phenytoin, rifampin]; decreased by hypothyroidism. Half-life of T4 = 7 days; T3 = 1 day. Degree of protein binding is major factor accounting for pharmacokinetic differences between T3 and T4. Long half-life of T4 allows once-daily dosing and maintenance of a steady state despite occasional missed doses; fluctuation in plasma levels is less than 15% between doses

Answer 315

Synthetic T4 is preparation of choice for thyroid replacement. Advantages include: Stability, content uniformity, lack of allergenic foreign protein (relative to Thyroid USP); Low cost and long t1/2 allowing once-daily dosing (relative to T3). Can be given orally or IV. Generic formulations: No evidence to support superiority of any brand name product over any generic formulation and FDA allows pharmacists to switch patient from one product to another unless prescriber indicates “dispense as written”. However, in clinical practice, it is advisable to use the same levothyroxine product (whether brand or generic) throughout the treatment for any individual patient. Could be as much as 10% difference between “equivalent” products. Thyroid function tests should be checked 6 weeks after any change in levothyroxine product formulation.

Answer 316

synthetic T3. Well absorbed, rapid action, but shorter duration of effect that permits quicker dosage adjustments (at 1- 2 weeks intervals). NOT recommended for routine replacement due to short t1/2 (hence greater fluctuations in plasma levels between doses), high cost. Reasonable option to add if symptoms persistent on optimal levothyroxine therapy. Optimal T4 / T3 ratio is ~ 10:1. Should be avoided in patients with cardiac disease (increased thyroid hormone activity associated with greater risk of cardiotoxicity). Used in T3 suppression test (differentiate hyperthyroidism from euthyroidism)

Answer 317

4:1 mixture of T4 and T3. More expensive, no advantage since T4 conversion to T3 in periphery results in near normal ratio. Rarely required, not recommended. Combination therapy may cause increased incidence of low TSH concentrations and increased markers of bone turnover

Answer 318

Thyroid Strong (50% stronger). Dessicated porcine thyroid extract containing thyroxine and liothyronine; absorption characteristics and half-lives of T4 and T3 are same as in non-combination products. Disadvantages include: Variable T4/T3 ratio and content that may produce unexpected toxicities (generally higher T3:T4 ratio in swine than is desirable in humans); Protein antigenicity; Product instability. Less desirable than levothyroxine, use in hypothyroidism is not recommended

Answer 319

Toxicity due to excessive T4 directly related to plasma hormone level, thus is equivalent to signs and symptoms of hyperthyroidism. Children: Restlessness, insomnia, accelerated bone maturation and growth. Adults: Anxiety, heat intolerance, palpitation/tachycardia, tremors, weight loss and increased bowel movements. Can precipitate cardiac arrhythmias, angina pectoris, or myocardial infarction in patients with cardiac disease. Drug interaction with thyroid hormones: Will see increased adrenergic effect of sympathomimetics like epinephrine or decongestants

Answer 320

Most common form of hyperthyroidism is Graves’ disease that results from thyroid stimulation by autoantibodies (thyroid-stimulating antibody [TSAb]) that mimic stimulation by TSH. Other forms of hyperthyroidism result from TSH receptor-independent release of thyroid hormone including toxic uninodular and multinodular goiter (benign neoplasias that are autonomous from normal TSH regulation)

Answer 321

Multisystem clinical syndrome, predominant signs of metabolic and CVS hyperactivity. Weight loss (with hyperphagia), heat intolerance, insomnia, nervousness / anxiety, smooth-warm moist skin, muscle weakness, weakness. Signs of autonomic nervous system overactivity include: β-adrenergic (atrial tachycardia, tremor), sympathetic cholinergic (increased sweating), and parasympathetic (increased GI motility). Subclinical hyperthyroidism associated with increase in bone and cardiovascular disease incidence

Answer 322

Reduction of thyroid activity and hormone effects accomplished by: Modifying tissue response (symptomatic improvement) (beta-blockers, corticosteroids). Interfering with hormone production (thionamides, iodides). Glandular destruction (surgery, radioactive iodine)

Answer 323

Thionamides. Overview: Best if mild diseases, small gland, or young patient. Frequent relapses. Leaves gland intact (some patients avoid permanent hypothyroidism), but 60-70% relapse. Methimazole until remission (1-15 yrs). Beta-blocker for symptomatic relief until hyperthyroidism is resolved. Propranolol has advantage of blocking T4 -> T3 conversion; metoprolol/atenolol are β1 selective, longer t1/2. Methimazole generally preferred because of efficacy at lower doses, once-daily dosing, and lack of serious hepatotoxicity). Thionamides are treatment of choice for hyperthyroidism in pregnancy. Both drugs cross placenta but PTU is thought to be safer in pregnancy (increased protein-binding) and has not been associated with teratogenic effects.

Answer 324

Absorption: Rapid, PTU incomplete (50-80%), methimazole 100% absorbed. Distribution: Both cross placenta and are concentrated by fetal thyroid requiring caution if used in pregnancy; PTU more protein-bound, so crosses placenta less readily and less secretion into breast milk (higher amounts with methimazole). Elimination: Relatively short half-lives (PTU 1-2 hrs, methimazole 5-13 hrs), but drugs are accumulated in thyroid and durations of action are longer (PTU: 12-24 hrs; methimazole: 40 hrs). Thus, PTU can be given 2-3 times daily and methimazole once daily.

Answer 325

Prevent T4 / T3 synthesis by blocking iodine organification and coupling of the iodotyrosines. High doses of PTU will block peripheral conversion of T4 to the more active T3. Synthesis (not release) inhibited so requires 3-4 weeks to deplete T4 stores. Beta-blockers can be used to alleviate symptoms (esp. palpitations and tachycardia) until thionamide takes effect. NOTE: These agents only work in thyrotoxicosis [high RIU] due to excess thyroid hormone production (NOT thyroiditis [low RIU])

Answer 326

Some clinical resolution of thyrotoxicosis within 2 weeks and biochemical resolution in about 6 weeks. Follow-up testing of thyroid function at 4-6 week intervals until stabilized. Patients with small goiters, low levels of anti-TSH receptor antibodies, and mild-to-moderate hyperthyroidism, achieve remission within 12-18 months on thionamide alone. About one-third of patients experience lasting remission, but overall recurrence rate of Graves’ hyperthyroidism is 50-60%.

Answer 327

Adverse reactions (3-12%); most common pruritic rash, gastric intolerance, arthralgias. Most dangerous is agranulocytosis (0.3-0.6%). Routine measurement of complete blood counts (CBC) is controversial, but should be obtained if sore throat / fever are present. Hepatotoxicity with PTU is rare (1:1000 in children and adults) but severe enough (deaths and liver transplants [3rd leading drug cause]) to raise concerns about routine use. If allergies occur, cross-sensitivity to the agents is 50%, thus switching is not recommended

Answer 328

SSKI [potassium iodide], Lugol’s solution [potassium iodide and iodine]. Used since 1920’s, but rarely used as sole therapy today. Mechanism of action. Complex action, transient effect. High doses (> 6 mg daily) inhibit hormone synthesis (via elevated intracellular [I-]) and hormone release (via elevated plasma [I-]) through inhibition of thyroglobulin proteolysis. Effect occurs rapidly, thus iodide is useful in patients with severe thyrotoxicosis and in thyroid storm. Disadvantages include: variable effects (some patients show no response), rapid reversal of inhibitory effect when withdrawn, and potential that the iodide may be used to produce new thyroid hormone and worsen hyperthyroidism

Answer 329

Should not be used alone, gland “escapes” iodide block in 2-8 weeks and can see exacerbation of thyrotoxicosis upon withdrawal. Can delay onset of thionamide therapy (due to initial action to increase intraglandular stores), so initiate I- therapy after onset of thionamide effect occurs. Also used to decrease size and vascularity of hyperplastic gland prior to surgery (given for 10 days prior to surgery)

Answer 330

Uncommon, reversible (acneiform rash, rhinorrhea, metallic taste, swollen salivary glands). Selective accumulation in salivary glands

Answer 331

Preferred in patients over 21 and becoming more common in patients

Answer 332

(subtotal, treatment of choice if large gland). Rarely used today because radioactive iodine works so well that the risks of general anesthesia and parathyroid / recurrent laryngeal nerve damage become relatively great. Advantage of rapid, permanent cure of hyperthyroidism. Treated with antithyroid drugs until euthyroid (6 weeks) plus iodine several days prior to surgery. 50-60% of patients require thyroid supplementation after surgery (iatrogenic hypothyroidism). Can be utilized in 2nd trimester of pregnancy if needed

Answer 333

Sudden, acute exacerbation of thyrotoxicosis; may occur in a non-compliant, incompletely treated, or undiagnosed patient with hyperthyroidism who experiences an acute stress (infection, surgery, or trauma). Symptoms include fever, flushing, sweating, tachycardia / atrial fibrillation, high output heart failure, delirium, coma. Reflected in hypermetabolism and excessive adrenergic activity

Answer 334

control of symptoms, inhibition of release of preformed thyroid hormone, and block of conversion of T4 to T3. Propranolol, IV or po, controls cardiovascular manifestations (also blocks T4 to T3 conversion). Release of hormones slowed by sodium iodide IV, potassium iodide drops orally. Synthesis of hormones blocked by PTU as well as T4 to T3 conversion (but not by methimazole). Hydrocortisone protects against shock, blocks conversion of T4 to T3, and may modulate the immune response that lead to exacerbation of thyrotoxicosis

Answer 335

Levothyroxine [Synthroid, Levothroid, Levoxyl, Unithroid, plus numerous generics, Liothyronine [Cytomel], Liotrix [Thyrolar], Thyroid USP [Armour Thyroid]

Answer 336

Thionamides: Methimazole [Tapazole], Propylthiouracil (PTU). Iodides: SSKI [potassium iodide], Lugol’s solution [potassium iodide and iodine] Radioactive iodine (131I) [Iodotope]

Answer 337

Beta- Blockers: Propranolol [Inderal], Atenolol [Tenormin], Metoprolol [Lopressor] Hydrocortisone [Solu-Cortef]

Answer 338

Depression is 2–3 Dmes more common in diabe/cs than in the general populaDon. Results in poorer glycemic control and increased diabetic complications. Increased type 2 diabetes in pa/ents with bipolar disorder. Some due to the increased obesity in bipolar paDents, some iatrogenic due to the risk of weight gain with most mood stabilizers. Weight gain is associated with obstrucDve sleep apnea which also worsens insulin resistance.

Answer 339

Psychiatric symptoms are common in hyper-adrenalism and may appear before physical signs. Depression is most common, but anxiety, hypomania /mania, psychosis, and cognitive dysfunction all occur.

Answer 340

Symptoms in hyperparathyroidism directly reflect serum calcium. It is common for a person with mild-to-moderate hypercalcemia (10–14 mg/dL) to experience depression, apathy, irritability, lack of ini/a/ve, and lack of spontaneity. Severe hypercalcemia (>14 mg/dL) can result in delirium, psychosis, catatonia, or lethargy, and may progress to coma. In mild hypocalcemia, paDents have anxiety, paresthesias, irritability, and emo/onal lability. Mania, psychosis, tetany, and seizures are common in severe hypocalcemia.

Answer 341

primary (adrenal destruction) or iatrogenic (suppression of ACTH by corticosteroid therapy). Psychiatric symptoms: apathy, anhedonia, fa/gue, depression.

Answer 342

excess GH secreDon by a pituitary tumor. Psychiatric symptoms include mood lability, personality change, and depression

Answer 343

The most frequently occurring thyroid diseases in adults are autoimmune disorders: The most common cause of hypothyroidism is Hashimoto’s thyroiditis. The most frequent cause of hyper thyroidism is Graves’ disease. The brain is sensitive to thyroid hormone. The thyroid is important for both the maturation of the central nervous system and the maintenance of homeostasis. Receptors are located within networks throughout the brain. High concentrations of T3 receptors are found in the amygdala and hippocampus. These receptors, in turn, are able to influence neural activity. The effects of thyroid dysregulation on brain funcDon are variable at different stages of life. Interactions of the thyroid and neurotransmiber systems, primarily NE, 5HT and DA which help regulate mood and behavior. The prevalence of hypothyroidism ranges from 0.5% to 18%, depending on the study population. In general, hypothyroidism affects 4% to 10% of women, increasing with age. 10% females >60 F:M, 8:1. A significant proportion of individuals have asymptomatic chronic autoimmune thyroiditis, and 8% of women (10% of women over age 55 years, 20% >60) and 3% of men have subclinical hypothyroidism. The pathophysiology of hypothyroidism includes hypothalamic or pituitary disease, tissue resistance to thyroid hormone, and disorders directly affecting the thyroid gland. ~40% of clinically hypothyroid patients have symptoms of depression. Forgeiulness, fatigue, mental slowness, inabention, emotional lability, depression. Can mimic dementia. Perceptual changes: alterations of taste, hearing, and vision. Psychosis (myxedema madness), delusions, visual & auditory hallucinations typically develop aker physical symptoms, oken aker a period of years or months. Disorders of thought may occur in patients with clinical or subclinical hypothyroidism, which suggests that psychosis may be unrelated to the absolute degree of thyroid hormone deficit. Symptoms are usually reversed with return to euthyroid state, although severe hypothyroidism can result in irreversible dementia when not treated in time.

Answer 344

The prevalence of subclinical hypothyroidism in US adults who don’t have known thyroid disease is approximately 4–8%; this increases with age and subclinical hypothyroidism is present in up to 20% of women aged over 60 years. Subclinical hypothyroidism is a risk factor for 1. depression, 2. treatment resistant depression, 3. and is oken found in rapid cycling bipolar disorder. In subclinical hypothyroidism, the TSH is elevated (>4.0 μIU/mL) but T4 is low or normal and the patient has few or no symptoms. Increased serum TSH may be the first abnormality to appear in early thyroid failure i.e. subclinical hypothyroidism. Progression to clinical hypothyroidism occurs in about 3% to 18% of patients per year. Therefore, thyroid indices need to be repeated routinely.

Answer 345

Only 35–45% of depressed patients achieve complete remission with antidepressants. The rest are initially treatment resistant (25%) or have a partial response (15%). 7–15% intolerant to medications. Par/al response – if not addressed - can lead to increased recurrence, treatment resistance, suicide, increased health-care utilization, and poor social and work functioning. Approximately 50% of patients with treatment-resistant depression in one study had evidence of subclinical hypothyroidism compared with 8% to 17% in an unselected population of depressed patients. Treatment-resistant depression responds to thyroid hormone supplementation without lab evidence of thyroid malfunction. Clinical and subclinical hypothyroidism may adversely affect the course of bipolar disorder especially recovery from the depressive phase of the illness. At what point to treat with thyroid replacement in subclinical hypothyroidism remains controversial. 5-8% of all pregnancies are followed by postpartum thyroiditis which may result in permanent hypothyroidism. Thus, some post-partum moodiness & depressions may be due to thyroid disease. Thyroiditis symptoms are initially due to hyperthyroidism, then hypothyroidism. Generally mothers recover to the euthyroid state. But, hypothyroidism does not always resolve. May be confused with post-partum depression, Graves’ Disease relapse. Sheehan syndrome (hypo-pituitarism due to postpartum pituitary necrosis) is rare. Approximately 60% of thyrotoxic patients have an anxiety disorder. Between 31% and 69% have a depressive disorder. Patients who become manic when thyrotoxic usually have an underlying mood disorder or positive family history for bipolar illness.

Answer 346

Calcium plays two important physiological roles. The first is a structural role, since it is a major constituent of the mineral matrix of bone. Bone calcium also serves as a reservoir for maintenance of plasma calcium. The second is a biochemical role. Calcium is an essential regulator of excitation-contraction coupling, stimulus-secretion coupling, blood clotting, membrane excitability, cellular permeability and other metabolic functions.

Answer 347

The metabolic functions require that the plasma calcium be maintained within the narrow limits of 8-10 mg/dl (~2.5 mM). Plasma phosphate is maintained between 3 and 4 mg/dl (~1.1 mM). The structural functions require that overall calcium and phosphate balance be maintained within the body. IN = OUT, and BALANCE is achieved, as long as the distribution of calcium in three compartments is maintained. There is in addition, a fast exchange of up to 20 g/day between the ECF and labile bone, mediated by osteocytes.

Answer 348

Calcium is found within three major compartments: 1. Bone-99% of body calcium in the form of hydroxyapatite. 2. Intracellular compartment-contains a total of 10 g of calcium. Free cytosolic calcium is ~50-100 nM in resting cells. This level of cytosolic calcium is maintained by intracellular mobile calcium buffers, compartmentalization into ER calcium stores, by an ATP linked calcium pump and a Na/Ca antiporter. 3. Extracellular fluid-includes blood and interstitial spaces that are in equilibrium. Total concentration, 2.5 mM, ~1/2 is free, and filterable by the kidney, 10% as salts (bicarbonate and phosphate) which can also be filtered by the kidney and remainder bound to albumin. The kidney filters about 10g of calcium/day (60mg/l x 170L/day). About 98% of this is reabsorbed. Homeostasis refers to the minute-to-minute maintenance of free calcium levels. Free calcium levels are a regulated variable.

Answer 349

Phosphate also plays a structural role, since it is part of the mineral matrix of bone. In addition, it is a common intracellular buffer. It is required for phosphorylation reactions, which transfer energy from one compound to another as well as regulate cellular functions. About 85% of serum phosphate is free in the ionized active form (as HPO4-2 and H2 PO4-2). Normal serum phosphate levels are about 3-4 mg/dl. Like calcium, there is a net phosphate balance in the body between the various compartments.

Answer 350

PTH is produced by the parathyroid gland. It contains 84 amino acids but only the first 34 are required for activity. It is synthesized as a larger pre-prohormone of 115 amino acids. The first 25 are cleaved in the ER and another 6 are cleaved in the Golgi. PTH leads to increased plasma calcium by several means: BONE: Rapid effect-increased efflux of labile bone calcium, not accompanied by phosphate Slow effect-increased bone remodeling, releases both calcium and phosphate (seen mainly in pathological conditions). KIDNEY: Increased calcium reabsorption in distal tubule Decreased phosphate reabsorption. Increased synthesis of 1,25 (OH)2 Vitamin D. GI TRACT: Indirect via Vitamin D, which enhances calcium absorption-requires 1 day. N.B. PTH thus has complex effects on calcium and phosphate levels in the blood. The net consequence of PTH action is to increase serum calcium and decrease serum phosphate levels. Regulation of PTH secretion: PTH secretion is stimulated by a fall in the free ionized calcium in the plasma and inhibited by a rise. Since it acts to increase plasma calcium, this constitutes a classical negative feedback loop with plasma calcium as the regulated variable and the parathyroid gland as the sensor.

Answer 351

Calcitonin is produced by parafollicular or C cells of the thyroid. It is a 32 amino acid peptide. It is secreted in response to elevated calcium as well as certain GI hormones such as gastrin, cholecystokinin, secretin and glucagon. It acts on bone to decrease efflux of labile bone calcium. The level necessary to produce this effect is rather high and many have questioned its role in maintaining normal calcium balance. However, it is useful in therapeutically in slowing down high turnover bone disorders.

Answer 352

Synthesis and secretion: 7-dehydrocholesterol in skin is acted on by sunlight to produce Vitamin D (biologically inert). In the liver, one hydroxyl group is added to form 25-OH Vitamin D. In the kidney, a second hydroxyl is added in a reaction catalyzed by 1- hydroxylase yielding 1,25 (OH)2 Vitamin D, the most active form. The kidney also has 24-hydroxylase activity which leads to the production of 24,25 (OH)2 Vitamin D which is inactive. 1,25 (OH)2 Vitamin D is mostly transported in the blood bound to transcalciferin.

Answer 353

The major action of 1,25 (OH)2 Vitamin D is on the GI tract where it eventually interacts with a nuclear receptor increasing the synthesis of specific mRNAs and then proteins. One of these proteins is a calcium binding protein that appears in the lumen of the intestine. It is not clear exactly how both calcium and phosphate transport are promoted, but it is possible that pinocytosis of this binding protein is involved. 1,25 (OH)2 Vitamin D mobilizes bone in a way similar to PTH, possibly simply by sensitizing the bone to PTH action. In recovery from chronic Vitamin D deficient states (e.g., rickets) however, the improvement in plasma calcium brought about by increased calcium and phosphate absorption leads to increased calcium deposition in bone. The physiologic significance of the mobilization of bone calcium by 1,25 (OH)2 Vitamin D is not at all clear.

Answer 354

Several factors converge on the renal hydroxylase reactions to influence the synthesis of 1,25 (OH)2. 1,25 (OH)2 Vitamin D negatively affects the 1-hydroxylase; in this was, 1,25 (OH)2 Vitamin D acts in a negative feedback loop and regulates its own synthesis. Often, the two hydroxylase enzymes of the kidney, 1-hydroxylase and 24- hydroxylase, are reciprocally regulated by influencing factors. For example, increased levels of PTH positively and negatively affect the activities of 1-hydroxylase and 24- hydroxylase, respectively. High PTH will lead to increased levels of 1,25 (OH)2 Vitamin D, which then acts on the GI tract to increase calcium absorption. In this way, PTH and 1,25 (OH)2 Vitamin D act synergistically. In contrast, decreased levels of phosphate positively and negatively affect the activities of 1-hydroxylase and 24-hydroxylase, respectively. Thus, if plasma phosphate falls, 1,25 (OH)2 Vitamin D synthesis is increased; in turn, the increased levels of 1,25 (OH)2 Vitamin D will act on the GI tract and promote increased phosphate absorption and return of plasma phosphate levels to normal. Cyclic AMP is thought to be involved in mediating influences of PTH and phosphate on 1-hydroxylase and 24-hydroxylase activities.

Answer 355

The short term (minute-to-minute) regulation of blood calcium (homeostasis) is carried out primarily by PTH acting to mobilize calcium into the plasma when levels begin to become low. Calcitonin may be useful in increasing the rate of storage of an acute calcium load. PTH will mobilize calcium movement from the bone compartment into the blood. If this is continued for a prolonged time, calcium balance is affected negatively.

Answer 356

Vitamin D is the important hormone in the long-term regulation of body calcium and phosphate stores by regulating the intestinal absorption of these minerals. A simple way to consider this is if IN

Answer 357

In primary hyperparathyroidism, increased PTH increases calcium levels in plasma and urine (leading to renal stones). The effects of hypercalcemia include vague or overt symptoms of muscle weakness, depression and GI disorders. In severe cases, bone demineralization leads to bone pain and fractures. Secondary hyperparathyroidism can result from any disorder where plasma calcium is low such as rickets and renal failure.

Answer 358

The major symptom of the decreased plasma calcium caused by a lack of PTH is increased neuromuscular excitability that can cause muscle cramps, seizures as well as mental changes. One test for hypoparathyroidism is to tap the facial nerve, which evokes facial muscle spasms, called Chvostek’s sign). There is a PTH dependent decrease in calcitriol levels causing decreased serum calcium levels due to less absorption from intestines and less reabsorption through the kidneys. Bone demineralization is usually not a problem because of increased serum phosphate (due to increased reabsorption of phosphate from kidneys). It is usually treated with Vitamin D and calcium supplements.

Answer 359

This condition is called rickets in children and osteomalacia in adults. Rickets can lead to severe skeletal deformities whereas symptoms of osteomalacia can include bone pain and pathological fractures. Dietary lack of Vitamin D is rare in the USA because of supplementation of milk. It can be seen in certain liver diseases and renal dysfunction, both of which interfere with synthesis of the active hormone.

Answer 360

This results from ingestion of very large quantities of Vitamin D and can cause hypercalcemia with attendant symptoms described above in addition to pathological calcification of soft tissues.

Answer 361

Key hormonal regulators that effect Ca Homeostasis are: PTH, 1,25(OH)2D, and Calcitonin; of course many others can play a role, especially at specific times in the life cycle. Serum Ca is maintained in a very tight range at all costs. Absorption occurs passively in duodenum, jejunum, ileum; Active transport (effected by habitual intake via vitamin D) occurs in the duodenum. Enhancers of Absorption: Vitamin D; physiological demand; lactose; Gastric Acidity; protein. Impair Absorption: Vitamin D deficiency, Steatorrhea, Oxalic and Phytic Acid, Gastric Alkalinity. "Deficiency" acutely is a rare occurrence in adults because of the body's ability to maintain serum levels; with low Ca intakes, however, because maintenance of serum [Ca] is at the expense of bone Ca. Thus development of deficiency is a long-term, “silent” process.

Answer 362

Premature infants: 3rd trimester period of rapid bone mineral accretion; preterm infants at risk for “osteopenia of prematurity”. Adolescence: hormonal milieu during puberty favors calcium absorption and bone deposition; ~ 50% of total adult bone mineral mass is accrued during adolescence. After skeletal “maturity,” esp. peri-menopause: associated with relatively high requirements, increased losses, and frequently with low intake. Pregnancy and lactation: physiologic responses compensate for increased Ca demand so dietary requirements are not increased. Post-Bariatric Surgery

Answer 363

Lifetime calcium intake: Adolescent females average ~80% of recommended amount (1300 mg/d), Adolescence = key time for bone mineral accretion, Limited ability to adapt to low Ca intake, Lifetime low intake of dairy products associated with increased osteoporosis, Optimal calcium intake allows bone density to reach genetic potential. Protein intake: increased urinary calcium excretion (in some studies low Ca:protein intake associated with lower bone density); net effect may be negligible, but controversial. Phosphate intake: increased PTH, increased bone resorption. Vitamin D – critically linked to calcium absorption: Status frequently suboptimal, esp in elderly; 25(OH)D levels (+) correlated w/ BMD in middle-aged & elderly women; Target serum 25(OH)D level >30 ng/ml to reap skeletal benefits. Vitamin K - co-factor w/ osteocalcin & other bone forming proteins. Sodium intake – high Na++ intake -> increased urine Ca++ excretion. Vegetarian diet, w/ high fruit & veg intake (& K+, Mg++ ) associated w/ bone mass preservation, but if diet is low in dairy & high in sodium, not likely to be positive effect h) Caffeine – increases urine Ca++ excretion (small effect x lifetime). Whole Diet pattern: DASH may have benefits beyond increased Ca intake

Answer 364

Exercise: weight-bearing; muscle mass directly related to bone mass; Mechano-sensors in bone stimulate osteoblasts. Smoking. Alcohol - depresses osteoblasts

Answer 365

glucocorticoids, immobility, gastrectomy. Maintenance of regular menses. Chronic illnesses – associated w/ malabsorption, chronic systemic inflammation

Answer 366

Achieve “peak bone mass” when you can – ie, adolescence. Weight bearing activity. Maintain good calcium intake over lifetime. Avoid excessive alcohol and tobacco. Minimize practices that enhance calcium loss &/or bone resorption. Maintain healthy diet including other cofactors that support Bone Health. DASH diet: reduction in Na+ not only associated with reduced blood pressure but also with reduced Ca++ excretion and bone turnover.. Supplement (only) when necessary. Results of meta-analysis supports benefits of calcium supplementation ± Vit D supplementation on fracture reduction and reduced bone loss in subjects > 50 yr. Mild caution re Ca supplementation: Ca supplementation (w/o Vit D) associated with increased risk of myocardial infarction

Answer 367

The four, circular parathyroid glands are embedded within the posterior surface of the thyroid gland. Cells of the parathyroid gland include chief cells, which are often described as having a water-clear appearance and produce parathyroid hormone (PTH), and oxyphil cells, whose function is unknown. Histologically, the parathyroid glands are different from the thyroid. They contain densely packed cells, compared to the follicular structure of thyroid tissue.

Answer 368

PTH's three major functions are to increase serum [Ca2+], decrease serum [phosphate], and increase urine [phosphate]. PTH increases bone resorption of calcium and phosphate: PTH binds to receptors on osteoblasts, which secrete macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANK-L) in response. RANK-L binds RANK on osteoclast precursors which promotes their differentiation into mature osteoclasts that are capable of bone resorption and the release of calcium. Osteoblasts and osteoclasts must be 'tethered' in vitro for the resorptive effects of PTH to be observed. Sources are conflicting on whether PTH binds directly to osteoclasts. Increased hydroxyproline excretion reflects bone resorption due to the actions of PTH. PTH indirectly increases intestinal absorption of Ca2+. PTH stimulates 1α-hydroxylase in the kidney, which increases 1,25-(OH)2 vitamin D production. Vitamin D increases intestinal absorption of Ca2+. PTH increases renal Ca2+ reabsorption in the distal convoluted tubule. PTH decreases kidney reabsorption of phosphate in the proximal convoluted tubule, leading to an increase in phosphate excretion (phosphaturic effect). To remember this, use the mnemonic: PTH = Phosphate Trashing Hormone. PTH action at the proximal tubule results in increased urinary cAMP. PTH-related peptide (PTHrP) functions like PTH, and is commonly increased in malignancies (paraneoplastic syndromes). PTH release is regulated primarily by serum Ca2+ and Mg2+ concentrations. Phosphate and vitamin D also modulate PTH levels. A decreased free serum Ca2+ causes increased PTH secretion, by acting on Ca2+-sensing receptors on chief cells. Mild decreases in Mg2+ stimulate PTH secretion, while severe decreases in Mg2+ inhibit PTH secretion and produce symptoms of hypoparathyroidism. High plasma phosphate concentration causes the ionized calcium concentration to fall, which stimulates PTH secretion. High phosphate levels also directly stimulate PTH secretion. Vitamin D inhibits the transcription of PTH and decreases PTH secretion.

Answer 369

Diarrhea. Aminoglycosides. Diuretics (loop and thiazide). Alcohol abuse

Answer 370

Hypoparathyroidism is most commonly an inadvertent consequence of surgery. It can also be caused by: Autoimmune destruction of the parathyroid glands (autoimmune hypoparathyroidism); DiGeorge syndrome. The clinical manifestations of hypoparathyroidism are related to the severity of hypocalcemia, classically presenting as tetany (decreased serum ionized calcium concentration results in neuromuscular irritability). Other manifestations of hypocalcemia include: Mental status changes; Intracranial calcifications (basal ganglia); Ocular disease; Cardiovascular complications. Classic physical exam findings indicating hypocalcemia include: Chvostek sign- refers to the contraction of facial muscles that follows tapping along the course of the facial nerve. Trousseau sign- refers to carpal spasms following the occlusion of the brachial artery (e.g. blood pressure cuff inflated around the triceps).

Answer 371

Plasma Ca2+ exists in three forms: Free ionized (45%), Bound to albumin (40%), Bound to anions (15%). Free, ionized Ca2+ is biologically active. An increase in blood pH leads to decreased free calcium levels in the blood: Albumin and other calcium-binding proteins have negatively charged binding sites for positively charged ions, such as Ca2+ and H+. A decrease of H+ ions in the blood (increased pH) leads to increased protein binding of ionized calcium and decreased free calcium levels. This manifests clinically as hypocalcemia (e.g. cramps, pain, paresthesias, carpopedal spasm).

Answer 372

Diuretics can alter calcium levels. Loop diuretics decrease calcium reabsorption in the thick ascending limb of the nephron, while thiazides increase its reabsorption in the distal convoluted tubule. To remember this difference, use the mnemonic "The loop loses calcium". Active reabsorption by the Na+/K+/2Cl- cotransporter leads to a backleak of K+. The positive lumen potential created by this backleak will induce paracellular reabsorption of Mg2+ and Ca2+. Blocking the Na+/K+/2Cl- cotransporter with a loop diuretic will decrease calcium reabsorption into the blood. Thiazide diuretics block the apical Na+/Cl- symporter, and as a result intracellular sodium is reduced. This ramps up the activity of the basolateral Ca2+/Na+ exchanger (to increase Na+ pumped into the tubular cell), which will increase calcium reabsorption into the blood.

Answer 373

Cinacalcet increases the sensitivity of the Ca2+-sensing receptor (CaSR) in the parathyroid gland to circulating Ca2+. This decreases the secretion of parathyroid hormone. Cinacalcet is indicated in the treatment of: Hypercalcemia due to primary hyperparathyroidism (e.g. parathyroid carcinoma). Secondary hyperparathyroidism in chronic kidney disease patients. Cinacalcet may cause hypocalcemia.

Answer 374

There are two types of vitamin D: D2 (ergocalciferol) is ingested from plants, and D3 (cholecalciferol) is obtained through animal-product consumption, or formed in sun-exposed skin.

Answer 375

Good dietary sources of vitamin D3 include: Egg yolk, Fish oil, Fortified milk, Liver. D3 is made endogenously from its precursor (7-dehydrocholesterol) in the stratum basale of the skin, upon exposure to sunlight. 25-OH D3 is the storage form of vitamin D, while 1,25-(OH)2D3 is the active form of vitamin D. When its precursors are obtained from the diet (versus the skin), synthesis and appropriate function of the active form of vitamin D (1,25-OH2-cholecalciferol) requires a functional GI tract, liver, and kidney. D2/D3 absorbed from the GI tract is converted to 25-OH-cholecalciferol (aka calcifediol) by hepatic 25-hydroxylase in the liver. Next, 25-OH-cholecalciferol is converted to 1,25-(OH)2-cholecalciferol (aka calcitriol) by 1-α hydroxylase within the kidney (specifically, the proximal renal tubule cells).

Answer 376

The actions of Vitamin D produce a coordinated increase in both [Ca2+] and [phosphate] in the ECF in order to form a solubility product that favors the mineralization of bone. The effects of vitamin D in the intestines include increasing the absorption of Ca2+ via induction of vitamin-D dependent Ca2+-binding protein (calbindin-D-28K), and increasing the absorption of phosphate. Vitamin D weakly stimulates renal calcium reabsorption by increasing the number of calcium pumps. The bone is a major target of vitamin D. Its primary function is to facilitate the formation of bone (mineralization). In the setting of excess vitamin D (or hypocalcemia), vitamin D causes an increase in resorption of Ca2+ and phosphate.

Answer 377

The regulation of Vitamin D depends on the activity of renal 1α-hydroxylase. Factors that increase 1α-hydroxylase activity include: Low serum calcium, Low serum phosphate, High parathyroid hormone (PTH)1,25-OH2 vitamin D inhibits its own production by inhibiting 1α-hydroxylase (negative feedback). Vitamin D also inhibits the transcription of PTH which activates 1α-hydroxylase.

Answer 378

A lack of precursor molecules from a lack of sunlight or fat malabsorption. A lack of enzymes from liver failure and kidney failure. Increased deactivation of vitamin D in alcoholism (induction of CYP enzymes). Vitamin D deficiency causes rickets in children and osteomalacia in adults.

Answer 379

Vitamin D excess is seen in granulomatous diseases (notably sarcoidosis) due to the 1-α hydroxylase activity of activated macrophages. Signs of vitamin D excess include hypercalcemia and hypercalciuria, while symptoms include a loss of appetite and stupor.

Answer 380

Hypercalcemia is defined as a total serum calcium > 10.3 mg/dL if albumin levels are normal, or an ionized calcium level > 5.2 mg/dL. Hypercalcemia develops as a result of two factors: increased calcium ECF levels and a decrease in renal clearance of calcium. Hypercalcemia may be the result of endocrinopathies, malignancies, granulomatous disease, and pharmacological side effects. 90% of cases of hypercalcemia are the result of primary hyperparathyroidism or malignancy.

Answer 381

Primary hyperparathyroidism is the primary cause of hypercalcemia among ambulatory patients. Causes include a benign adenoma of a parathyroid gland (∼85%), parathyroid hyperplasia (∼15%), and parathyroid carcinoma (∼1%). Characterized by elevated Ca and decreased PO4. Malignancy is the most common cause of hypercalcemia among hospitalized patients. Hypercalcemia can result from osteoclast stimulation by tumor cells, PTHrP (PTH-related peptide) from tumor cells, and calcitriol produced by tumor cells. Malignancies associated with hypercalcemia include: Squamous cell lung cancer (PTH-rP), Multiple myeloma (lysis of bone by tumor cells and release of osteoclast-activating factor), Leukemias, Lymphomas

Answer 382

Hypercalcemia secondary to hypervitaminosis D can result from exogenous vitamin D exposure or increased production of calcitriol in diseases with chronic granulomatous inflammation (e.g. tuberculosis and sarcoidosis) and Hodgkin lymphoma.

Answer 383

Pharmacological causes of hypercalcemia include: Milk-alkali syndrome is the acute onset of hypercalcemia, alkalosis, and renal failure that results from consuming large amounts of antacids that contain calcium. Vitamin D intoxication. Thiazide diuretics (inhibit renal excretion). Lithium (may increase PTH levels). Other rare causes of hypercalcemia include adrenal insufficiency, Paget’s disease (osteoclastic bone reabsorption), familial hypocalciuric hypercalcemia and hyperthyroidism.

Answer 384

While hypercalcemia is defined as serum calcium > 10.3 mg/dL, symptoms generally do not appear until levels are > 12 mg/dL. Even then, primary hyperparathyroidism is often asymptomatic and discovered incidentally. Hypercalcemia-induced renal disease manifests with polyuria and nephrolithiasis. Gastrointestinal symptoms of hypercalcemia include constipation, anorexia, vomiting, and occasionally signs of pancreatitis. Hypercalcemia can cause neurologic symptoms of weakness, fatigue, confusion, stupor, and even coma. If hypercalcemia is the result of increases osteoclast activity, it can result in osteopenia, fractures, and if severe enough osteitis fibrosa cystica. Osteitis fibrosa cystica results in “brown tumors” of the bone and bone marrow replacement with fibrous tissue. EKG findings in hypercalcemia include shortened QT interval, and if severe enough, AV block. Mnemonic: Stones (nephrolithiasis), Bones (bone aches and pains d/t osteitis fibrosa cystica), Moans/groans (muscle pain, constipation, peptic ulcer disease), Psychiatric overtones (depression, fatigue, anorexia, sleep disturbances, lethargy)

Answer 385

Most often, a diagnosis of hypercalcemia can be made by a thorough history and physical and minimal laboratory testing. Since calcium levels are influenced by albumin levels, ionized calcium or a corrected calcium should be measured. This is because only the ionized calcium is metabolically active. Calcium levels decrease by 0.8 mg/dL for every 1.0 g/dL decrease in albumin. As such, the equation for finding a corrected (aka adjusted) calcium level is: [Ca2+]corrected = [Ca2+] + {0.8 X (4.0 – [Albumin]. [Ca2+]corrected is the corrected serum level of ionized (active) calcium. [Ca2+] is the measured concentration of total calcium. 4.0 is the normal value of serum albumin. [Albumin] is the measured level of albumin. To determine the etiology of hypercalcemia, first, serum PTH levels must be measured. Elevated levels of calcium should result in feedback inhibition of PTH. Hypercalcemia with elevated PTH suggests primary hyperparathyroidism and, less frequently, tertiary hyperparathyroidism. If serum calcium is elevated and PTH is LOW, PTHrP is measured to look for possible malignant causes of the hypercalcemia. If a patient is hypercalcemic with normal PTH and PTHrP levels, elevated vitamin D is investigated. Elevated vitamin D and normal PTH/PTHrP is seen in: Granulomatous disorders, Exogenous vitamin D overdose, Acromegaly. Patients with familial hypocalciuric hypercalcemia may have normal or slightly elevated PTH, making this condition difficult to distinguish from primary hyperparathyroidism. The main distinguishing feature of this condition is the low urine calcium excretion (as opposed to the normal or high calcium excretion seen in primary hyperparathyroidism). Serum phosphorus levels are also helpful in identifying the etiology of hypercalcemia. Primary hyperparathyroidism should result in decreased phosphorus levels while excess vitamin D can result in increased phosphorus levels.

Answer 386

Correction of hypercalcemia is based on severity, as indicated by the serum calcium level. Mild hypercalcemia 14 mg/dL. Correction of hypercalcemia should begin with correction of hypovolemia with 0.9% saline and maintenance of adequate hydration. Hypovolemia prevents normal calciuresis, so correcting volume depletion will increase renal calcium excretion. NOTE: Fluid administration is the most important step in treating hypercalcemia. In the event of moderate hypercalcemia, bisphosphonates may be used in addition to normal saline. Bisphosphonates are particularly excessive in treating hypercalcemia from increased bone reabsorption. Bisphosphonates decrease liberation of calcium from bone by inhibiting osteoclast function. Examples of bisphosphonates include pamidronate, zoledronate, and etodrinate. Calcitonin may be used in addition to saline and bisphosphonate therapy should serum calcium levels rise above 14 mg/dL. Calcitonin is antagonistic to the action of PTH and can decrease bone resorption of calcium. One benefit of calcitonin is that it is safe in renal failure. Loop diuretics can be used in patients with renal or heart failure, at risk for volume overload. Loops lose calcium (vs. thiazide diuretics that increase calcium retention). Glucocorticoids can decrease serum calcium levels in patients who are hypercalcemic due to malignancy or granulomatous disease. Gallium nitrate inhibits bone resorption with the same efficacy of bisphosphonates, but it is nephrotoxic and contraindicated if creatinine is > 2.5 mg/dL.

Answer 387

Multiple endocrine neoplasias (MEN) are a group of genetically inherited diseases that result in proliferative lesions of multiple endocrine organs. All three MEN syndromes are associated with autosomal dominant inheritance. MEN-2 is subclassified into three distinct syndromes: MEN-2A, MEN-2B, Familial medullary thyroid cancer

Answer 388

MEN-1, aka Wermer syndrome, is characterized by abnormalities involving the parathyroid, pancreas and pituitary. The involvement of these endocrine organs can be remembered as the "3 Ps" or the mnemonic “Para-Pan-Pit”: The most common parathyroid manifestation of MEN-1 is primary hyperparathyroidism. Parathyroid abnormalities include hyperplasia (monocolonal) and adenomas. Pancreatic endocrine tumors include gastrinomas (leading to Zollinger-Ellison syndrome) and insulinomas. MEN pancreatic tumors are usually aggressive, and are the leading cause of morbidity and mortality in MEN-1 patients. Pituitary adenomas are most frequently prolactinomas, although some patients develop growth hormone-secreting tumors (leading to acromegaly). MEN-1 syndrome is caused by mutations in the MEN-1 tumor suppressor gene, which encodes a poorly-understood product called menin, involved in transcription regulation. This gene is found on chromosome 11.

Answer 389

MEN-2A, or Sipple syndrome, is characterized by medullary carcinoma, pheochromocytoma, and hyperplasia of the parathyroid glands. These can be remembered using the mnemonic “MPH”. Medullary thyroid carcinomas are seen in almost 100% of patients. Pheochromocytomas in patients with MEN-2A are often bilateral, and occur in 40-50% of patients. (Note that the predominantly bilateral presentation of pheochromocytomas in patients with MEN-2A is unique, as merely 10% of all pheochromocytomas are bilateral.) Hyperplasia of parathyroid, with evidence of hypercalcemia or renal stones, occurs in 10-20% of patients. MEN-2A has been linked to mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase. This proto-oncogene is found on chromosome 10.

Answer 390

MEN-2B has significant clinical overlap with MEN-2A (medullary thyroid carcinoma and pheochromocytoma), but is accompanied by neuromas and a marfanoid habitus. Medullary thyroid carcinomas are typically multifocal and more aggressive than those found in MEN-2A. Multiple neuromas (neoplasias of nerve tissue) of the skin and mucosa, called oral and intestinal ganglioneuromatosis, accompany MEN-2B. A marfanoid habitus describes the disproportionately long limbs and hyperextensible joints seen in MEN-2B. Marfanoid habitus is also seen in: Marfan syndrome, Homocystinuria, Ehlers-Danlos syndrome. MEN-2B is associated with a single amino acid change in the RET proto-oncogene, affecting a critical region of the tyrosine kinase catalytic domain. This is distinct from the mutations seen in MEN-2A.

Answer 391

Hypocalcemia is defined as a total serum calcium concentration

Answer 392

Hypoparathyroidism (most common cause) can result from: Autoimmune disease. Malignant or infectious infiltrate. Iatrogenic cause (thyroidectomy). Rare congenital syndromes such as DiGeorge’s syndrome. PTH release is impaired in hypomagnesemia ( 6 mg/dL). Except in cases of severe deficiency, vitamin D deficiency does not normally result in hypocalcemia because the secondary hyperparathyroidism is usually sufficient to correct calcium levels. Severe vitamin D deficiency is seen in: Renal failure (decreased 1-α-hydroxylase activity), Nephrotic syndromes, Advanced liver disease (decreased synthesis of vitamin D precursors), Elderly with limited sun exposure. Significantly elevated serum phosphorus can result in hypocalcemia because phosphorus binds and precipitates calcium in the tissue. Hypocalcemia also results from certain drugs which bind calcium: citrate, foscarnet, and fluoroquinolones. Alkalosis can result in hypocalcemia because alkalosis results in an increase in the number of negatively charged sites on albumin, which then bind calcium.

Answer 393

Pseudohypocalcemia is when total calcium is reduced due to decreased albumin but ionized (and hence metabolically active) calcium is normal.

Answer 394

Moderate hypocalcemia results in increased excitability of muscles and nerves, which can lead to peri-oral tingling, parasthesias and tetany (Chvostek's and Trousseau's signs). Severe hypocalcemia can cause laryngospasm, confusion, seizures, bradycardia and decompensated heart failure.

Answer 395

The two subtypes of lamellar bone are cortical (compact) bone and cancellous (trabecular) bone. The two subtypes of woven bone are immature bone and pathologic bone. Immature bone (e.g., embryonic skeleton, fracture callus) is not stress oriented. Pathologic bone (e.g., osteosarcoma, fibrous dysplasia) is weak and flexible due to its random organization and increased bone turnover rate.

Answer 396

Cortical (compact) bone has a structure oriented along lines of stress which gives it strength. An example of cortical bone is the femoral shaft.

Answer 397

Cancellous (trabecular) bone is more elastic (i.e. - softer, weaker, and more flexible) than cortical bone because its structure is not oriented along lines of stress. An example of cancellous bone is the distal femoral metaphysis.

Answer 398

Endochondral (“cartilage-mediated”) ossification is the following bone-forming process: Chondrocytes form a cartilage model. Osteoclasts and osteoblasts then replace the cartilaginous model with woven bone. Woven bone is subsequently remodeled into lamellar bone. The following are instances of endochondral bone formation: Embryonic long bone formation, Linear growth at the epiphyseal (growth) plates of long bones, Fracture callus

Answer 399

Intramembranous (“non-cartilage-mediated”) ossification is the following bone-forming process: Undifferentiated mesenchymal cells condense and form aggregates. These aggregated mesenychymal cells subsequently differentiate into bone-forming osteoblasts. The following are instances of intramembranous bone formation: Embryonic flat bone formation (e.g., clavicle, calvarium, and facial bones), Bone formation during distraction osteogenesis. Distraction osteogenesis, an example of intramembranous bone formation, occurs when using an external fixator to lengthen bone. Note, many bones including the clavicle, scapula, and occipital bones feature some regions derived from intramembranous ossification and other regions derived from endochondral ossification. For instance in the clavicle, the medial portion is derived from endochondral ossification, whereas the lateral portion is derived from intramembranous ossification.

Answer 400

Achondroplasia is the most common form of human dwarfism. Achondroplasia is an autosomal dominant (with full penetrance) disorder caused by a gain-of-function point mutation in the FGFR3 gene. Note, homozygosity for this mutation is lethal. FGFR3 (fibroblast growth factor receptor 3) is a tyrosine kinase transmembrane receptor. FGFR3 (fibroblast growth factor receptor 3) is encoded by the FGFR3 gene on chromosome 4. Normally, FGFR3 functions as a negative regulator of linear bone growth by inhibiting both the proliferation and terminal differentiation of chondrocytes within epiphyseal (growth) plates of long bones. In achondroplasia, mutation of the FGFR3 gene results in decreased chondrocyte proliferation and terminal differentiation. This results in impaired cartilage formation leading to impaired endochondral (cartilage-mediated) ossification. In achondroplasia, the midface is typically hypoplastic (e.g., depressed nasal bridge, dental crowding). In achondroplasia, impaired endochondral (cartilage-mediated) ossification in the epiphyseal growth plates of long bones results in short limbs. In achondroplasia, normal intramembranous (non-cartilage-mediated) ossification results in normal (and, therefore, relatively prominent or disproportionately large): Trunk height, Head, Mandible. Forehead (i.e., prominent frontal bossing). At birth, patients with achondroplasia may also present with: Trident hand where the fingers have three-pronged (trident) appearance due to inability to adduct the 3rd and 4th digits. Thoracolumbar gibbus is a sharply-angled kyphosis of the thoracolumbar spine that results in a hump-back appearance. Studies suggest that achondroplasia patients have: Normal fertility and Normal intelligence

Answer 401

Osteoporosis is a quantitative disorder of bone, meaning there is a reduction in bone mass despite the bone being sufficiently mineralized. Osteoporosis primarily affects trabecular bone, resulting in decreased bone mass and density with fewer trabecular interconnections. Type I (postmenopausal) occurs in women 50-70 years old and presents primarily with fractures of the distal radius (Colles’ fracture) and vertebral bodies. Type II (senile) occurs in patients over 70 years old and presents with fractures of the hip and pelvis. This type of osteoporosis does not show the same female predilection as type I osteoporosis.

Answer 402

Risk factors for osteoporosis include anything which contributes to an imbalance in bone production and bone resorption, resulting in diminishing bone mass. Unmodifiable risk factors of osteoporosis include: Caucasian ethnicity, Rheumatoid arthritis, Advancing age, Postmenopausal status, Previous fragility fracture, Genetics, including parental history of osteoporotic hip fracture. Modifiable risk factors of osteoporosis include: History of heavy/protracted glucocorticoid use, Low body weight, Current cigarette smoking, Excessive alcohol consumption, Poor diet/exercise. To remember the unmodifiable and modifiable risk factors for osteoporosis, use the mnemonic CRAPPy Gene LAGS (Caucasian ethnicity, Rheumatoid arthritis, Age, Postmenopausal status, Previous fragility fracture, Genetics, and Low body weight, Alcohol in excess, Glucocorticoids, Smoking).

Answer 403

There are no clinical manifestations of osteoporosis until the patient suffers a fracture. Achy pain, in the absence of a fracture, is unlikely to be osteoporosis. The incidence of fracture types related to osteoporosis is as follows (in order of decreasing frequency): 1. Vertebral body, 2. Hip (femoral neck), 3. Distal radius. Patients over the age of 65 may have insurance coverage for DEXA scans for osteoporosis screening. Fragility fractures occur with minimal impact from falls from a standing height or less, such as a Colles' fracture of the distal radius or a vertebral body fracture. NOTE: It may sometimes be important to distinguish a true fragility fracture from a pathological fracture. The latter is associated with osteolytic malignancy and presents as pain preceding a fracture that occurs with minimal trauma (e.g. picking up a grocery bag) and is not associated with a fall from a standing height or less. Accumulation of vertebral body fractures can cause progressive kyphosis of the thoracic spine (Dowager’s hump), respiratory compromise, restrictive lung disease, and an increased risk of pneumonia. Risk for future fragility fracture is much greater in patients with a history of existing fragility fracture.

Answer 404

The differential diagnosis for patients presenting with apparent fragility fracture includes the following: Osteoporosis, Osteomalacia, Osteopetrosis, Malignancy, Paget disease of the bone, Hyperparathyroidism

Answer 405

While not indicated strictly for the evaluation of osteoporosis, labs reveal normal serum calcium, phosphate, alkaline phosphatase and parathyroid hormone (PTH). The diagnosis of osteoporosis can be made clinically in a patient presenting with a fragility fracture and otherwise clinically consistent picture (postmenopausal female, over 70 years old, no evidence of malignancy, etc.), or based on a dual X-ray absorptiometry (DXA) scan measurement of bone mineral density showing a T-score more than 2.5 standard deviations below the mean. Measurement of femoral neck bone mineral density is used to estimate risk of hip fracture and any major osteoporosis-related fracture (wrist, hip or vertebral body) in untreated patients with the fracture risk assessment tool (FRAX). This uses clinical data, risk factors, and the patient’s bone mineral density as measured at the femoral neck to calculate the risk for a fragility fracture within the next ten years.

Answer 406

Bisphosphonates are considered the first-line pharmacologic therapy for patients with osteoporosis. Bisphosphonates inhibit osteoclastic bone resorption. Side effects of bisphosphonate use include: Esophagitis, Dysphagia, Gastric ulcers, Osteonecrosis of the jaw. Since estrogen has a protective effect on bone, hormone replacement therapy can be considered for women with type I (postmenopausal) osteoporosis. Raloxifene can be used in post-menopausal female patients with osteoporosis. Raloxifene inhibits bone resorption by acting as an estrogen agonist in the bone. Additional therapies include teriparatide (recombinant PTH) and denosumab (monoclonal anti-RANKL Ab). Note that pulsatile administration of PTH promotes osteoblastic activity, while constant dosing promotes bone resorption. Regular weight-bearing exercise helps to maximizing peak bone mass, which is key in the prevention of osteoporosis. Calcium and vitamin D supplementation is recommended for all ages. Smoking accelerates bone loss; cessation is encouraged for the prevention of osteoporosis.

Answer 407

Osteomalacia (in adults) and rickets (in children) are bone pathologies that result from the decreased mineralization of newly formed bone matrix (osteoid). Osteomalacia and rickets are qualitative defects in bone formation - the process of bone mineralization is abnormal. Comparatively, a defect like osteoporosis is a quantitative defect in bone formation - bone loss occurs despite normal mineralization. Vitamin D functions to reabsorb calcium (and phosphate) from the gut in order to maintain a solubility product adequate enough to mineralize bone. In osteomalacia and rickets, vitamin D deficiency decreases serum calcium. Decreased serum calcium from vitamin D deficiency may lead to hypocalcemic tetany (hypertonia). Decreased serum calcium due to vitamin D deficiency leads to decreased mineralization of osteoid. This results in soft bones with decreased bone density and increased unmineralized osteoid matrix with widening between osteoid seams.

Answer 408

Vitamin D deficiency causes osteomalacia in adults and rickets in children. Causes of vitamin D deficiency include: 1. Poor intake: Impaired cutaneous production, Vitamin D deficient diets, GI disorders (eg, prolonged cholestasis) → malabsorption of fat-soluble vitamins, including vitamin D. 2. Increased Loss of Vitamin D: Increased metabolism (barbiturates, phenytoin, rifampin), Impaired enterohepatic circulation, Nephrotic syndrome. 3. Impaired 25-hydroxylation: Liver disease, isoniazid. 4. Impaired 1α-hydroxylation: Renal osteodystrophy: chronic renal failure → ↓ 1-α-hydroxylase activity → ↓ 1,25(OH)2 vitamin D, Enzyme mutation, Hypoparathyroidism, X-linked hypophosphatemic, Rickets, Oncogenic osteomalacia, Ketoconazole, Aluminum-containing phosphate-binding antacids (eg, Aluminum Hydroxide). 5. Target Organ Resistance: Vitamin D receptor mutation, phenytoin

Answer 409

Clinical findings specific to Rickets (i.e., not found Osteomalacia) include: Genus varus: lateral bowing of weight bearing bones, Rachitic “rosary chest”: bony prominence at costochondral junctions, Harrison’s sulci: indentations in lower ribs, Pectus carinatum ("pigeon chest"): chest deformity due to a protrusion of the sternum and ribs, Craniotabes: softening of skull bones, Growth retardation due to defective mineralization at growth plates of long bones

Answer 410

Decreased 25(OH) vitamin D (storage form), Decreased Calcium, Decreased Phosphate, Increased Alkaline Phosphatase, Increased Parathyroid hormone (PTH)

Answer 411

Treatment of Vitamin D deficiency should be based on the underlying cause and severity, and repletion should always be done with calcium supplementation. For dietary causes, pharmacologic repletion (50,000 IU weekly) for 3-12 weeks followed by maintenance therapy (800 IU daily) is recommended. For impaired 1α-hydroxylation, give the active form, 1,25(OH)2 vitamin D. Osteomalacia may be reversible if vitamin D is replaced. Although Rickets may be partially reversible with vitamin D replacement, some of the pathology specific to Rickets (eg, growth retardation) may not be completely overcome by vitamin D supplements. Treatment: Oral vitamin D and calcium is the treatment of choice for vitamin D-dependent osteomalacia. Calcium supplementation should be 1.5-2 g/d

Answer 412

Hypophosphatemia is defined as a serum phosphate

Answer 413

Signs and symptoms of hypophosphatemia typically develop once serum levels are

Answer 414

The etiology of hypophosphatemia is often elicited through the patient history and may be further evaluated by 24-hour urine collection. Renal urinary excretion > 100 mg in 24 hours or a fractional excretion of phosphate > 5% is indicative of excessive renal phosphate loss often in the setting of hyperparathyroidism or vitamin D deficiency. Renal urinary excretion

Answer 415

Paget disease of bone (osteitis deformans) is characterized by massive bone turnover caused by increased and unbalanced osteoclastic and osteoblastic activity. The increased activity leads to the formation of abnormal bone architecture. Paget disease of bone is believed to be caused by both genetic and environmental factors. Inheritance appears to be autosomal dominant with variable penetrance. There is some evidence linking Paget disease of bone to a slowly progressive viral infection from a member of the paramyxovirus family, such as the measles or respiratory syncytial virus, although this theory is controversial.

Answer 416

The pathogenesis of Paget disease of bone involves 4 phases: Lytic phase, Mixed phase, Sclerotic phase, Quiescent phase. The lytic phase (first phase) of Paget disease of bone is characterized by increased osteoclast activity and normal osteoblast activity. This results in massive bone turnover that leads to poorly organized woven bone. The initiating lesion in Paget disease of bone is caused by an excessive increase in osteoclast activity. This activity leads to shaggy lytic bone lesions. In the mixed phase (second phase) of Paget disease of bone, osteoclastic activity decreases while the activity of osteoblasts greatly increases and predominates during this phase. The initial lytic insult in osteitis deformans is followed by a robust osteoblastic response, which results in increased alkaline phosphatase levels in the serum. Excessive activity of osteoblasts leads to increased production of disorganized woven bone, also known as “mosaic bone,” which is weak, thick, and highly vascular with ragged lytic areas of radiolucency throughout the bone matrix. In the sclerotic phase (third phase) of Paget disease of bone, osteoclastic activity declines to negligible levels, while the activity of osteoblasts remains elevated. In the sclerotic phase of Paget disease of bone, woven bone is replaced by focal pockets of abnormal, highly cellular lamellar bone with irregular “cement lines.” The decreased levels of osteoclastic activity leads to absent/minimal bone turnover, and results in the production of sclerotic bone that is characterized by: Enlarged/widened bones, Absent Haversian systems, Marrow spaces replaced by vascular fibrous tissue. The quiescent phase (fourth phase) of Paget disease of bone is characterized by minimal osteoclast and osteoblast activity.

Answer 417

The clinical findings and potential complications of Paget disease of bone include: Skull involvement that presents as Headaches, Increased hat size, Hearing loss if it involves the bone surrounding the inner ear and/or narrows the auditory foramen, “Cotton wool” appearance on x-ray imaging, Loss of vision and other cranial nerve lesions may also occur (however it is uncommon). Commonly, there is involvement of weight bearing bones that manifests in bone pain, long bone “chalk-stick fractures,” and large joint osteoarthritis. There is a small risk of Paget disease of bone developing into osteogenic sarcoma. Pagetoid bone is highly vascular with extensive arteriovenous shunting that may significantly increase blood flow, leading to increased cardiac output. This results in compensatory left ventricular hypertrophy and eventually, in severe cases of Paget disease of bone, high-output heart failure.

Answer 418

The labs and imaging in Paget disease of bone include: Serum chemistry levels reflect the increased bone turnover present in Paget disease and show: Normal calcium levels, Normal phosphate levels, Normal parathyroid hormone levels, Increased alkaline phosphatase levels. X-ray imaging reveals thickened bone cortex with shaggy radiolucent lytic lesions interspersed throughout the bone matrix. Bone with these features are described as having a cotton wool appearance.

Answer 419

The treatments for Paget’s disease of bone include: Bisphosphonates (eg, alendronate, pamidronate, etidronate) are first-line agents. Calcitonin is the drug of choice if there is extensive disease in weight-bearing bones

Answer 420

Important minerals for general cellular function as well as major constituents of bone. Plasma levels of calcium are regulated within narrow limits [8.8-10.4 mg/dl]. Intracellular Ca++ involved in muscular contraction, fusion and release of storage vesicles for hormones and neurotransmitters, and as critical 2nd messenger; in extracellular fluids, Ca++ promotes blood coagulation and supports formation and remodeling of skeleton. Intracellular PO43- component of: phospholipids, phosphorylated nucleotides, glycolytic pathway intermediates, phosphate buffer systems. 98% of Ca++ and 85% of PO4--- stored in bone. Plasma Ca++: Ionized (50%), protein-bound (46%), complexed with organic ions (4%)

Answer 421

Coordinated response between Parathyroid Hormone and Vitamin D at target tissues [site of entry (intestine) - site of exit (kidney) - site of storage (bone)] to regulate serum levels of Ca++ and PO4---. 1,25(OH)2D3 stimulates the intestinal absorption of Ca and P. Both PTH and 1,25(OH)2D3 promote bone formation and resorption by stimulating osteoblasts and osteoclasts. At the kidney, both 1,25(OH)2D3 and PTH enhance reabsorption of Ca - 1,25(OH)2D3 enhances P retention while PTH and FGF23 stimulate renal excretion of P. Feedback loops include: PTH stimulation of activation of D via the kidney; D and Ca++ inhibition of PTH synthesis and release from parathyroid glands; FGF23 inhibition of D activation in the kidney; CT is less critical for calcium homeostasis but in pharmacologic concentrations can reduce serum Ca and P by inhibiting bone resorption.

Answer 422

Structure / Pharmacokinetics. Single chain 84 AA; 1-34 fragment is biologically active [teriparatide]. Cleared from liver and kidneys with t1/2 of minutes. Pharmacodynamics: Primary stimulus for synthesis and secretion is hypocalcemia (decreased if hypercalcemia). Vitamin D interacts with receptor on parathyroid gland to decrease PTH release; In bone, PTH increases the number and activity of osteoclasts via actions on osteoblasts to induce a membrane-bound protein called RANK (receptor activator of nuclear factor 􏰂B) ligand (RANKL). This factor then acts on osteoclasts precursors and osteoclasts, increasing their number and activity, and increasing bone remodeling. This is a specific sequence of cellular events initiated by bone resorption and followed by osteoblastic bone formation. Net effect of excess PTH is to increase bone resorption, BUT low and intermittent doses of PTH stimulate formation without first increasing bone resorption. In kidney, PTH increases ability of nephron to reabsorb calcium, but reduces reabsorption of phosphate. Also important action to stimulate renal production of active D3 [1,25(OH)2D3]

Answer 423

Biosynthesis / Pharmacokinetics. Dietary vitamin D requires metabolism to active form. 7-dehydrocholesterol is photoconverted via ultraviolet irradiation in skin to form Vitamin D3. Vitamin D3 (dietary vitamin D) is converted to 25(OH) Vitamin D3 in liver. 25(OH) Vitamin D3 is converted to 1,25(OH)2 Vitamin D3 in kidney (most potent agent)

Answer 424

vit D3. Preferred over vitamin D metabolites because of modest cost.

Answer 425

vit D2. Studies have shown that ergocalciferol is LESS efficient than D3 in elevating serum 25-OHD3, thus D3 should be used when possible.

Answer 426

25-Hydroxyvitamin D3. Does not require hepatic 25-hydroxylation and is most useful in patients with liver disease. Onset of action is more rapid and half-life is shorter than D3. Alfacalcidol only available in Canada.

Answer 427

1,25-Dihydroxyvitamin D3. Most useful in patients with decreased synthesis of calcitriol (chronic renal failure or type 1 vitamin D-dependent rickets). Calcitriol has a rapid onset of action and a half-life of only 6 hours. Associated with hypercalcemia so patients should be followed closely.

Answer 428

Functionally equivalent to 􏰎α-OHD3, requires hepatic 25-hydroxylation to become therapeutically active. Alternative for use in disorders that calcitriol is used. Rapid onset of action and relatively short duration of action.

Answer 429

Synthesis of calcitriol (1,25-dihydroxyvitamin D3, most active form of vitamin D) in kidney is stimulated by PTH (released in response to hypocalcemia). Hypophosphatemia also stimulates calcitriol synthesis directly. In intestine, calcitriol appears to act by induction of new protein synthesis (calcium binding-protein and TRPV6-intestinal calcium channel) and by modulating calcium flux across brush border. These actions result in enhanced absorption of calcium and phosphate. This effect occurs at lower concentrations of vitamin D and is the basis for its use in the treatment of rickets (osteomalacia). The increase in serum concentrations of Ca++ and PO43- leads to increased bone mineralization. In bone, calcitriol has effects similar to PTH. Can induce RANK ligand in osteoblasts and proteins such as osteocalcin which may regulate the bone mineralization process. This effect on RANKL occurs at higher concentrations of vitamin D that stimulate release of calcium from bone. In kidney, calcitriol decreases excretion of calcium and phosphate. In parathyroid gland, calcitriol decreases release of PTH, thus reducing its own synthesis (negative feedback). Analogs of calcitriol are available for the treatment of secondary hyperparathyroidism. They inhibit release of PTH, but will NOT cause hypercalcemia (NO increase in intestinal Ca++ absorption or bone Ca++ mobilization (Paracalcitol [Exemplar®], Doxercalciferol [Hectorol®])

Answer 430

These hormones can influence calcium and phosphate homeostasis under certain physiologic circumstances. BUT, a deficiency or excess of these secondary regulators does NOT produce the homeostatic disturbances seen in situations of deficiency of PTH, vitamin D, or FGF23. However, in pharmacologic amounts, calcitonin, glucocorticoids, and estrogens have actions on bone mineral homeostasis that can be exploited pharmacotherapeutically.

Answer 431

Structure / Pharmacokinetics: 32 AA peptide with essential disulfide bond; secreted by parafollicular cells of thyroid. Human CT has t1/2 of 10 min; salmon CT has longer t1/2; clearance through kidney. Primary stimulus for synthesis and release is hypercalcemia (also increased by glucagon, TSH / thyroxine, adrenergic agents, gastrin). Inhibits osteoclastic bone resorption -> Decreased Ca++ and PO43-. Reduces reabsorption/increases excretion of Ca++ and PO43- -> Decreased Ca++ and PO43-

Answer 432

P􏰋ositi􏰑e effects on bone mass as a􏰒onist at 􏰓􏰔α receptors on osteoblasts and osteoclasts􏰐. Estrogens directly regulate osteoblasts and increase synthesis of type I collagen, osteocalcin, osteopontin, osteonectin, alkaline phosphatase, and other markers of osteoblast differentiation. Estrogens also decrease apoptosis of osteocytes. Major effect of estrogens is to decrease number and activity of osteoclasts by altering cytokine signals from osteoblasts (􏰍 stimulating signals [IL-6, TNF-α􏰕 and increase anti-resorptive BMP-2 and TGF-β􏰗􏰐. Estrogens increase osteoblast production of osteoprotegerin (OPG), a “decoy” receptor that binds RANK ligand (RANKL) which inhibits binding of RANK ligand to its “real” receptor, RANK (receptor activator of NF-􏰘􏰙􏰗􏰚 thereby preventing subsequent osteoclast activation. Estrogens also increase osteoclast apoptosis.

Answer 433

pharmacologic doses (physiologic levels are required for osteoblast differentiation). Osteoporotic bone fractures may develop in 30-50% of patients on chronic glucocorticoids. Glucocorticoids decrease bone density by multiple mechanisms: Lowering of serum Ca++ by antagonizing vitamin D-stimulated intestinal Ca++ transport, which then causes an increase in PTH that stimulates osteoclast activity; Increase production of RANK ligand by osteoblasts, but decrease production of osteoprotegerin, thus more RANK ligand is available to bind RANK, activating osteoclasts and increasing bone resorption; Suppressive effects on osteoblasts. Glucocorticoids cause decreased bone resorption in large doses and were once used for intermediate- term treatment of hypercalcemia of malignancy (production of PTH-like peptide in myelomas, leukemias, lymphomas). Bisphosphonates are more effective and are preferred therapy.

Answer 434

In quiescent trabecular bone, cytokines such as insulin-like growth factor (IGF) and transforming growth factor (TGF- 􏰃), shown as dots, are embedded in the bone matrix. During bone resorption, osteoclast (OC) precursor cells, recruited by cytokines and hormones, are activated by osteoblasts (OB) to form mobile multinuclear OCs that move along the bone surface, resorbing bone and releasing the embedded cytokines. During bone formation the released cytokines recruit OBs, which lay down osteoid and embed cytokines (IGF and TGF-􏰃) in it. Some OBs also become embedded, forming terminal osteocytes. The osteoid then becomes mineralized, and lining cells cover the area

Answer 435

Estrogens and raloxifene (a selective estrogen receptor modulator) cause apoptosis of OCs. Pharmacological concentrations of glucocorticoids have the effects specified above, but physiological concentrations are required for OB differentiation. Bisphosphonates embed in the bone mineral matrix and are released slowly as bone is resorbed by osteoclasts, exposing the OCs to high concentrations of these drugs.

Answer 436

Osteoblast is stimulated by calcitriol, PTH, and interleukins to express a surface ligand, the RANK ligand (RANKL). RANKL interacts with a receptor on the osteoclast – an osteoclast differentiation and activation receptor termed RANK (receptor activator of nuclear factor kappa B) that causes formation of mature osteoclasts. The osteoblast also releases “decoy” molecules of osteoprotegerin (OPG) which can bind RANKL and prevent activation of the RANK receptor

Answer 437

Recombinant OPG (r-OPG) is in clinical trials. Estrogen (not shown) may also increase production of OPG by osteoblasts. Anti-RANKL antibodies (denosumab) bind RANKL and prevent the RANK-RANKL interaction. Bisphosphonates inhibit bone resorption by osteoclasts

Answer 438

Abnormal bone loss predisposing to fractures (in 30-50% of women and 15-30% of men). Most common metabolic bone disease that is estimated to cause 1.5 million fractures each year in the U.S. Primary osteoporosis. Loss of trabecular bone in postmenopausal women due to an increase in osteoclastic activity (loss of estrogen inhibition of osteoclasts). Can occur with aging in both men and women due to decrease in osteoblastic activity (primarily in cortical bone, but also trabecular bone) related to long-term remodeling inefficiency, activation of parathyroid axis with age, and dietary inadequacy (􏰍increase 1,25 (OH)2 D3 levels with reduced Ca++ transport). Secondary osteoporosis can result from systemic illness (e.g., thyrotoxicosis, Cushing’s syndrome, hyperparathyroidism) or drugs such as glucocorticoids or phenytoin

Answer 439

Ultimate goal of therapy is prevention of future bone fractures, not increase in bone mineral density per se. on-pharmacologic therapy should include: (1) diet [supplemental elemental calcium: 500-1000 mg, for daily total of 1500 mg; Vitamin D: 800 IU], (2) exercise [weight-bearing regimen], (3) cessation of smoking.

Answer 440

Alendronate [Fosomax􏰌]), Risedronate [Actonel􏰌], Ibandronate [Boniva􏰌], Zoledronate [Reclast􏰌]. Pyrophosphate analogs in which P-O-P bond is replaced by P-C-P structure that chelates divalent cations such as Ca++ and thus have high affinity for bone. Bisphosphonates bind to active sites of bone remodeling and have direct inhibitory effects on osteoclasts involving 2 primary mechanisms: (1) osteoclast apoptosis, (2) inhibition of multiple steps in cholesterol pathway responsible for prenylation of proteins necessary for osteoclast function. Interfere with formation of “ruffled border” at osteoclast attachment site: inhibits enzyme pathway producing lipids essential for GTPase signaling

Answer 441

1-10% of oral dose absorbed, gastric irritation common; half of that amount accumulates in bone, half excreted unchanged in urine. Not recommended if CrCl

Answer 442

GI effects: heartburn, abdominal pain, diarrhea. Esophagitis can be a problem requiring special administration technique (taken after overnight fast, in upright position, with full glass of water, nothing by mouth for 30-60 minutes, avoiding lying down). Severe bone, joint, and/or muscle pain has been observed; rarely osteonecrosis of the jaw (more likely in cancer patients receiving high-dose IV bisphosphonates). Relative contraindications include achalasia, scleroderma esophagus, or esophageal strictures

Answer 443

Selective Estrogen Receptor Modulators (SERMs). SERMs are agonists on bone and liver, inactive on uterus, and antagonists on breast tissue. They reduce risk of vertebral fractures, but have less efficacy than estrogen or bisphosphonates. Advantages over estrogen include reduced risk of breast cancer and coronary events. Disadvantages relative to estrogen are worsening of vasomotor symptoms (hot flashes) and leg cramps. Increased risk of thromboembolic disorders (agonist action on liver) is similar to estrogen. Use in osteoporosis: Option for prevention and treatment if patient cannot tolerate any BP or is at increased risk for invasive breast cancer. NEW in 2014: Conjugated estrogens/bazedoxifene combination (Duavee􏰌) indicated for prevention of osteoporosis and severe vasomotor symptoms. Bazedoxifene (a SERM) inhibits stimulating effect of estrogen on breast and uterus but not positive effects on bone density and hot flushes. VTE risk uncertain.

Answer 444

Reduce bone resorption via inhibitory effects on osteoclasts [described above]. Most effective given in first 5 years after menopause; administration of progestational agent reduces endometrial carcinoma risk. Reduced enthusiasm for estrogen use as report of Women’s Health Initiative study in 2002 showed reduced benefit-risk ratio. Positive benefit of estrogen therapy on preserving bone and preventing osteoporotic fractures is clearly evident, but is outweighed by increased risk of coronary heart disease, breast cancer, stroke, and venous thromboembolism. Use in osteoporosis. No longer first-line agent. Current consensus is estrogen (as menopausal hormonal therapy [MHT]) for osteoporosis prevention should be limited to women with significant vasomotor symptoms who are not at risk for heart disease (individualization of risk-benefit assessment)

Answer 445

Mechanism of action: RANKL is essential to the function of bone resorption by osteoclasts by accelerating osteoclastogenesis via interaction with its receptor, RANK. Denosumab is a humanized monoclonal antibody against RANKL that reduces osteoclast activation and improves bone mineral density. Pharmacokinetics: Administered by subcutaneous injection every six months. It is NOT cleared by kidney, so dosage adjustments for chronic kidney disease not necessary. Use in osteoporosis: For treatment in patients with high fracture risk - shown to reduce risk of spine-hip- other non-vertebral fractures. Exact role unclear. Due to absence of long term safety data, oral BPs would be preferred. Denosumab could be used in select patients at high risk for fractures who are intolerant of or unresponsive to bisphosphonates. Adverse effects: Generally well tolerated, flu-like symptoms in 8%. Symptomatic hypocalcemia possible in predisposed patients (kidney disease, malabsorption syndromes, hypoparathyroidism). Uncertain if long-term suppression of bone remodeling could weaken bone.

Answer 446

Synthetic amino terminal human PTH fragment (AA 1-34). Only agent available for treatment of osteoporosis that stimulates bone formation. All other treatments are anti-resorptive agents. Mechanism of action: NOTE: While continuous administration of PTH or high circulating levels of PTH (in primary hyperparathyroidism) causes bone demineralization and osteopenia, intermittent administration of this PTH analog increases osteoblastic activity and bone formation. Daily subcutaneous dose results in peak levels at 30 minutes, decline to undetectable within 3 hours. Use in osteoporosis: Approved for treatment of severe osteoporosis in both men and postmenopausal women at high risk of fractures. Expensive. Adverse effects include nausea, headache, dizziness, and severe muscle pain. Hypercalcemia reported, avoid by limiting daily calcium to less then 1000 mg.

Answer 447

Mechanism of action: Inhibition of osteoclastic bone resorption; given subcutaneously or via nasal spray [Miacalcin􏰌]. Modest increase in bone mass in patients with osteoporosis, does not appear as effective as bisphosphonates or teriparatide. Useful if back pain is a problem. Use in osteoporosis: Approved by FDA for treatment, but not prevention, of osteoporosis. Does not have strong fracture efficacy data; less effect on BMD than other osteoporosis meds. Expensive. Side effects include nausea, hand-swelling, urticaria cramps – rhinitis and epistaxis with intranasal formulations. Equal frequency with human and salmon calcitonin. 2014 FDA warning of increases in malignancies. No longer recommended by many experts.

Answer 448

[Hydrochlorothiazide]. Possible role in patients with hypercalciuria. Action to reduce urinary calcium excretion (and decrease hypercalciuria and incidence of kidney stones). REMEMBER: Loop diuretics increase urinary calcium excretion. Act via either enhancement of PTH to stimulate reabsorption of Ca++ or secondarily via effects to block Na+ reabsorption, which indirectly results in increased Ca++ reabsorption. Effective doses for reducing Ca++ excretion generally higher than those for blood pressure control

Answer 449

Potentially lethal; main causes are hyperparathyroidism (surgical resection of hyperplastic gland almost always required) and cancer (tumor production of PTH related proteins). Elevated plasma Ca++ levels will increase threshold for nerve / muscle excitation. Symptoms include muscle weakness, lethargy, coma. Effective treatments reduce calcium by: (1) increasing urinary calcium excretion, (2) inhibiting bone resorption, (3) or decreasing intestinal calcium absorption.

Answer 450

Saline diuresis (± furosemide, a loop diuretic). Hypercalcemic patients are frequently dehydrated so fluid resuscitation should be early and aggressive. Once volume is repleted, loop diuretics can both increase Ca++ excretion and counteract plasma volume expansion by saline (esp. in patients with renal insufficiency or heart failure). Response within hours. Generally not sufficient if severe hypercalcemia and concurrent treatment with bisphosphonates ± calcitonin is required. Bisphosphonates: Mainstay of treatment of hypercalcemia of malignancy (response within 2 days). Parenteral agents are more effective than oral bisphosphonates, so pamidronate (Aredia􏰌) or zoledronate (Zometa􏰌) as a single dose infusion (over 2-4 hrs vs 15 min, respectively) are preferred. Both produce a potent inhibition of osteoclastic bone resorption, resolving the hypercalcemia over 24-72 hours and lasting for several weeks. Calcitonin (Calcimar􏰌, Miacalcin􏰌): Potential use in hypercalcemia. Given subcutaneously it can rapidly reduce serum Ca++ (within 4-6 hours) but “escape” may occur within several days (efficacy limited to first 48 hours). Produces a decrease in Ca++ mobilization from bone (as seen with bisphosphonates). Glucocorticoids (high dose prednisone): Used for chronic hypercalcemia resulting from overproduction (sarcoidosis or lymphoma) or excess ingestion of calcitriol. Glucocorticoids act via decrease in Ca++ absorption (􏰍 calcium-binding protein via decreased production of 1,25 (OH)2 D3) or increased urinary excretion. Response to GCs is slow (2-5 d). Phosphates: Via the oral route for short-term hypercalcemic control (pre-surgery for hyperparathyroidism). IV sodium phosphate is fastest, surest way to reduce Ca++ but not recommended due to associated risks (sudden hypocalcemia, ectopic calcification, renal failure) except for rare patient who is hypophosphatemic.

Answer 451

Major causes are hypoparathyroidism, Vitamin D deficiency, renal failure (via decreased synthesis of calcitriol), and malabsorption. Hypomagnesemia is a common cause of hypocalcemia and if present it is difficult to correct low calcium without first normalizing serum magnesium. Primary symptoms are neuromuscular (tetany, paresthesias, muscle cramps, convulsions) when hypocalcemia develops acutely. Treatment varies depending on severity and underlying cause of hypocalcemia. Absolute level of calcium as well as rate of decrease determine severity of symptoms.

Answer 452

Calcium – Acute Replacement: Severe hypocalcemic tetany [ 50 years old and men > 70 years old: 1200 mg. Elemental calcium differs among the various salts: carbonate (40%), phosphate (25%), citrate (21%), lactate (13%), gluconate (9%). Pharmacokinetics: Absorption is generally poor (10-12%), increased if taken with food. Differences in absorption of different Ca++ salts are generally small (citrate 25% > CO3, less pH dependence, recommended if patient on PPIs or H2 antagonists). Can compensate for differences with slight changes in dosage. Adverse effects: Usually well tolerated (doses up to 1500-2500 mg/day); GI effects (constipation, intestinal bloating, nausea) have been reported, particularly with CaCO3, less with citrate. Vitamin D Supplementation – Chronic. Modest supplementation (400-800 IU/day) may improve intestinal Ca++ absorption, suppress bone remodeling, and improve BMD in patients with deficient vitamin D status, especially > 50 years old. Recommended daily allowance of vitamin D – Institute of Medicine: Adults up to 70 years old: 600 IU, Adults > 71 years old: 800 IU. Adverse effects [safe upper limit at 4000 IU/day, but higher doses (10,000 IU/day) appear safe over several months]: First signs of toxicity are hypercalciuria and hypercalcemia.