Endocrinology:

By: Dr Suyash Sharma

GFR corresponds with Salt (Na+), Sugar (glucocorticoids), and Sex (androgens). The deeper you go, the sweeter it gets. Pheochromocytomamost common tumor of the adrenal medulla in adults. Neuroblastomamost common in children. Pheochromocytoma causes episodic hypertension; neuroblastoma does not.

Adrenal gland drainage

Left adrenal left adrenal vein left renal vein IVC. Right adrenal right adrenal vein IVC. Same as left and right gonadal vein.

Cortisol
S ource Function Adrenal fasciculata. 1. Anti-inflammatory 2. gluconeogenesis, lipolysis, proteolysis 3. immune function 4. Maintains blood pressure 5. bone formation

Regulation

CRH (hypothalamus) stimulates ACTH release (pituitary), causing cortisol production in adrenal fasciculata.

Bound to corticosteroid-binding globulin (CBG). Chronic stress induces prolonged

1. Glucocorticoid effects are involved in intermediary metabolism, inflammation, immunity, wound healing, and muscle and myocardial integrity. 2. Mineralocorticoids are involved in salt, water, and mineral metabolism; these effects are predominantly mediated by aldosterone.

Steroid withdrawal

administration of glucocorticoids inhibits the release of CRH and, thus, suppresses both the synthesis and release of ACTH. causes atrophy of the adrenals and the ACTH-releasing cells of the anterior pituitary. After chronic therapy with high-dose glucocorticoid, 6 months are required for normal ACTH secretion to occur, while 6 to 9 months are required to regain normal cortisol secretion.

Mineralocorticoids

Aldosterone activity. Aldosterone promotes renal Na+ retention, promotes water retention if ADH is present. It also promotes K+ and H+ ion excretion by the kidney. It is synthesized in the zona glomerulosa. a. It increases active Na+ reabsorption, K+ secretion, and H+ secretion in the renal distal tubule and collecting duct. In the presence of ADH, water is reabsorbed passively, following the sodium.

b. There is decreased Na+ secretion in the sweat glands. c. Na+ (and water) absorption is increased in the colon.

Renin-AngiotensinAldosterone system(RAAS)

Pituitary gland(hypohysis)
Bilobed organ that lies at the base of the brain. Lodges in a bony cavity called the sella turcica. Controlled by the hypothalamus. Control over other endocrine glands. divided into the adenohypophysis and neurohypophysis based on its embryologic origins.

Adenohypophysis
arises from an outpocketing of the ectoderm in the roof of the primitive mouth called Rathke pouch. Derived from neuroectoderm. Divided into pars distalis, the pars tuberalis, and the pars intermedia. FSH, LH, ACTH, GH, TSH, melanotropin (MSH), prolactin. FLAT PiG:

Neurohypophysis
is derived from nerve tissue. posterior lobe. Derived from oral ectoderm. Glial cells, called pituicytes, surround the nerve terminals in the neural lobe.

 subunitcommon subunit to TSH, LH, FSH, and hCG. subunitdetermines hormone specificity.

Anterior pituitary cells are classified as: Chromophils, based on their affinity for acid or basic dyes. 2 types, acidophils; basophils Chromophobes, based on their lack of affinity for these dyes. cytoplasm unstained. Folliculostellate cells form a network of support-like cells; their function is unknown.

B- FLAT

Hypothalamohypophysial tract.

The median eminence and stalk of the infundibulum and the pars nervosa contain a tract of unmyelinated axons belonging to secretory nerve cells that have their cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus.

1. The secretory nerve cells produce the polypeptide hormones oxytocin and antidiuretic hormone (ADH), or vasopressin. packaged into secretory granules and are moved by axoplasmic transport to the pars nervosa. There they accumulate in nerve terminals near capillaries in clumps called Herring bodies. Secreted by exocytosis.

Vascular anatomy of the hypophysis

two superior hypophysial arteries on each side of the organ: the anterior and posterior superior hypophysial arteries supply the median eminence and the stalk of the infundibulum form looped sinusoidal capillaries drain into venous trunks of the hypophysial portal system, sinusoidal capillaries in the anterior lobe conducts neurohormone

The anterior and posterior inferior hypophysial arteries supply the neurohypophysis & form an arterial circle at the junction to the anterior and posterior lobes. perfused via sinusoidal capillaries lined with fenestrated endothelium.

Oxytocin induces uterine contractions and stimulates milk let-down. ADH increases the water resorption in the kidney.

Hypothalamic-Releasing Hormones TRH CRH GnRH GHRH PRH Hypothalamic inhibitory Hormones Somatostatins(inhibit TSH & GH) Prolactin inhibitory factor (dopamine)

Classification of Pituitary hormones

three basic groups according to their chemical structure. 1. Straight-chain peptides containing disulfide bridges (somatomammotropic group) Growth hormone (somatotropin, GH), Prolactin (PRL), human placental lactogen (hPL). 2. Glycoproteins composed of and subunits include LH, FSH, and (TSH). (LFT Glyco)

3. Straight-chain peptides and polypeptides (corticotrophs): MSH, ACTH, -lipotropin (-LPH) Pro-opiomelanocortin (POMC) hormone precursor synthesized in the hypothalamus. It is hydrolyzed in the anterior pituitary to ACTH, -lipotropin( -LPH), and endorphin. Posterior Pituitary Hormone: ADH and oxytocin are produced in separate cells; both types of cells are distributed within the SON and PVN.

GH:
stimulates growth in childhood. It acts as an anabolic and anticatabolic agent. Stimulates the production of somatomedins (insulin like growth factor, IGF) in the target tissues, which mediate many of growth hormones key growth actions. Like the insulin receptor, the IGF receptor has tyrosine Kinase activity. Nicotine is a potent stimulus for release of ADH and its neurophysin, unless ADH is

Metabolic effects of GH
Increasesp rotein synthesis Decreases sensitivity to insulin; diabetogenic effect. Increased lipolysis. GH is released in pulses throughout the day. GH is released following stress hypoglycemia, vasopressin or L-dopa injection, during exercise, and during sleep

Control of GH
GHRH stimulates secretion Somatostatin blocks the secretion Somatomedins exert negative feedback by (-) GH secretion from the anterior pituitary and (+) somatostatin release from the hypothalamus Both GHRH and GH inhibit their own release by feeding.

Prolactin (PRL)
Secreted from the acidophilic mammotrophs. Milk synthesis in the mammary gland. Causes of hyperprolactinemia include: (1) Pituitary tumors (2) Dopamine antagonists (antipsychotics) (3) Primary hypothyroidism (TRH)

PROLACTIN REGULATION

Prolactin dopamine synthesis and secretion from the hypothalamus. Dopamine subsequently inhibits prolactin secretion. Dopamine agonists (e.g., bromocriptine) therefore inhibit prolactin secretion, whereas dopamine antagonists (e.g., most antipsychotics) stimulate prolactin secretion. In females, prolactin inhibits GnRH synthesis and release, which inhibits ovulation. Amenorrhea is commonly seen in prolactinomas

Glycoproteins composed of and subunits

LH, FSH, and TSH. The subunit is similar in structure in FSH, LH, and TSH. The subunit conveys the biologic specificity of the hormone. hCG, secreted by the placenta, has a subunit that is almost identical to that of LH.

Straight-chain peptides and polypeptides (corticotrophs)

ACTH, LPH, MSH ACTH also has the ability to stimulate pigment cells(because of its structural similarity to MSH). in Addison's disease, a form of adrenal insufficiency.

ACTH secretion can be inhibited by adrenal corticosteroid

Cushing disease due to hypersecretion of ACTH from an adenoma of the anterior pituitary. Cushing syndrome can be due to multiple causes such as: Adrenal cortical adenoma/carcinoma Ectopic ACTH production by nonpituitary tumors, most commonly small cell carcinoma of the lung. Corticosteroid medication

 Lipotropin
Cleavage of POMC(Proopiomelanocortin) ACTH & LPH LPH stimulates melanocytes to produce melanin and can be cleaved into further smaller fragments(- lipoprotein, -MSH, -MSH, -MSH, , , endorphin and Met-enkephalin)

MSH
stimulates melanocytes (pigment cells) produced by the corticotropin (chromophobe) cells found in the pars intermedia. -lipotropin ( -LPH)(weak lipolytic) A class of opiate-like peptides known as enkephalins and endorphins are derived from POMC, and are fragments of B-LPH.

Endorphins: effects on pain mechanisms, behavior disorders, and narcotic addiction Enkephalins: are endogenous pentapeptides that bind to opiate receptors in the brain. produce transient analgesia pain and emotional behavior

ADH

Diabetes insipidus/ nephrogenic diabetes insipidus Absence of ADH secretion or lack of a renal response to ADH results in either central (neurogenic) or nephrogenic diabetes insipidus, respectively SIADH: Excess ADH secretion, S IADH causes increased water retention, hypoosmolarity and hyponatremia, concurrent with hypertonic urine excretion.

Oxytocin
Secretion is stimulated by infant suckling. Dilation of the cervix during labor and orgasm are also stimuli for oxytocin secretion. Physiologic effects a. Milk let-down occurs due to the contraction of the myoepithelial cells in the mammary gland. b. Causes uterine contraction; can be used to induce labor late in pregnancy.

Normal growth requires normal levels of:

Nutrition GH lGF-1 Thyroid hormone Cortisol lnsulin

THYROID GLAND
The thyroid diverticulam arises from the floor of the pharynx and enters the neck via the thyroglossal duct. This duct usually disappears but, thyroid tissues and cyst may remain as accessory thyroid. (e.g. the pyramidal lobe). The thyroid is a lobulated gland that consists of two pear-shaped lateral lobes connected by an isthmus.

synthesis of thyroxine

import of iodine into the cell via active transport mechanism ( NaI.)

The iodination of tyrosine in Thyroglobin with thyroid peroxidase enzymes

TSH stimulates the release of T3 and T4 from thyroglobulin.

THYROID GLAND

The thyroid synthesizes and secretes T3 and (T4, thyroxine), which regulate cell metabolism, development, growth, and differentiation. Most T3 formed in blood. T4 is major product. T4 is converted to T3 by peripheral tissue. T3 binds receptors with greater affinity than T4. Releases calcitonin, (calcium homeostasis) 2 types occur: follicular cells and parafollicular cells

Thyroxine-binding globulin (TBG) binds most T3/T4 in blood; only free hormone is active. TBG in hepatic failure; TBG in pregnancy (estrogen TBG).

T3 Function 4 Bs
Brain Maturation Bone Growth(synergism with GH) Beta-adrenergic effects( CO, HR, SV, contractility) BMR (via Na+/K+-ATPase, activity = O2

consumption, RR, body temperature)

Thyroxine binding globulin(TBG) binds most T3/T4 in blood; only free hormone is active. TBG in Pregnancy(Estrogen TBG) glycogenolysis, gluconeogenesis, lipolysis

Regulation

TRH (hypothalamus) stimulates TSH (pituitary), which stimulates follicular cells. Negative feedback by free T3 to anterior pituitary sensitivity to TRH. TSI, like TSH, stimulates follicular cells (Graves disease).

(1) Follicular cells

are the principal thyroid cells. They are simple cuboidal epithelial cells that line the follicular cavity and secrete thyroid hormones. Their apical surfaces face the follicular cavity into which thyroglobulin is released, and their basal poles rest on a basal lamina. Rounded nuclei, cytoplasm is basophilic and PAS-positive indicating

Parafollicular cells, or C cells

larger cells,w hich possessli ghtstaining cytoplasm Secretion of calcitonin,

Vascular supply of Thyroid: 1. paired superior thyroid arteries (branches of the external carotids) 2. paired inferior thyroid arteries (branches of the thyrocervical trunks).

Parathyroid

The epithelial parenchymal cells, arranged in irregular cords or clusters, are composed of two cell types, which may represent different functional states of a single cell type. a. Chief cells: are small polyhedral cells with round nuclei. They are generally arranged in cords but occasionally occur in clumps. They secrete parathyroid hormone (PTH),

b. Oxyphil cells: are larger and much less numerous than the chief cells. They appear as eosinophilic cells. Unknown function.

PTH Function

1. bone resorption of calcium and phosphate 2. kidney reabsorption of calcium in distal convoluted tubule 3. kidney reabsorption of phosphate 4. 1,25-(OH)2 vitamin D (calcitrol) production by stimulating kidney 1hydroxylase PTH serum Ca2+, serum (PO4) --- urine (PO4)---. PTH stimulates both osteoclasts and osteoblasts. PTH = Phosphate Trashing Hormone.

Shown above are the main actions of PTH and 1,25-(OH)2D in the maintenance of calcium (A) and phosphate (B) homeostasis.

Vitamin D S ource Vitamin D3 from sun exposure in skin. D2 ingested from plants. Both converted to 25-OH vitamin D in liver and to 1,25-(OH)2 vitamin D (active form) in kidney. 1. absorption of dietary calcium 2. absorption of dietary phosphate 3. bone resorption of Ca2+ and (PO4)3 PTH causes 1,25-(OH)2 vitamin D production. [Ca2+] 1,25-(OH)2 vitamin D production. phosphate 1,25-(OH)2 vitamin D production. 1,25-(OH)2 vitamin D feedback inhibits its own production.

Function

Regulation

C alcium, phosphate, and alkaline phosphatase levels

Disease Ca2+ Phosphate Alkaline phosphatase N/ N N PTH

Hyperparathyroidism Pagets disease of bone Vitamin D intoxication Osteomalacia Osteoporosis Renal insufficiency

N/ N

N N

C alcitonin

Source Function

Parafollicular cells (C cells) of thyroid. bone resorption of calcium.

Regulation

serum Ca2+ causes calcitonin secretion.

Calcitonin opposes actions of PTH. It is probably not important in normal calcium

Endocrine pancreas cell types

Islets of Langerhans are functional units of the endocrine pancreas(collections of , , and endocrine cells) (most numerous in tail of pancreas). Islets arise from pancreatic buds. = glucagon (peripheral); = insulin (central); = somatostatin (interspersed). PP(F) cell pancreatic polypeptide

Islet cells contain gap iunctions that link them together, possibly allowing cell-cell communication Synthesized as preproinsulin; proinsulin. Within proinsulin, residues1 -30 will form the B chain. Residues 66-86 will form the A chain of insulin. Residues 31-65 form the "connecting peptide" (C-peptide).

Measurement of circulation C-peptide indicates -cell secretory activit. Note that Exogenously administered insulin will not contribute circulating Cpeptide.

Stimulatory agents

(1) Hyperglycemia( threshold >l mg/ml) (2) Amino acids( especially Arg) (3) Fatty acids especially long chain( 16-18C ) (4) Gastointestinal hormones ,GIP, gastrin, secretin (oral dose of glucose greater production of insulin than via IV because of these hormones) (5) GH, cortisol (6) Acetylcholine( parasympathetic stimulation) (7) Sulfonylureas (used to treat noninsulindependend diabetes mellitus)

Inhibitory agents

(1) Hypoglycemia (2) Somatostatin (3) Norepinephrine (4) Epinephrine

When stimulated by glucose, secretion is biphasic. (1) Initial burst for 5-15 minutes (2) More gradual and sustained release (3) Secreted in fed-state-hormone of nutrient abundance

Primary target cells for insulin are liver, skeletal muscle, and adipose tissue. Insulin receptor a. Heterotetramer with two - subunits held together by disulfide bonds ( I ) Subunits are extracellular contain insulin binding sites. (2) -Subunits are transmembrane

Skeletal muscle and adipose tissue depend on insulin for glucose uptake (GLUT-4). Brain and RBCs take up glucose independent of insulin levels (GLUT1). Brain depends on glucose for metabolism under normal circumstances and uses ketone bodies in starvation.

Metabolic effects of insulin

Glucose transport: Insulin promotes uptake of glucose from blood into cells. carriers are involved to facilitate glucose diffusion (GLUT 1 to GLUT 6) Insulin promotes translocation of GLUT 4 transporters from inactive intracellular pools (smooth ER) to plasma membrane-therefore, increased glucose uptake.

Glycogen synthesis Glycolysis Decreases gluconeogenesis Promotes lipogenesis Inhibits breakdown of triglycerides Increases activity of lipoprotein lipase Protein synthesis and degradation Hypokalemia: Insulin increases cellular uptake of K+. This effect can be used therapeutically-patients with hyperkalemia.

Glucagon
Secreted by cells in response to decreased blood sugar. Synthesized as preproglucagon in cells of the islets and also by cells of the gastrointestinal tract and some brain cells. Primary regulator of secretion is a decrease in blood sugar below ~1 mg/ml. Like insulin, glucagon secretion is stimulated by amino acids (especially Arg) and inhibited by somatostatin.

Secretion
Stimulatory agents (1) Hypoglycemia (2) Amino acids (3) Acetylcholine (4) Norepinephrine (5) Epinephrine (6) ccK Inhibitory agents (1) Hyperglycemia (2) Fatty acids, (3)ketones (4) Somatostatin (5) Insulin

Antidote for overdose with beta blockers; the likely mechanism of action is the increase of cAMP in the myocardium, effectively bypassing the -adrenergic second messenger system. Drug interactions: Glucagon interacts only with oral anticoagulants, increasing the tendency to bleed.

Steroid/thyroid hormone mechanism

The need for gene transcription and protein synthesis delays the onset of action of these hormones. Steroid/thyroid hormonesPET CAT: Progesterone Estrogen Testosterone Cortisol Aldosterone Thyroxine and T3

Steroid hormones are lipophilic (insoluble in plasma;) Requires protein career (globulin)to circulate in blood. levels of sex hormonebinding globulin (SHBG) lower free testosterone gynecomastia. SHBG raises free testosterone hirsutism.

Bound to corticosteroid-binding globulin (CBG). Chronic stress induces prolonged secretion.

Signaling pathways of endocrine hormones

cAMP cGMP IP3 Steroid receptor Tyrosine kinase

ACTH LH FSH TSH ADH (V2) hCG MSH CRH PTH Calcitonin Glucagon

ANP, EDRF NO

GnRH, TRH, GHRH, ADH (V1) Oxytocin

Glucocorticoi Insulin d IGF-1 FGF Estrogen Progesteron e Testosterone Aldosterone Vitamin D T3/T4

Endocrine Pathology

HYPOTHALMUS and PITUITARY

Lesions of the hypothalamus Destructive lesions include tumors such as craniopharyngiomas gliomas, hamartomas and inflammatory conditions (e.g., Sarcoidosis). Craniopharyngiomas arise from ectodermal remnants of Rathke pouch, forming the most common pituitary tumor in children. Pathology shows stratified squamous epithelium with areas of keratinization and cysts. Lamellar bone deposits and calcium may be seen.

arises from rests of odontogenic (toothforming) epithelium within the suprasellar/ diencephalic region. contains deposits of calcium, which are evident on an x-ray. Histologically, craniopharyngiomas resemble adamantinomas (the most common tumors of the tooth). Patients may present with bitemporal hemianopia, as the tumor may compress the optic chiasm.

Anterior pituitary hyperfunctioning

Etiology: Most cases caused by adenomas, which usually secrete prolactin, GH, or ACTH. 2. Clinical syndromes correspond to the hormone secreted. a. Hyper-prolactinemia: (amenorrheagalactorrhea syndrome) serum PL associated with pituitary adenomas(prolactinoma). most common pituitary tumor. Women: results in amenorrhea and galactorrhea;

Other causes of elevated prolactin, such as reserpine, phenothiazines, estrogens, or a hypothalamic lesion, should be ruled out. b. Excess growth hormone Gigantism: occurs if there is excessive GH secretion before the growth plates are fused (i.e., before the end of puberty). Excessive skeletal growth may result in heights close to 9 feet tall.

Acromegaly occurs if there is excessive secretion after closure of the epiphyseal plates. There is a gradual coarsening of facial features (i.e., thick lips, protruding jaw, large tongue) and enlargement of the hands and feet. It may be associated with diabetes mellitus, hypertension, osteoporosis and other symptoms associated with space-occupying lesions in the pituitary region, such as visual field defects.

Anterior pituitary hypofunction

is usually manifested as panhypopituitarism, (at least75% of the adenohypophysis) Cx: include symptoms of hypothyroidism, hypoadrenalism, and hypogonadism. GH deficiency in children results in primary dwarfism with normal limb and skull proportions. a. Sheehan syndrome is due to hemorrhagic or ischemic infarction of the pituitary following postpartum hemorrhage with excessive bleeding or shock. It may

b. Empty sella syndrome is due to atrophy of the pituitary. The sella is enlarged on skull x-ray and may mimic a pituitary neoplasm. Surprisingly, it is usually asymptomatic. c. Nonsecreting-chromophobe adenomas may present with hypopituitarism or symptoms of a spaceoccupying lesion. d. Turberculosis( TB), sarcoid , irradiation, and metastasis from other

Syndrome of inappropriate ADH secretion (SIADH)

Diabetes insipidus

Characterized by intense thirst and polyuria together with an inability to concentrate urine owing to lack of ADH (central DIpituitary tumor, trauma, surgery, histiocytosis X) or to a lack of renal response to ADH (nephrogenic DIhereditary or 2 to hypercalcemia, lithium, demeclocycline).

Diagnosis: Water deprivation test urine osmolality doesnt . Response to desmopressin distinguishes between central and nephrogenic. Findings Urine specific gravity < 1.006; serum osmolality > 290 mOsm/L. Treatment Adequate fluid intake. For central DIintranasal desmopressin (ADH analog). For nephrogenic DI hydrochlorothiazide, indomethacin, or amiloride.

Adrenal cortical hyperfunctioning

1. Cushing syndrome is caused by cortisol excess. Etiology: Cushing syndrome may take one of four distinct forms, depending on its cause. (1) Pituitary Cushing syndrome (approximately two-thirds of the cases of Cushing). Pituitary or hypothalamic dysfunction is the most common non iatrogenic cause. basophilic adenomas, referred to as Cushing disease, multiple corticotroph microadenomas. Pituitary Cushing syndrome is characterized by bilateral adrenal hyperplasia and elevated serum ACTH.

Diagnosis: Administration of high-dose dexamethasone suppresses ACTH secretion, causing decreased serum cortisol and decreased urinary 17hydrorycorticosteroid(l7-OHCS) excretion; in normal individuals, low-dose dexamethasone suppresses ACTH secretion. (2) Adrenal Cushing syndrome is usually caused by an adrenal adenoma. It is Characterized by low serum ACTH and failure of dexamethasone suppression of cortical secretion.

(3) Ectopic Cushing syndrome is caused by ectopic secretion of ACTH, most commonly by bronchogenic cancer, but also by pancreatic neoplasms and thymomas. It is characterized by bilateral adrenal hyperplasia and failure of dexamethasone suppression. (4) Iatrogenic Cushing syndrome is rather common and is caused by exogenous administration of glucocorticoids or ACTH.

Clinical features: usually result from excess cortisol but may also be due to excess aldosterone, corticosterone or adrenal androgens. most common in women in the 20 40-yearold age group. hypertension, abnormal glucose tolerance (frank diabetes 200), truncal obesity, muscle wasting in the extremities, moon facies, buffalo hump, cutaneous striae, osteoporosis, hirsutism and amenorrhea in women, weight gain, edema, weakness fatigue, susceptibility to infection and personality disturbances.

Children show growth retardation, delayed skeletal maturation, and precocious puberty if associated with adrenal androgens. Pathology (1) In the pituitary, Crooke hyaline degeneration of basophils results from prolonged feedback inhibition by cortisol.

In the adrenals, there is bilateral cortical hyperplasia, adrenal cortical adenoma or, rarely, carcinoma in Cushing syndrome due to primary causes. Nodular hyperplasia or atrophy of the adrenal cortex is seen with exogenous ACTH or glucocorticoids, respectively

Primary hyperaldosteronism (Conn syndrome)

is due to increased aldosterone secretion, producing sodium retention, increased total plasma volume, increased renal artery pressure, and inhibition of renin secretion. Etiology: Adrenal adenoma most common cause, idiopathic hyperaldosteronism, in which bilateral cortical nodular hyperplasia of the zona glomerulosa is seen, or, rarely, adrenal carcinoma, congenital bilateral zona

Clinical features

Extracellular fluid expansion, and potassium depletion with diastolic hypertension, weakness fatigue, polyuria, polydipsia and headache. Laboratory values reveal hypokalemia, low renin levels, metabolic alkalosis, hypernatremia and (for adenomas) failure to suppress aldosterone with salt loading. Pathology usually shows a single benign adenoma, which is a well-circumscribed, encapsulated small lesion composed of lipid-laden clear cells. Tx: spironolactone, a K+-sparing, aldosterone antagonist.

Secondary hyperaldosteronism

Due to renal artery stenosis, chronic renal failure, as an aldosterone antagonist. CHF, cirrhosis, or nephrotic syndrome. Kidney perception of low intravascular volume results in an overactive reninangiotensin system. Therefore, it is associated with high plasma renin. Laboratory values include high renin levels, hypernatremia, and hypokalemia. Secretion of aldosterone is triggered by elevated renin-angiotensin levels.

Congenital adrenal hyperplasia (CAH)

Etiology: CAH is usually due to a congenital enzyme deficiency of adrenal steroid synthesis resulting in cortisol deficiency and marked enlargement of the adrenals. Types: The three most common forms all cause virilism and are called adrenogenital syndromes. (1) 2l-hydroxylase deficiency causes simple virilizing CAH . There is normal aldosterone function and impaired cortisol production.

Clinical features of adrenogenital syndromes are virilization in women, sexual precocity and premature epiphysea cllosure. Pathology of all types shows diffuse or nodular bilateral adrenal cortical hyperplasia

Adrenal cortical hypofunction

l. Acute adrenocortical insufficiency can be caused by:

a. Rapid withdrawal of exogenous steroids in patients with chronic adrenal suppression b. Stress( e.g.,trauma, surgery, infection), Addison disease or chronic adrenal suppression caused by administration of exogenous corticosteroids c. Adrenal apoplexy, such as in the Waterhouse-Friderichsen syndrome: a massive, sudden adrenal hemorrhage

Chronic or primary adrenocortical insufficiency (Addison disease)

Etiology: Tuberculosis was once the most common cause. The most common etiology today is idiopathic (probably autoimmune). Other possibilities include infections (e.g., fungal, WaterhouseFriderichsen syndrome), iatrogenic causes, metastases, adrenal hemorrhage, and pituitary insufficienry. Pathogenesis: To produce clinical insufficiencf 90% of the adrenal gland must be nonfunctional

Clinical features are due to insufficient cortisol and aldosterone secretion, leading to weakness, weight loss, anorexia, nausea, vomiting, hypotension, skin pigmentation, hypoglycemia with prolonged fasting, inability to tolerate stress, and abdominal pain. Laboratory values show decreased serum sodium and chloride with metabolic acidosis and increased serum potassium. Low serum cortisol and urinary 17-OH CS and low l7-ketosteroids, before and after ACTH administration, should also be measured. ACTH levels are high.

Pathology shows bilateral atrophied adrenal glands. In the idiopathic type, there are lymphocytic infiltrates and zones of fibrosis surrounding islets of remaining epithelial cells

Secondary adrenocortical insufficiency

Etiology: Causes include metastases irradiation, infection, and infarction, affecting the hypophysial-pituitary axis and resulting in decreased ACTH. Clinical features: Secondary insufficiency usually produces less mineralocorticoid malfunction and less pigmentation

Adrenal neoplasms
Adrenal adenomas Clinical features: Adrenal adenomas are mostly asymptomatic and nonsteroid producing. Steroid-producing adenomas may produce Conn syndrome, Cushing syndrome, or virilization in women. They may also occur with multiple endocrine neoplasia (MEN) syndromes.

Pathology: Adrenal adenomas are usually small and unilateral, yelloworange on cut section, and poorly encapsulated. When adrenal adenomas are large, hemorrhage, cystic degeneration or calcification may be seen. Nonsteroid-producing adenomas are usually composed of lipid-filled cells; steroid-producing tumors are often mixed with lipid-filled cells and compact cells.

Adrenal carcinomas Clinical features. Adrenal carcinoma is relatively rare and usually very malignant. Greater than 90% are steroidproducing( often more than one steroid). Pathology: The tumors are often large and yellow with areas of hemorrhage, cystic Degeneration and

Pheochromocytoma
The most common tumor of the adrenal medulla in adults. Etiology: Pheochromocytoma is a neoplasm of neural crest-derived chromaffin cells that secrete catecholamines, resulting in hypertension. Incidence: The highest incidence is in children and in adults age 30-50. Associated with MEN IIa and MEN III (aka IIb), neurofibromatosis or von Hippel-Lindau disease.

Clinical features are related to catecholamine release. Paroxysmal or constant hypertension is the most classic symptom. Also, sweating, headache, arrhythmias, palpitations and nervousness may be seen in any combination. Laboratory values show elevated urinary catecholamines and catacholamine metabolites (e.g., homovanillic acid, HVA, and vanillylmandelic acid, VMA).

Pathology
Tumors are well defined and fibrous, creating a lobulated appearance. The cut surface is light brown, often with areas of hemorrhage and necrosis. Cells are stained with chromium salts (chromaffin reaction) and have a basophilic cytoplasm with secretory granules.

Neuroblastoma
The most common tumor of the adrenal medulla in children, but it can occur anywhere along the sympathetic chain. Less likely to develop hypertension. N-myc oncogene is involved. Tumors grow rapidly, metastasize widely (especially to bone). Produces elevated urinary catecholamines. The prognosis is better if patients are less than1 year old.

Tumors may regress in young infants. The presence of ganglion cells also improves prognosis. The tumors are lobulated with a gray cut surface, showing areas of necrosis, hemorrhage, and calcification. Microscopically, malignant small cells are often seen in a rosette pattern around nerve fibrils.

Hypothyroidism and hyperthyroidism

Hyperthyroidism:
Hyperthyroidism may be seen most often in Graves disease, toxic multinodular goiter, and toxic adenoma. Thyroiditis, thyroid carcinoma, and iodine ingestion are less frequent causes. Pathogenesis is due to increased circulating levels of the thyroid hormones triiodothyronine and thyroxine causing a hypermetabolic state.

Hypothyroidism

Etiology:
a. Congenital thyroid dysplasia or hypoplasia b. Hypothalamic or pituitary disease c. Thyroid conditions causing goiter including iodine deficiency and Hashimoto (autoimmune) thyroiditis d. Surgical or radiation destruction of gland e. Peripheral resistance to thyroid hormone

2. Clinical features depend on the age group.

a. Infants lacking sufficient thyroid hormone develop cretinism. The major effects are on skeletal and CNS development (i.e., short stature, retarded bone age, epiphyseal dysgenesis and mental retardation). Once apparent, the syndrome is irreversible. The initial presentation includes failure to thrive, feeding difficulties, constipation, and somnolence.

Children develop protuberant abdomens, wide-set eyes, dry rough skin, broad nose, and delayed epiphyseal closure. Neonatal screening for elevated TSH is Essential for early detection. b. Older children show short stature, retarded linear growth, and delayed onset of Puberty.

Older children show short stature, retarded linear growth, and delayed onset of puberty. In adults, hypothyroidism causes lethargy, weakness, fatigue, decreased appetite, weight gain, cold intolerance, hair loss, dry skin, constipation, apathy, myopathy, psychosis, metrorrhagia (irregular uterine bleeding), and accelerated atherosclerosis with elevated serum cholesterol.

Myxedema, a syndrome associated with severe hypothyroidism, shows periorbital puffiness, pale doughy skin due to accumulation of hydrophilic mucopolysaccharides, sparse hair, cardiac enlargement, cardiomyopathy, pleural effusions anemia, and thickened facial features. Diagnosis of primary hypothyroidism is based on an elevated TSH and low T4.

Graves disease

Graves disease peaks in the 3rd & 4th decades and is 5 times more common in women. familial predisposition, Associated with other autoimmune diseases such as pernicious anemia and Hashimoto thyroiditis. HLA-DR3- and HLA-B8 positive individuals. Autoimmune, resulting from production of thyroid-stimulating immunoglobulin (TSI) and thyroid growth immunoglobulin,

a. Thyrotoxicosis has symmetric glandular enlargement. b. Ophthalmopathy: lid lag, retraction of the upper lid, proptosis, periorbital edema, and stare. It does not always respond to anti-thyrotoxicosis treatment. c. Dermopathy is characterized by thickened edematous nodules or plaques on the lower extremities and is present in 10% of Graves patients.

Grossly there is a diffuse moderate symmetrical enlargement of the gland. Microscopically, hyper-cellulariry producing small follicles with little colloid and papillary infoldings into the lumen, is seen. The stroma exhibits increased vascularity and variable lymphocytic infiltrate. These changes are not associated with an increased incidence of thyroid

Hashimoto thyroiditis
is a chronic lymphocytic thyroiditis lymphocytic and plasma cell infiltrates, Eventual development of hypothyroidism. Etiology is autoimmune. Autoantibodies to the TSH receptor, microsomes, and thyroglobulin. Hashimoto thyroiditis is the most common type of thyroiditis and is the leading cause of goitrous

The highest incidence is in middle aged women, and there is a higher incidence in patients with a family history of Hashimoto or other autoimmune diseases (e.g., Graves disease, Sjogren syndrome, systemic lupus erythematosus). The incidence of Hashimoto thyroiditis is increased in HLA-DR5 and HLA-B5 individuals.

Clinical features of Hashimoto

include painless goiter. Hypothyroidism develops, along with malaise, fever, a decreased T4, and elevated TSH. Pathology:

The gland is enlarged, usually symmetric, and firm. It contains a lymphocytic and plasma cell infiltrate with occasional germinal centers. Acini are partly atrophic, with little colloid and variable fibrosis, increasing as the disease progresses. Follicular epithelium is transformed into Hurthle cells characterized by an eosinophilic granular

Diffuse nontoxic goiter

Diffuse enlargement of the gland in euthyroid Patients. Endemic goiters have a high incidence in certain geographic regions (e.g., mountainous regions or regions far from the ocean). caused by iodine-deficient diets or increased intake of goitrogens (e.g., calcium, fluorides). Sporadic simple goiter is less common. The incidence in women is much greater than in men. Pathogenesis: variable abnormalities with thyroid hormone synthesis resulting in compensatory hypertrophy and hyperplasia of follicular epithelium. The gland becomes hyperplastic, then accumulates colloid

Multinodular goiter
develops from chronic diffuse goiters; it may be toxic or nontoxic and may become very large. Clinical features: Glandular enlargement may cause stridor, dysphagia, and even superior vena cava syndrome (mass effect). 50% produce thyrotoxicosis. These tumors must be differentiated from thyroid cancer, particularly asymmetric tumors in euthyroid patients. Pathology: Glands may be as large as 2 kg and nodular with areas of hemorrhage, scarring, and calcification. They are usually

de Quervain granulomatous subacute thyroiditis

Etiology is probably viral. 2nd most common form of thyroiditis with the incidence in women greater than in men. peaks in the 2nd -5th decades. Symptoms often begin following a viral syndrome, most commonly mumps and coxsackievirus. The course lasts several weeks with a tender gland, a goiter in 30% of patients, fever malaise, and dysphagia. Early in the course, the patient may have mild symptoms of thyrotoxicosis; lately patients are usually euthyroid, and the disease follows a

Pathology a. Grossly, there is moderate irregular enlargement of the gland. b. Microscopically, degeneration of follicular epithelium causes leakage of colloid from follicles, which initiates an inflammatory response with foreign body giant cells, histiocytes, and granuloma formation. The degeneration of epithelial cells is presumably due to a viral infection, but a specific etiology is usually not

Riedel thyroiditis

is a rare disease characterized by connective tissue proliferation, causing destruction of the thyroid gland and fibrosis of surrounding structures. Incidence is greatest in middle age and greater in women than in men. Clinical features. Fewer than 50% of patients are hypothyroid. They may present with stridor, dyspnea, dysphagia, or a painless lump. Grossly, the gland is firm and hard, nodular, and irregular; size varies. Microscopically, complete fibrous replacement of the gland is seen. It may mimic carcinoma.

Congenital thyroid conditions

1. Agenesis or dysgenesis are frequent causes of cretinism. 2. Thyroglossal duct or cyst may communicate with the skin or base of the tongue. It is formed from nests of incompletely descended midline thyroid tissue. 3. Ectopic thyroid nests are usually at the base of the tongue. Prior to removal, it must be documented that the patient has other functioning thyroid tissue.

Tumors:
Thyroid nodules are very common but thyroid cancer is uncommon (less than 2 cases per 1,000 nodules). There is a higher incidence of neoplasia in solitary nodules and in younger patients. Adenomas. Follicular adenoma is the most common. Adenomas may cause pressure symptoms, pain, and, rarely, thyrotoxicosis. There are usually solitary lesions less than 3 cm in diameter that are well encapsulated and compress adjacent

There is a sharp demarcation from surrounding thyroid with a variable amount of colloid, interstitial connective tissue, and acinal size. Cysts make up 25% of solitary nodules and usually represent cystic degeneration of follicular adenomas. Carcinomas represent neoplasia of follicular cells (i.e., papillary, follicular, or anaplastic cancer) and/or parafollicular cells (i.e., medullary cancer). Risk factors include radiation and a genetic predisposition.

Papillary carcinoma
is the most common type. The incidence is higher in women. Pathology: Grossly, there is a papillary branching pattern, which may be cystic or solid. Microscopically, there is a single layer of tumor epithelium on a fibrovascular stalk. Nuclei have a characteristic ground-glass appearance (Orphan Annie). Forty percent of tumors contain psammoma bodies. risk with childhood irradiation. Spread to local nodes is common. Hematogenous spread is rare. Resection is curative in most cases. Radiotherapy with iodine 131 (I131) is also

Follicular carcinoma
makes up 20% of thyroid cancers and is more malignant than papillary cancer. Pathology: Tumors are occasionally encapsulated with penetration through the capsule. They show an adenomatous pattern with development of acini or follicles that are lined by large cells compared to those lining normal follicles. Colloid is sparse. Clinical features: Local invasion and pressure causes dysphagia, dyspnea, hoarseness and cough. Hematogenous metastasis to lungs or bones is common.

Medullary carcinomas
arise from parafollicular cells (C cells). Produce Calcitonin Sheets of cells in an amyloid stroma. Uncommon A minority are associated with MEN IIa and MEN III (IIb) syndromes.

Anaplastic carcinoma
is rapid growing, aggressive and has a poor prognosis. affects older patients (60-80 years old). Tumors are usually bulky and invasive. They are composed of undifferentiated, anaplastic and pleomorphic cells. Early, widespread metastasis and death within 2 years.

Thyroid Lymphoma:
non-Hodgkin type more common in women than in men 60+ associated with Hashimotos thyroiditis. CHOP regimen which consists of cyclophosphamide, doxorubicin, vincristine and prednisone followed by radiation therapy.

Cretinism
Endemic cretinism occurs wherever endemic goiter is prevalent (lack of dietary iodine); sporadic cretinism is caused by defect in T4 formation or developmental failure in thyroid formation. Findings: pot-bellied, pale, puffy-faced child with protruding umbilicus and protuberant tongue.

Acromegaly
Excess GH in adults. Findings: large tongue with deep furrows, deep voice, large hands and feet, coarse facial features, impaired glucose tolerance (insulin resistance). GH in children gigantism. Treat medically with octreotide. GH is normal in stress, exercise, and hypoglycemia. Test with oral glucose tolerance test.

Hyperparathyroidism
Primary Hyperparathyroidism: Usually an adenoma. Hypercalcemia, hypercalciuria (renal stones), hypophosphatemia, PTH, alkaline phosphatase, cAMP in urine. Often asymptomatic, or may present with weakness and constipation (groans). Stones, bones, and groans. Osteitis fibrosa cystica (von Recklinghausens syndrome) cystic bone, spaces filled with brown fibrous tissue (bone pain).

Secondary Hyperparathyroidism: 2 hyperplasia due to serum Ca2+, most often in chronic renal disease. Hypocalcemia, hyperphosphatemia, alkaline phosphatase, PTH. Renal osteodystrophybone lesions due to 2hyperparathyroidism due in turn to renal disease.

Hypoparathyroidism
Hypocalcemia, tetany. Due to accidental surgical excision (thyroid surgery), autoimmune destruction or DiGeorge syndrome. Chvosteks signtap facial nerve contraction of facial muscles. Trousseaus signocclusion of brachial artery with BP cuff carpal spasm. Pseudohypoparathyroidism autosomal-dominant kidney unresponsiveness to PTH. Hypocalcemia, shortened 4th/5th digits,

Hypercalcemia

CHIMPANZEES.

a persistent serum calcium over 10.4 m/dl. Hypercalcemia Caused by Calcium ingestion (milk-alkali syndrome), Hyperparathyroid, Hyperthyroid, Iatrogenic (thiazides), Multiple myeloma, Pagets disease, Addisons disease, Neoplasms, Zollinger-Ellison syndrome, Excess vitamin D, Excess vitamin A, Sarcoidosis. Renal stones are often seen; hyperparathyroidism is also usually associated with hypercalciuria and with hypophosphatemia. Alkaline phosphatase activity is usually elevated. Path: metasis to osteoclasts tunneling through

Pituitary adenoma
Most commonly prolactinoma amenorrhea, galactorrhea, low libido, infertility. Bromocriptine (dopamine agonist) causes shrinkage. Can impinge on optic chiasm bitemporal hemianopia.

Diabetes mellitus

Acute manifestations Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar coma (type 2), unopposed secretion of GH and epinephrine (exacerbating hyperglycemia).

Chronic manifestations
Nonenzymatic glycosylation: 1. Small vessel disease (diffuse thickening of basement membrane) retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, nephropathy (nodular sclerosis, progressive proteinuria, chronic renal failure, arteriosclerosis leading to hypertension, KimmelstielWilson nodules) 2. Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease and gangrene, cerebrovascular disease

Osmotic damage: 1. Neuropathy (motor, sensory, and autonomic degeneration) 2. Cataracts (sorbitol accumulation) Tests Fasting serum glucose, glucose tolerance test, HbA1c (measures longterm diabetic control).

Type 1 vs. type 2 diabetes mellitus

Diabetic ketoacidosis
One of the most important complications of type 1 diabetes. Usually due to an in insulin requirements from an in stress (e.g., infection). Excess fat breakdown and ketogenesis from the in free fatty acids, which are then made into ketone bodies (-hydroxybutyrate > acetoacetate).

Signs/symptoms
Kussmaul respirations (rapid/deep breathing), nausea/vomiting, abdominal pain, psychosis/delirium, dehydration. Fruity breath odor (due to exhaled acetone). Labs: Hyperglycemia, H+, HCO3 (anion gap metabolic acidosis), blood ketone levels, leukocytosis. Hyperkalemia, but depleted intracellular K+ due to transcellular shift from insulin.

Complications Life-threatening mucormycosis, Rhizopus infection, cerebral edema, cardiac arrhythmias, heart failure. Treatment Fluids, insulin, and potassium (to replete intracellular stores); glucose if necessary to prevent hypoglycemia.

Carcinoid Syndrome

MEN Syndrome
Autosomal dominant disorders Type 1 MEN (Wermer Syndrome)

Parathyroid glands, Pancreatic islets Anterior pituitary

Type II MEN (Sipple Syndrome)

Medullary thyroid carcinoma (MTC), Pheochromocytoma (about 50% of cases), and Parathyroid gland hyperplasia (about 20% of cases).

Type 2B MEN(Type III) is defined by

Medullary thyroid cancer and Pheochromocytoma. Mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus

Zollinger-Ellison syndrome
Gastrin-secreting tumor(Gastrinoma) of pancreas or duodenum. Abdominal pain, Diarrhea, recurrent ulcers, Vomiting bood May be associated with MEN type I. Tx with PPI Surgery if it has not spreaded.

Endocrine Pharmacology

Diabetes drugs
Treatment strategy for type 1 DM low-sugar diet, insulin replacement. Treatment strategy for type 2 DM dietary modification and exercise for weight loss; oral hypoglycemics.

Oral Hypoglycemic Agents

Anti Obesity Drugs:

Orlistat Mechanism: Alters fat metabolism by inhibiting pancreatic lipases. Clinical use: Long-term obesity management (in conjunction with modified diet). Toxicity: Steatorrhea, GI discomfort, reduced absorption of fat-soluble vitamins, headache. Sibutramine: Mechanism: Sympathomimetic serotonin and norepinephrine reuptake inhibitor. Clinical use: Short-term and long-term obesity management. Toxicity: Hypertension and tachycardia

Insulin: Lispro (short-acting) Aspart (short-acting) NPH (intermediate) Lente (long-acting) Ultralente(long-acting)

Propylthiouracil, methimazole
Mechanism: Inhibit organification and coupling of thyroid hormone synthesis. Propylthiouracil also peripheral conversion of T4 to T3. Clinical use Hyperthyroidism. Toxicity Skin rash, agranulocytosis (rare), aplastic anemia.

Hypothalamic/pituitary drugs
Drug GH Somatostatin(octre otide) Oxytocin Clinical use GH deficiency, Turners syndrome Acromegaly, carcinoid, gastrinoma, glucagonoma Stimulates labor, uterine contractions, milk let-down; controls uterine hemorrhage Pituitary (central, not nephrogenic) DI

ADH (desmopressin)

Levothyroxine, triiodothyronine
Mechanism Thyroxine replacement. Clinical use Hypothyroidism, myxedema. Toxicity Tachycardia, heat intolerance, tremors, arrhythmias.

Glucocorticoids

Hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone. Mechanism: the production of leukotrienes and prostaglandins by inhibiting phospholipase A2 and expression of COX-2. Clinical use: Addisons disease, inflammation, immune suppression, asthma. Toxicity: Iatrogenic Cushings syndrome buffalo hump, moon facies, truncal obesity, muscle wasting, thin skin, easy bruisability,

A 53-year-old woman is found to have extreme~ low levels of serum calcium, due to a paraneoplastic effect of a lung cancer in her right upper lobe. Her physician determines that the paraneoplastic effect is due to a calcitonin homologue being secreted by the patient's tumor. In explaining the homeostasis of calcium within the body, the patients physician produces the above diagram. which of the following labels describes the action of calcitonin?

A. A B. B C. C D. D E. D and A

Woman presents with diffuse goiter and hyperthyroidism.

What are the expected values of TSH and thyroid hormones?

Low TSH and high thyroid hormones.

48-year-old woman presents with progressive lethargy and extreme sensitivity to cold temperatures.

What is the diagnosis?

Hypothyroidism.

Patient with elevated serum cortisol levels undergoes a dexamethasone suppression test. 1 mg of dexamethasone does not cortisol levels, but 8 mg does.

What is the diagnosis?

Pituitary tumor.

50-year-old man complains of diarrhea. On physical exam, his face is plethoric and a heart murmur is detected.

What is the diagnosis?

Carcinoid syndrome.

Nondiabetic patient presents with hypoglycemia but low levels of Cpeptide.

What is the diagnosis?

Surreptitious insulin injection.

Patient complains of double vision, gynecomastia, and headaches.

What is the most likely diagnosis?

Prolactinoma.

Patient presents with hypotension and bronzed skin.

What is the most likely diagnosis?

1 adrenocortical deficiency (Addisons disease).