Endo Cards (I)

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Tall stature

Constitutional or family hx/genetic Endocrine causes - excess of hormones • Excess GH - pituitary gigantism • Excess androgens - sexual precocity • Excess thyroid hormones - thyrotoxicosis • Excess insulin - infant of diabetic mothers, promotes fetal growth Evaluation: family hx, investigate growth velocity/signs of puberty, look for syndromes • Rarely tx and only if can block excess hormone, estrogen can promote epiphyseal fusion of growth plate

Secondary AI

Def: interruption fo hypothalamic-anterior pituitary axis such that deficit in cortisol, CRTH/ACTH dysregulation, no effect on aldosterone, leads to atrophy of adrenal glands over time Etiology: • STEROIDS - exogenous glucocorticoid administration • Any cause of hypopituitarism: tumors, infiltrative diseases, lymphocytic hypophysitis, Sheehan's, head trauma Pathophysiology: deficit in hypothalamus/pituitary, CRH and ACTH fall so adrenal gland decreases production of cortisol/androgen, over time atrophies Associated symptoms of hypopituitarism: sexual dysfunction, loss of libido, loss of sexual hair, diabetes insipidus (polyria, thirst), headache, visual field deficits Lab Values: hyponatremia (cortisol only), hypoglycemia, hypotension, eosinophilia

Osteoporosis

Def: systemic skeletal disease characterized by low bone mass & microarchitectural deterioration of bone tissue (quality) - too little bone/too little mass + fundamental disruption of mass which is present • Consequences: increase in bone fragility and risk of fracture • DEXA def - >2.5 SD below mean of young adults (Z-scores compared to same age group) • Clinical def: poor bone strength = bone density + bone quality Peak bone mass - total am't of mass which could have achieved based on genes & environment being perfect - factors - genes, ethnicity, estrogen, exercise, nutrition, tobacco use, calcium/vit D, chronic disease, meds • Rapid turnover w/ resorption in excess so depending upon how much have to lose will develop disease faster Systemic diseases associated w/ osteoporosis: post-menopause, endocrine, nutritional disorders, arthritis Effect of lack of estrogen on bone: upregulation of inflammatory environment (IL-1,6, m-cSF, RANK-ligand & receptor) leading to increase in bone resorption, increased Ca • More inactive, decreased weight bearing exercise + decreasedtime in sun - all contribute to osteoporosis Clinical manifestation: fractures of bone. Vertebral fractures kyphosis, decreased residual capacity of lungs, compression of abdominal cavity Dx: DEXA, 1-2.5 SD osteopenia, >2.5 osteoporosis, 2.5-4 severe osteoporosis Risk increases w/ age, women esp after menopause, fracture risk doubles ever SD below 1, osteopenia 50% by age 60 Fragility fracture - fracture w/ minimal trauma • Bone densities predict future risk of fracture in each site, lowest site is total person's risk • Types of fractures: vertebral/compression, hip, wrist • Women higher risk of fractures • Risk factors: 1st degree relative w/ fragility fracture, low body weight, smoking, steroid therapy >3 mths

Aldosterone - Mineralocorticoid (MR)

Made by zone glomerulosa in adrenal cortex by aldosterone synthase - composed of 11 hydroxylase and 11 oxidase Stimuli for secretion/production: AII, K, minor - ACTH Functions: promotes Na reabsorption, K excretion and H+ excretion in distal tubule of kidney

Fetal growth..Is linked to adult onset diseases.

"Barker Hypothesis"-in poor nutritional conditions, a pregnant woman can modify the development of her unborn child such that it will be prepared for survival in an environment in which resources are likely to be short, resulting in a thrifty phenotype.

V. Natriuretic peptides "escape phenomenon"

"escape phenomenon" is responsible for the absence of edema in most patients with primary hyperaldosteronism. - Natriuretic peptides made by cardiac atria and ventricles when they are distended by ↑BC. ANP and BNP are ↑ ↑ in 1o hyperaldosteronism. They inhibit most of the effects of RAAS and act as vasodilators. o BNP is being used as a marker of increased intravascular volume and heart failure in clinical practice, and it is also being used in the treatment of CHF.

The three problems of pharmacologic glucocorticoid therapy

* Cushing's syndrome. Over time, some or all of the symptoms of excess glucocorticoids (Cushing's syndrome) can develop. Osteoporosis, for example, occurs in at least 50% of persons who require long-term glucocorticoid therapy. In addition, suppression of the inflammatory response creates increased susceptibility to infections. In children, pharmacologic glucocorticoid therapy is a potent growth inhibitor. * Symptom exacerbation on withdrawal. * Adrenocortical suppression. Prolonged treatment with glucocorticoids by suppressing secretion of CRH leads to atrophy of the patient's own adrenals, pituitary cells producing ACTH, and hypothalamic cells producing CRH. Hypothalamic neurons and adrenal cortex in particular can be very slow to recover. Therefore, even if the patient is treated without undue side effects, and the drug is successfully withdrawn, the patient may be left in a state of functional adrenal insufficiency. HPA may take months to recover normal function), during which time a stressful situation can provoke adrenal crisis. POSSIBLE OUT: It appears that some of the side effects of pharmacologic treatment with a glucocorticoid, as well as the development of atrophy of the patient's own adrenals, can be reduced by giving the drug less often—every 48 hours, rather than on a daily schedule. This program appears to give the patient's tissues an opportunity to recover from excessive glucocorticoid effects. On the days in which the drug is not given, enough ACTH seems to be secreted to prevent the adrenals from becoming completely atrophic.

What feedback controls exist over cortisol secretion? how can they be demonstrated?

* High circulating levels of free glucocorticoids inhibit CRH, ACTH, and thus cortisol secretion (sigmoid dose-response curve). - Glucocorticoid feedback inhibition occurs at both the hypothalamus and the pituitary. After prolonged treatment with glucocorticoids, the hypothalamus may remain suppressed for several months. Thus ACTH secretion is determined by two opposing forces: the stimuli converging through the median eminence to increase ACTH secretion, and the negative feedback action of glucocorticoids to inhibit ACTH secretion.

Defects in VLDL secretion occur in both familial combined hyperlipidemia and familial hypertriglyceridemia. How do the VLDL differ in the two disorders?

* familial hypertriglyceridemia (FHTG) are characterized by overproduction of TG - leading to normal number of VLDL particles with excess amount of TG in each. or "hypo apoB100" * familial combined hyperlipidemia (FCHL) primarily oversecrete apo B-100 into VLDL and/or LDL particles; these particles tend to be smaller than normal. Can have a variable even familial pattern after fasting.

Disease of Adrenal Cortical Excess

*Hyperaldosteronism (Conn's Syndrome) Hypertension and hypokalemia Na retention and K secretion Adenoma vs bilateral hyperplasia *Hypercortisolism (Cushings Syndrome) Myriad of symptoms ACTH dependent and ACTH Independent Exogenous administration *Hyperandrogenism Adrenal cancer more commonly than adenoma Excess of DHEAS / Testosterone causing virilization

Adrenal Insufficiency - Treatment Chronic Adrenal Insufficiency

*Primary AI Glucocorticoid Replacement Hydrocortisone\ Mineralocorticoid replacement Fludrocortisone *Secondary AI Hydrocortisone Dexamethasone at bedtime Prednisone at bedtime

Nonfunctioning pituitary tumors- Treatment

*Medical therapy In general, the first line of treatment for patients with a prolactinoma is medical rather than surgical. Most patients (80 percent) will have their prolactin levels restored to normal with medication alone. The medications mimick the activity of dopamine, thereby sending the message to the prolactin-producing cells to stop making prolactin. Cabergoline (Dostinex) is usually the preferred medication because it is very effective, has the fewest side effects, and the easiest dosing schedule (twice a week). It is more expensive, however Bromocriptine (Parlodel) is sometimes used, but its effectiveness is commonly limited by side effects (most common are nausea, headache, and dizziness) With treatment, most women experience a return of menses and many become fertile again. The size of the prolactinoma will be reduced in the majority of patients, which can improve vision and end headaches. The management of medical therapy for fertility and during pregnancy requires special consideration. As of now, Cabergoline is not FDA-approved for use during pregnancy, and therefore bromocriptine may be necessary *Surgery For patients that do not respond to medical treatment with cabergoline or bromocriptine, surgery is considered Ideally, surgery should be performed within six months of starting medical treatment because the tumor may become more difficult to remove thereafter. Transsphenoidal surgery is effective for women with relatively small adenomas. The long-term cure rate is 80 percent to 90 percent. The cure rate is lower for larger tumors, particularly in men. Urgent transphenoidal surgery is advised for patients with pituitary apoplexy. *Radiotherapy Because most patients with prolactinomas respond well to medical therapy, radiation is used in few patients. Stereotactic radiation is generally preferred over external beam radiation therapy because a higher dose of radiation can be delivered to the tumor and less to normal brain structures.

Acromegaly Clinical Features

- Age at Diagnosis (~ 40 years) Delay to Diagnosis (~8 years) *Enlargement of hands and feet -soft and doughy *Distal fingers and toes are widenned "paddle" toes *Acral/facial changes (98%)" enlargement of forehead and jaw, under bite, spreading teeth, enlarging tongue, nose and lips *Sleep apnea *Hyperhydrosis *Entrapment Neuropathy *Arthritis *Macroadenomas -compressive symptoms *Headaches *Hyperprolactinemia and or pituitary hormone deficiency

(GUNNER) - Type I: Hyperchylomicronemia

- autosomal recessive; deficiency of LPL or mutation in apoC-II (required co-factor for LPL) LPL degrades TGs in circulating chylomicrons and VLDL → ↑ serum TG and ↑ chylomicrons Clinical presentation: fatty liver changes, chylomicron-induced acute pancreatitis, red-orange xanthomas (cholesterol-laden deposits), milky, lipid-laden supernatant in centrifuged blood sample No increased risk of atherosclerosis

Addison's disease is associated with hypotensive shock. Explain why this occurs.

- maybe hemmoraghe or not enough ADH?

Conditions affecting plasma catecholamine levels

- through sympathetic nervous system + adrenal medulla • Increase catecholamine levels - change in posture, low intravascular volume, exercise, smoking, stress, hypoglycemia, pheochromocytoma • Decrease catecholamine levels - change in posture down, autonomic nervous system deficiency, bilateral adrenalectomy • NE & Epi rise differentially in response to each stimulus

Metabolic Effects of GH

-Promotes protein synthesis -Stimulates lipolysis (increases FFA's) -Antagonizes the action of insulin on glucose metabolism (decrease peripheral glucose uptake) Promotes hepatic glucose production

→ ↑ ↓ 2o 1o

...

(GUNNER) - Functions of thyroid hormone:

1) Metabolism: ↑ basal metabolic rate, oxygen consumption, cardiac output, and minute ventilation. Also ↑ glycogenolysis, gluconeogenesis, and lipolysis. 2) Growth and maturation: bone growth, synergism with growth hormone and IGF-1 (insulin growth factor-1) 3) CNS (central nervous system): perinatal maturation; hypothyroid neonate has increased risk for mental retardation 4) ANS (autonomic nervous system): increases sympathetic activity because it up-regulates β1-adrenergic receptors in the heart. 5) Temperature regulation: increases thermogenesis For thyroid hormone functions, remember the 4 B's. Brain maturation Bone growth Beta-adrenergic effects BMR ↑

The mobilization of thyroid hormones from thyroglobulin begins with the endocytosis of colloid by the follicular cell.

1) This process is mediated by pinocytotic extensions of microvilli from the apical membrane. 2) The endocytotic vesicles enter the cell and fuse with lysosomes to form phagolysosomes. 3) Proteolysis of thyroglobulin with release of T3, T4, MIT, and DIT occurs as the phagolysosomes migrate toward the base of the follicular cell. 4) The active thyroid hormones diffuse out of the follicular cell and enter the circulation, while MIT and DIT undergo "dehalogenation" reactions with reclamation of liberated iodide. A small amount of this reclaimed iodide leaks out of the gland, but the majority is reutilized for a new cycle of thyroid hormone synthesis.

Thyroid Cancer - Differentiated Thyroid Cancer Follicular

2nd most common Hurthle cell (oncocytic) variant is more aggressive Hematogenous spread - lung and bone Surgery is mainstay of therapy + RAI using I-131 + LT4 suppression Follow serum Tg as marker of disease Associated with a slightly worse prognosis

Short Stature

A common clinical problem A symptom, not a disease May represent a variant of normal growth May indicate pathology

Adrenal Cortex - Feedback

ACTH NOT in control of Glomerulosa/Cortisol

Actions of ADH

ADH acts via two different receptors, V1 and V2. - V1 = vasopressor. - V2 = antidiuretic effects . o In DCT to increase permeability. results in hypertonic urine and decreased urine volume. o BL side → AC → cAMP → Luminal PKA activation → AQ2

Abnormal fetal growth linked to

Adult onset Obesity Type 2 diabetes Dyslipidemia Hypertension Coronary artery disease Abnormal kidney development

EMPTY SELLA SYNDROME

An enlarged empty sella may be primary (due to a congenital diaphragmatic defect) or secondary to surgery, radiation, or pituitary infarction. The majority of patients with congenitally empty sella have normal pituitary function. Hypopituitarism (and/or hyperprolactinaemia) may be found in instances due to previous pituitary disease. Occasionally, a cystic pituitary mass may simulate an empty sella on CT or MRI, necessitating a cisternogram for precise delineation.

Laboratory Findings in Hypothyroidism

Anemia Hyponatremia Abnormalities in liver enzymes Increase in creatine kinase Hypercholesterolemia and Hypertriglyceridemia (mild)

(GUNNER) - Apolipoproteins are proteins that bind to lipids; they have various functions:

ApoA-I activates LCAT ApoB-100 is the sole protein component of LDL ApoB-48 lacks the LDL-receptor binding sequence that ApoB-100 has ApoC-II activates lipoprotein lipase (LPL) in capillaries

Treatment- Short

Based on etiology GH, IGF-1 Synthroid Long acting GnRH

Physical examination in growth evaluation:

Check for syndromes such as Turner, Noonan, or hypochondroplasia Thyroid evaluation Determine pubertal status Check for bone malformations Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Soci

(GUNNER) - The innermost layer is the medulla, which secretes catecholamines

Chromaffin cells are found in this layer

What are the most common causes of the chylomicronemia syndrome?

Chylomicronemia is usually the result of both a genetic and an acquired defect in lipoprotein metabolism. Primary (genetic) defects: Familial combined hypercholesterolemia -↑ apo B production Familial hypertriglyceridemia- ↑ triglyceride production Remnant removal disease- ↓ removal remnants,↑ lipid production Secondary (acquired) defects -Medical disorders: Diabetes (~50%) Hypothyroidism Uremia / dialysis Cushing's syndrome Rapid weight gain Nephrotic syndrome Lipodystrophy -Drugs β-blockers Diuretics Estrogen Glucocorticoids Alcohol Retinoids

Prolactinoma Summary

Common Presentation Headaches and hypogonadism Amenorrhea - galactorrhea Diagnosis Prolactin levels and imaging (consider the hook effect) Rule out Physiological causes of elevated prolactin Incidentaloma, Macroplactinemia Treatment -Medical

Nodular Thyroid Disease

Commonly associated with normal FT4 and TSH (Non-toxic) Usually asymptomatic - but always need to monitor for symptoms Dysphagia Dypsnea with arms raised or lying down Hoarseness which does not resolve Stridor Substernal nodules are not amenable to physical exam OR US CT neck and chest (if needed) Asymptomatic nodules require further evaluation for cancer >1 cm nodules usually need FNA High risk individuals include...Family history and Radiation exposure

Consequences of Untreated Hypothyroidism

Continued symptoms and disability Hypercholesterolemia Congestive heart failure Effusions Anemia Neurologic abnormalities Myxedema Coma

Hypothyroidism - Signs

Dry skin Cold skin - diverted blood flow Periorbital edema - GAGs Depressed affect Hypertension Bradycardia Decreased myocardial contractility Lethargy Edema (non-pitting) Brittle nails and hair

(GUNNER) - Secondary Hyperaldosteronism

Due to over activity of the renin-angiotensin system Low intravascular volume stimulates renin-angiotensin system which increases aldosterone production Causes include: CHF (congestive heart failure), cirrhosis, chronic renal failure, nephrotic syndrome, and renal artery stenosis Results: same as for primary (increased intravascular sodium, water, with decreased potassium, and metabolic alkalosis) Diagnosis: increased aldosterone levels with high plasma renin. Renin levels differentiate primary from secondary hyperaldosteronism Treatment: correct inciting causes, beta-blocker or diuretic for hypertension

Familial short stature

Family history of short stature Birth weight above 2.5 kg Height below -2 SD for age Growth parallel to the curve Appropriate bone age for chronological age Normal onset of puberty

(GUNNER) - Reidel thyroiditis:

Fibrous tissue replaces thyroid parenchyma, with fibrosis extending beyond the thyroid capsule into surrounding tissue. Hypothyroidism may occur.

Nonfunctioning pituitary tumors- Radiation treatment

Fractionated external bean Gamma knife o linear accelerator stereotactic radiosurgery Improvement 18 months after radiotherapy Most will have radiation induced hypopituitarism

GH DEFICIENCY DIAGNOSIS

GH measurements unreliable IGF-I STIMULATION TEST Insulin tolerance test (ITT) Glucagon test Arginine stimulation Combinations -Arginine + GHRH

"GH is not only for growth"

GH plays an important role in the anabolic state and fuel regulation

Growth Hormone Deficiency- Clinical manifestations

Growth retardation Fatigue Decreased general well being Decreased exercise tolerance Reduced bone remodeling activity - Increased adiposity -central obesity Hyperlipidemia > atherogenesis

Factors influencing fetal growth are:

Hormones *Insulin excess-macrosomia, deficiency-IUGR GH and thyroid hormone not major players Leptin and Placental GH levels in maternal serum are decreased in IUGR Growth factors *Insulin-like growth factor (IGF-I (late), IGF-II (early)) IGF binding protein-3 (IGFBP-3) Epidermal growth factor-lung, adrenal and GI Transforming growth factor Platelet-derived growth factor Fibroblast growth factor-limb and skeletal (FGF-R mutation results in Achondroplasia) Nerve growth factor

(GUNNER) - 21-carbon steroids include progesterone, deoxycorticosterone, aldosterone, and cortisol.

Hydroxylation at C-21 leads to the production of deoxycorticosterone, which has mineralcorticoid (but not glucocorticoid) activity. Progesterone is the precursor for the others in the 21-carbon series. Hydroxylation at C-17 leads to the production of glucocorticoids (cortisol).

Be able to identify the stages of, and what the lab tests will look like, in the course of a thyroiditis.

Hyperthyroidism on the basis of glandular destruction with release of preformed hormone may occur either after radioiodine administration or in the disease process referred to as "subacute thyroiditis". - The latter condition, which is felt to be caused by a viral infection, is characterized by intense inflammatory infiltration of the thyroid and disruption of the follicles. Thyroid swelling with pain and local tenderness are typical of this condition. A painless form of thyroiditis with transient hyperthyroidism may occur in women after childbirth.

A primer on managing weight disorders

Hypocaloric Diets Behavioral Modification Intense exercise regimens Combinations of 1+2+3 Pharmacotherapy BMI >27 + a co-morbidity BMI > 30 Combinations of 1+2+3+5 Weight Reduction Surgery Hypocaloric Diets 1 lb of fat = 3500 kcal Therefore, a deficit of 500 kcal per day would lead to loss of 1 lb per week Change in Energy Stores = Energy Intake - Energy Expenditure Assess patient's intake and energy expenditure Utilize physiology rather than prescribing a "generic" caloric goal Work with a patient to reach of goal of 500 kcal deficit per day Utilize exercise to promote increased energy expenditure The main role of exercise is to promote weight maintenance

Cat Synth & Secretion.

I. Synthesis: 1) *RLS: tyrosine hydroxylase catalyzed: tyrosineDOPA 2) glucocorticoid-induced enzyme (PNMT) needed to methylate NE/E. a. Epinephrine i. secreted by the adrenal medulla ii. normally only CAT to exert CV or metabolic effects b. NE: i. Secreted by postganglionic sympathetic nerve endings (less from medulla). 1. Medullary tumors make lots of NE - high enough to have CV/Met effects. c. Dopamine i. not a normal product of the adrenal medulla.

Adrenal Insufficiency - Secondary Defining this disorder

Interruption of the hypothalamic-anterior pituitary axis such that a deficit in cortisol production occurs No effect on aldosterone (b/c of renin) May be hypothalamic or pituitary in origin Over time, the lack of adrenal stimulus by ACTH causes atrophy of the adrenal glands

(GUNNER) - Venous drainage of adrenal gland:

Left adrenal gland drainage involves the left adrenal vein, left renal vein, and inferior vena cava Right adrenal gland drainage involves the right adrenal vein and inferior vena cava There is no involvement of right renal vein

Explanation of why the outer visual fields are lost when a pituitary tumor extends above the pituitary fossa

Local tumor growth. The growth of a tumor within a small bony cavity can cause pressure on important local nearby structures. If the tumor extends outside the pituitary fossa it may put pressure on the optic chiasm which lies directly above Since the fibers of the optic chiasm are crossing over, coming from the medial parts of both retinae, it is the outer parts of the visual fields which are lost first

Growth hormone dependent growth factorsStructure and synthesis of insulin and IGF-I/ somatomedin-C

Major action is growth promotion and mitogenic effect Transgenic mice without hepatic IGF-1 develop normally People with absent GH receptors Laron dwarfism are short

Thyroid and growth

Major contributor of postnatal growth Hypothyroidism occurring postnatally results in profound growth failure and arrest of skeletal maturation Thyroid hormone has direct effects on epiphyseal cartilage Permissive effect on GH secretion Decreased GH secretion

Thyrotoxicosis - A word on Thyroiditis

Many different forms of Thyroiditis - this pattern is the most common (independent of etiology) course for any patient. Etiology includes... Subacute - painful - post-viral, post-bacterial,post-fungal, post-mycobacteria Acute thyroiditis - fluctuance, severe pain, fever, marked ESR rise - bacterial Painless (silent) thyroiditis - most common = post-partum (TPO+) Drug induce - Amiodarone, IFN-α, post-iodinated contrast load, post-RAI-131 - usually painless Reidels thyroiditis - fibrosis

Prolactinoma -Treatment

Medical therapy In general, the first line of treatment for patients with a prolactinoma is medical rather than surgical. Most patients (80 percent) will have their prolactin levels restored to normal with medication alone. The medications mimick the activity of dopamine, thereby sending the message to the prolactin-producing cells to stop making prolactin. Cabergoline (Dostinex) is usually the preferred medication because it is very effective, has the fewest side effects, and the easiest dosing schedule (twice a week). It is more expensive, however Bromocriptine (Parlodel) is sometimes used, but its effectiveness is commonly limited by side effects (most common are nausea, headache, and dizziness) With treatment, most women experience a return of menses and many become fertile again. The size of the prolactinoma will be reduced in the majority of patients, which can improve vision and end headaches. The management of medical therapy for fertility and during pregnancy requires special consideration. As of now, Cabergoline is not FDA-approved for use during pregnancy, and therefore bromocriptine may be necessary Surgery For patients that do not respond to medical treatment with cabergoline or bromocriptine, surgery is considered Ideally, surgery should be performed within six months of starting medical treatment because the tumor may become more difficult to remove thereafter. Transsphenoidal surgery is effective for women with relatively small adenomas. The long-term cure rate is 80 percent to 90 percent. The cure rate is lower for larger tumors, particularly in men. Urgent transphenoidal surgery is advised for patients with pituitary apoplexy. Radiotherapy Because most patients with prolactinomas respond well to medical therapy, radiation is used in few patients. Stereotactic radiation is generally preferred over external beam radiation therapy because a higher dose of radiation can be delivered to the tumor and less to normal brain structures.

Genetic Expectations

Midparental height Boys: [(M+F) + 5 inches]/2 Girls: [(M+F) - 5 inches]/2 Familial timing of puberty and growth Ethnicity

Thyroid Cancer - Differentiated Thyroid Cancer Papillary

Most common Lymphatic metastasis - neck lymph nodes Also spreads to lung and bone Excellent Prognosis Responds to I-131 Surgery is mainstay of therapy +/- RAI using I-131 + LT4 suppression Follow serum thyroglobulin as marker of disease

Atherogenic Cholesterol - How do we calculate?

Non HDL Cholesterol= VLDL + IDL + LDL= Total Cholesterol minus HDL - when TG over 200 - predictive of CV events

What factors affect HDL levels, both positively and negatively?

Obesity, smoking, high carb, hyper-TG, steroids - Low HDL major causes.

Symptoms caused by Pituitary Failure

Partial Panhypopituitarism Deficiency of sex hormones Hypothyroidism GH deficiency Adrenal insufficiency

Adrenal Insufficiency - Complications of Steroids

Problems with Glucocorticoid Replacement / Therapy Iatrogenic cushings syndrome Use lowest effective dose in patients with AI Use lowest effective dose for shortest period of time in pharmacotherapy Recurrence of Disease Processes - Steroid sparing regimens Rheumatoid arthritis Transplant patients Adrenal insufficiency Equivalent of 5 mg prednisone for > 2 weeks HPA suppression - Most common cause of Secondary AI Tapering doses vs cessation of steroids

Tx of Cushings

Resect tumor, dose after surgery b/c axis suppressed, monitor by withholding replacement of steroids and see undetectable levels, symptoms improves in wks to mths

Adrenal Insufficiency Clinical Manifestations Specific to Primary AI

Skin pigmentation - increased endogenous production of melanins secondary to ACTH stimulation -Palms, dorsal surface of hands -Buccal mucosa -Sun-exposed areas Salt craving

Hyperthyroidism - Treatment of Storm

Storm or Thyrotoxic Crisis Precipitated by an acute insult or illness Increased risk in poorly treated or inadequately treated thyrotoxicosis Avoid point scoring systems - it is a clinical diagnosis! PS - if the patient is calm, afebrile and can take PO without nausea or emesis, it is almost assuredly not storm If they are agitated, febrile and cannot take PO - treat as storm until proven otherwise High mortality from cardiovascular causes These patients require the ICU Treatment Algorithm High doses of Propranolol 40 - 60 mg PO q4H (or i.v. beta-blocker) High doses of Methimazole (PO, NG, PR enema) 1 hour after Methimazole dose - can give Iodine solution Why one hour? High dose steroids +/-

Adrenal Insufficiency Clinical Manifestations - Acute Adrenal Crisis

Syndrome dominated by -Hypotension followed by shock -Hypoglycemia -Abdominal pain and emesis -Orthostatic hypotension -Hyponatremia and Hypoglycemia Treatment Aggressive IVF (2-3 liters bolus) Random cortisol +/- cosyntropin testing Hydrocortisone 100 mg iv t.i.d. No clear role for mineralocorticoid at these doses M-Receptor is completely saturated Treat underlying illnesses

Pathologic causes of short stature

Syndromes: Turner syndrome Noonan Syndrome Trisomy 13,18,21 Hypo/achondroplasia Russell-Silver syndrome Prader-Willi syndrome Systemic disease: Renal failure Inflammatory bowel disease Malnutrition Cystic fibrosis Congenital heart disease Drugs: High-dose estrogens High-dose androgens Glucocorticoids

Be able to describe the clinical manifestations, end-organ effects, diagnostic evaluation, and therapy for hypothyroidism. How would you clarify if a patient has primary or secondary hypothyroidism?

The most common autoimmune cause of hypothyroidism is referred to as Hashimoto's disease or chronic lymphocytic thyroiditis. The microscopic features of this disease include lymphocytic infiltration with the formation of germinal centers and a fibrotic response which eventually replaces functional thyroid tissue. A characteristic change of the follicular cells seen in Hashimoto's disease is the so called Hürthle cell. This cell is a large eosinophilic cell with an eccentric nucleus and a high mitochondrial content. The thyroid peroxidase enzyme has been identified as the thyroid microsomal antigen that is a major target of autoantibodies and cell-mediated destruction of the thyroid gland in Hashimoto's disease. The progress of this disease process may be followed clinically by measuring the thyroid anti-microsomal antibody titer. A low free thyroxine index and high TSH are diagnostic of hypothyroidism, except in the 5% of cases due to pituitary failure in which the TSH will not be elevated. SYMPTOMS: Clinically the hypothyroid patient complains of being cold and often gains weight due to impaired calorigenesis and fluid accumulation. The skin appears gray due to cutaneous vasoconstriction or occasionally is somewhat yellow in appearance due to impaired turnover and clearance of carotine pigments. Impaired turnover of interstitial glycosaminoglycans causes accumulation of these highly hydrophilic molecules below the skin. This so called myxedema leads to puffiness around the eyes and a doughy dry consistency to the skin. Myxedematous changes of the vocal cords and tongue can lead to hoarseness and macroglossia. Impairment of hypoxic and hypercarbic ventilatory drives leads to impaired ventilation and oxygenation. Heart contractility may be reduced with a fall in cardiac output. Decreased blood oxygen saturation and cerebral blood flow lead to progressive mental impairment. If untreated, the patient may eventually succumb to myxedema coma. T4 is inert and allow systemic circulation to compensate accordingly. Be careful with old people. Hypothyroidism is treated by T4 replacement therapy. Replacement therapy with T4 as opposed to T3 ensures a steady hormone supply due to the long half-life of T4. Peripheral conversion of T4 to T3 provides adequate T3 levels. The T4 dose is adjusted to bring the TSH level just into the normal range. Excessive T4 replacement, as revealed by TSH suppression, may lead to an increased rate of bone loss and exacerbation of osteoporosis in women. It is imperative in advanced cases of hypothyroidism to replace thyroid hormone slowly to avoid excessively rapid acceleration of the metabolic rate. In the latter situation increased circulatory demands can precipitate cardiac arrhythmias and sudden death. An exception to the rule of slow thyroid hormone replacement is made in the case of patients who present in myxedema coma. In this situation, rapid T4 replacement may be life-saving. Glucocorticoid replacement must also be provided in myxedema coma to meet the increased tissue needs which occur with rapid acceleration of the metabolic rate.

Treatment of tall stature

Treat underlying cause Promote epiphyseal fusion with estrogens

What are the primary classes of drugs that are used for treatment of lipoprotein disorders?

Use of medications should be reserved for those who fail to achieve target cholesterol levels with dietary intervention alone. Five classes of medications are currently available: 1) fibric acid derivatives (gemfibrozil; fenofibrate), 2) HMG CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, and atrovastatin), 3) bile acid binders (cholestyramine, colestipol), 4) cholesterol absorption inhibitors, and 5) niacin. One's choice for a first line medication depends on the cause of the hyperlipidemia (niacin and fibric acid derivatives are best for disorders of triglyceride metabolism while the "statins", bile acid binders, and cholesterol absorption inhibitors are better for reducing elevated LDL cholesterol). Combination therapy may be used to help achieve target goals.

CAUSES OF SHORT STATURE

VARIATIONS OF NORMAL (90%) - Constitutional delay - Familial short stature PATHOLOGIC SHORT STATURE

(GUNNER) - Lipoprotein complexes are composed of

cholesterol, TGs (triglycerides), and phospholipids Lipoprotein complexes include: chylomicrons, VLDL, IDL, LDL, and HDL

"Stalk Effect"

might have infiltration into the skull. May have some AP issues with the exception of PRL.

Incidentaloma

tumor found incidentally for the wrong reason. Needs to be worked up, tend to be non-functioning.

Primary Hypercholesterolemia

• Clinically: LDL cholesterol >160 - ¼ of American adults, very common • ¼ polygenic - no specific gene • Very rarely - familial types w/ specific mutation

(GUNNER) - Type IV (hyperlipidemia):

↑ hepatic VLDL production leads to ↑ serum VLDL and ↑ serum TG High VLDL levels are also frequently associated with chronic alcoholism Leads to pancreatitis

Paget's Disease

Aggressive osteoclast resorption of bone w/ increased, disorganized osteoblast mediated bone repair • Osteoclasts - increased in number & size, increased nuclei and appear bizarre • Structural weakness prevails Etiology - genetic, viral (nuclear inclusions on biopsy) Biochem - normal ecept for increased alkaline phosphates Radiographic features - coarse trabeculae, cortical thickening, lytic & sclerotic changes Complications: deformity - hearing loss, gait abnormalities • Bone weakness w/ fracture, pain, neoplastic transformation -osteosarcoma, heart failure Tx: high dose bisphosphonates

Hypothalamus/Pituitary

Anterior pituitary - derived from gut, posterior - terminations of neurons from hypothalamus Rathke's pouch - of anterior pituitary - cyst/tumor due to prob w/ differentiation Hormones of the hypothalamus affecting anterior pituitary: TRH, GnRH, Somatostatin (inhibits GH and TSH), CRH, GHRH Anterior pituitary - 3 classes of hormones • Corticotrophin-lipotrin - ACTH - (Adrenal CORTICOTROPHIN hormone) - POMC, vasopressin also stimulates • Glycoproteins - LH, FSH, TSH - same alpha, beta confers specificity, carb unit biologically active • Somatomammotropins - GH, Prolactin - only hormone which is inhibited so w/o inhibition is secreted Blood supply: portal system from hypothalamus to anterior pituitary

Hypothyroidism

Causes of Primary Hypothyroidism: • Most common - removal or destruction w/ iodine radiation • Hashimoto's Disease - next most common • autoimmune - Anti-TPO antibodies - not cause of disease, just a marker • lymphocytic infiltration of thyroid w/ gradual replacement of thyroid cells by lymphocytes • gradual progressive, cell-mediated, when reaches a critical point get symptoms • iodine deficiency - rare in N. America due to supplements Lab values: low (free) T4 and high TSH (up to 16) Symptoms: • Cold - poor heat granulation, low body temp - blood to central organs, not periphery and so muscle cramps • Increased peripheral resistance & mild HTN • Non-pitting edema - accumulation of high protein fluid • Heart slows - fatigue, mental functioning low • Thyroid - firm and enlarged Treatment: not reversible so give synthetic thyroxin supplementation - T4, organs normal • Half life ~1 wk so 3-4 wks for dose to equilibrate and to feel better, 4-6 wks to test Secondary hypothyroidism - T4 low and TSH also low - pituitary prob

Hyperaldosteronism - most common endocrine cause of HTN Clinical presentation:

Clinical presentation: • Sodium increase - increased reabsorption: HTN • Alkalosis - H ions also excreted • Hypokalemia - increased excretion - fatigue, muscle weakness, polyuria, thirst, headache, glucose intolerance, tetany, cardiac arrhythmias - potentially life-threatening "Aldosterone Escape" -aldosterone produced continuously yet effect limited - increases BP, Na till reach expansion of intravascular volume and then shuts off - but only in primary w/ increase of volume

CAH - Congenital Adrenal Hyperplasia

Def: autosomal recessive genetic diseases w/ diverse phenotype - defect in normal production of cortisol leading to elevated ACTH and subsequent adrenal hyperplasia • Heterogeneous type based upon level of enzyme defect - will shift to other pathways • Lack 21 hydroxylase - cannot make aldosterone or cortisol, just lots of androgen • Block 17 hydroxylase - get excess aldosterone w/o cortisol or androgens • Partial defects - variable severity 21 hydroxylase deficiency • Cannot make aldosterone or cortisol, only androgen and so get androgen deficiency • Males - normal infant genitalia but female ambiguous genitalia - clitoromegaly, labio-scrotal fusion • Symptoms in both: premature puberty in early childhood, advanced growth & bone age but early closure of growth plates so short later in life, acne, oily skin, early pubic hair • Adult females - hirsutism, oligomenorrhea, infertility • 3 variants of presentation • Classic - Na wasting, virilized, AI: full enzymatic defect so acute AI at birth as lack cortisol which cannot be overcome and lack aldosteron so salt wasting - hyponatremia, hyperkalemia, acidosis, vascular collapse Symptoms as if primary AI Ambiguous genitalis in females • Classic - simple virilizers Compound heterozygote w/ low but sufficient production of cortisol and aldosterone to prevent AI and salt wasting Virilization - less severe at birth, progressive if untreated Rapid bone growth but premature closure so short stature, acne & pubertal hair • Late-onset - virilized Mild enzymatic defect, most common, adequate cortisl & aldosterone Excess adrenal androgens w/ onset in adolescence or early adulthood - normal genitalia at birth Secondary amenorrhea, acne, hirsutism, premature puberty - tho may be asymptomatic • Ethnic proclivity - Adhkenazis, Hispanics, Italian • Dx: heelstick on newborn w/ high levels of 17 OH progesterone, may require ACTH stimulation test to further drive system • Tx: steroid replacement - treat Ai by turning off excess ACTH w/ both glucocorticoids & mineralocorticoids and closely following growth and bone age • Late onset - steroid suppression of ACTH - lowest possible dose to avoid iatrogenic Cushings • Pre-natal dx - CVS - perhaps give dexamethasone to prevent virilization but don't know what steroids will do to baby in utero

Short Statue

Def: child w/ height 2SD for age & gender Variant of normal growth • Constitutional delay - family hx of delayed puberty, so start later but will catch up, nothing else wrong simply delayed w/ bone age appropriate and predicting appropriate height, growth velocity above rate • Familial short stature - parents also short, kid short but always growing and never deviates from % tile, appropriate bone age w/ normal onset of puberty, don't intervene unless extreme Pathology: deviation from % tile • Syndromes: Turner's syndrome, trisomy • Systemic diseases, drugs • Endocrine causes: GH deficiency, hypothyroidism, glucocorticoid excess, DM under poor control, DI, rickets • GH deficiency - at any level: hypothalamus/pituitary, GH deficiency by pituitary, GH insensitivity (receptor doesn't recognize GH - Laron dwarf), IGF-1 deficiency, IGF-1 insensitivity • Causes: congenital malformation of hypothalamus/pituitary, genetics, tumors, chronic inflammation, idiopathic, radiotherapy or chemo for cancer • GH resistance - GH receptor defect or post receptor defect • Phenotype of GH deficiency: frontal bossing, depressed nasal bridge, lots of midline abnormalities, poor growth velocity, delayed skeletal maturation, high-pitched voice, short stature, truncal obesity, chubby face, low IGF-1, IGFBP3 • Tx: GH injections or other hormones for other causes - thyroid, GnRH to prevent puberty • Approved indications for GH: GH deficiency, chronic renal failure w/ short stature, Turner's syndrome, IUGR w/ adult disease • Side effects of GH tx: early edema, joint pain, rare epiphyseal slipping or gynecomastia, worsening of scoliosis, hyperinsulinemia (only theoretical risk of diabetes), no risk of cancer tho active malignancy would be contra-indication

Primary Adrenal Insufficiency

Def: destruction of glucocorticoid producing capabilities of adrenal cortex - and loss of mineralocorticoid and adrenal androgen production as well but medulla ok • Must be bilateral and destruction of 90% Etiology: #1 cause - US - autoimmune adrenalitis - antibodies vs enzymes involved in steroid production • Type I APS - rare - hypoparathyroid, candidiasis, gonadal failure, AI • Type II APS - more common - AI!!! + autoimmune thyroid, Type 1 Diabetes Mellitus, gonadal failure • #1 cause rest of world - infections - TB, HIV, fungal bacterial • Carcinoma (lung, breast, renal), hemorrhage, thrombosis - sepsis, warfarin, APLS Pathophysiology - obliteration of adrenal cortex, cortisol decreases, CRH & ACTH rise, renin also rises Unique to primary AI - excess ACTH + skin hyperpigmentatio + hyperkalemia + acidosis • excess ACTH in order to try to raise cortisol, POMC precursor of ACTH also precursor of molecule which pigments the skin so hyperpigmentation of exposed areas, extensors... • hyperkalemia & acidosis - due to aldosterone deficiency, upregulation fo renin, salt wasting, potassium elevation & retaining hydrogen Clinical manifestations: skin pigmentation & salt craving Labs: Hyponatremia (cortisol + aldosterone), hyperkalemia, metabolic acidosis, hypoglycemia, hypotension, eosinophilia

Cushing's Syndrome

Def: diseases w/ common theme of excess glucocorticoid exposure Pathophysiology: due to excess glucocorticoids • Excess central adiposity w/ peripheral lipolyis central obesity, moon facies, buffalo hump (dorsal fat pad) • Excess catabolism (muscle breakdown) to make glucose muscle weakness, fatigue, poor wound healing • Osteoblast apoptosis increasing bone turnover, reduced Ca gut absorption osteoporosis • Increased HGP & decreased insulin sensitivity diabetes mellitus & HTN • Weakened collagen fibers in dermis viiolaceous striae & easy bruising, thinning of skin • Co-secretion of adrenal androgens hirsutism • Suppression of GnRH pulsatility amenorrhea • Immune suppression infections • Apparent mineralocorticoid excess HTN, metabolic alkalosis, hypokalemia • Depression & psychosis • Typical presentation: easy bruising & bleeding, recurring skin fungal infection, new onset depression, hirsutism, oligomenorhea, inability to climb stairs, new onset HTN, 65 lb weight gain

Adrenal Insufficiency - primary & Secondary

Diagnosis: establish low cortisol and then ACTH to establish level of deficit (high- primary, low - secondary) • Basal cortisol: <3 AI, >18 not AI, 3-18 unclear; ACTH >100 primary AI Diagnostic tools: basal measurement, ACTH stimulation test, insulin induced hypoglycemia/CRH (dangerous) • Dynamic testing - ACTH stimulation - large am'ts of ACTH and see if cortisol rises o at least 18-20 - use if cortisol 3-18 & if time imp't • Results: primary AI - no rise in cortisol (even with super-stimulation over 2 days) • Acute secondary AI - appropriate rise in cortisol • Chronic secondary AI - will not respond (but super-stimulation over 2 days will respond) Treatment: • Primary AI - glucocorticoid AND mineralocorticoid replacement • Secondary AI - just glucocorticoid replacement • Acute Adrenal Crisis • clinical manifestation: Hypotension, shock, hypoglycemia, abdominal pain, emesis, orthostatic hypotension, hyponatremia • treatment: aggressive IV fluid replacement, random cortisol testing (if this sick, should have cortisol), massive doses of hydrocortisone (acts as MR as well), treat underlying illness • at home precautions: bracelet, dexa injection kit, double steroid doses, PO pill or go to ER • Complications of steroids: • Dosing - too little still AI and too much - iatrogenic Cushing's • Recurrence of disease process - steroid sparing regimen; must taper doses carefully so that not acutely AI

Adrenal Insufficiency - primary & Secondary (dx and rx)

Physiology of Weight Regulation

Energy balance = energy taken - energy expenditure CNS regulation • Meal initiation signals: Ghrelin - meal initiation signal peaks before each meal whereas as soon as food enters signal suppressed and thus meal termination signal • Meal termination signals: suppression of ghrelin, secretion of CCK,PYY - satiety hormones as food enters small intestine, glucagon-like peptide - also satiety signal - nausea & fullness, treat T2DM • Leptin - secreted in proportion to fat mass, signals to stop eating unless decreases and then get hungry • should govern weight lose in obese individuals yet leptin resistant • Orexigenic/Anabolic molecules: Neuropeptide Y & Agouti-related peptide - to go eat • Anorectic/Catabolic molecules: POMC, MCR4, alpha MSH - not eat • Increased adipose tissue • Leptin increased due to increased fat mass, goes to arcuate nucleus where inhibits AgRP so that no longer inhibits POMC and MCR 4 • POMC & MCR4 can interact and decrease hunger - neg energy balance & lost fat mass • Leptin also directly stimulates POM C • Decreased adipose tissue: leptin decreased, no longer inhibits AgRP so AgRP inhibits POMC and MCR4 which will NOT inhibit hunger and thus hungry Many more mechanisms which fight moving to the L rather than which fight moving to the R (gaining weight) Energy expenditure: dietary thermogenesis, exercise - voluntary & involuntary physical activity, resting metabolic rate - highest proportion of daily thermic activity - directly related to fat free mass • Weight gain - energy expenditure increases due to increase in fat free mass & even more w/ goal to move back to lower weight • Weight loss - observed energy level lower than predicted - trying to shift back to original weight

Fetal Growth

Environmental factors effecting: maternal size, maternal nutrition, good placental function, absence of infection or substance abuse, altitude (higher body needs more O2 so baby gets less & smaller) Fetal factors: hormonal factors, chromosomal abnormalities, inborn errors or metabolism, malformations, infections Hormonal factors • Insulin - most impt for fetal growth, excess - macrosomia large baby, deficiency - IUGR • Leptin & placental GH levels in maternal serum may be relevant Growth factors • IGF-2 - earlier in fetal growth • IGF-1 - later in fetal life • Epidermal growth factor - lung, adrenal gland, GI tract • Transforming growth factor, platelet derived growth factor, fibroblast growth factor (limb & skeletal growth), nerve growth factor - neurons Fetal growth linked to adult onset diseases - "barker hypothesis" - in poor nutritional conditions, pregnant woman can modify development of her unborn child to be prepared for survival in environment where resources are scarce - thrifty phenotype - baby geared toward storing food as faty • Adult onset diseases: obesity, T2DM, dyslipidemia, HTN, CAD...

Hypopituitarism

Etiology of pituitary diseases - generally • Mass lesions • Hypersecretion • Hyposecretion • Empty Sella syndrome: primary - never develops • Secondary - give dopamine for prolactinoma and shrinks • Dipahragma sellae - reflection of dura around sellae is fenestrated and arachnoid cyst can slowly invade & restructure Causes of Hypopituitarism • Congenital • Tumors • Inflammation • Blood-borne • Vascular - Sheehan's - post-partem pituitary necrosis • Pituitary gland doubles during pregnancy due to lactrotrophs • Vascular supply tenuous due to low pressure portal system • If severe hypotension during delivery, can cause ischemic necrosis • Apoplexy - hemorrhage into pituitary • Aneurysm of circle of willis Clinical features • Absence of secondary sex characteristics • Thin, not doing well • Facial characteristics • Hypogonadism - GH deficient, more fat Tx - deal with underlying cause + replace hormones - thyroxin, GH & testosterone

Bone

Functions: mobility, support, protection, ion reservoir, hematopoiesis Types of bone: • Cortical bone - periosteal layer, 80% weight vs 20% area, turns over 1x 10 yrs, wrist > hip > vertebrae • Trabecular bone - spongy bone, 20% area vs 80% weight, vertebrae >hip>wrist, turns over more frequently Bone cells: osteoblasts - active cells which make osteoid and mineralize bone, become osteocytes in bone, endocrine responders to PTH and Vit D • Osteoclasts - resorb bone, lack endocrine function, multi-nucleated giant cell w/ ruffled borders - lysosomes and acid release Communications b/w cells/Activation of Osteoclasts • RANK-ligand on osteoblasts • Upregulated by PTH, active Vit D, IL-6,1,11,TNF • RANK-receptor on osteoclasts • up-regulated by m-CSF from osteoblasts • binding of RANK ligand and receptor activates pre-osteoclasts to mature, active osteoclasts • osteoprotegerin - mimics RANK receptor & prevents osteoclasts from binding and being activated, protective dampening • bone turnover markers - Type I collagen, bone formation markers - bone specific alkaline phosphate or osteocalcin

Growth Hormone

GHRH stimulates secretion whereas somatostatin inhibits • Sleep and stress/exercise stimulate Affects: adipose tissue - secrete free fatty acids • Liver - secrete IGF-1 • Stomach - secrete ghrelin - which itself stimulates GH secretion (need food to grow) • Muscles - make muscle • Anti-insulin GH receptor: dimerization of tyrosine kinase to produce IGF-1 and IGF-BP3 • IGF and insulin similar structures, receptors similar, high concentrations, insulin can bind IGF receptors GH secretion is episodic - small rise after each meal and large rise during sleep IGF-1 good surrogate marker for GH except in specific nutritional states which is also control secretion of IGF-1 - IGF-1 spikes when refed after fasting Genes regulate GH: genetics, disease, development of anterior pituitary, somatostatin, GHRH, GH, receptor GH decreased due to: probs w/ anterior pituitary, GH abnormal, emotional deprivation, receptors abnormal Test of GH levels - b/c episodic must use stimulatory test to test for deficiency • Counter-regulatory to insulin so give insulin to make hypoglycemic, and GH should rise • Can also stimulate w/ arginine, GHRH (rare & only tests pituitary) or others... • Follow growth chart - predicted vs actual growth, chronological age vs height

Genes within environment Obesity

Monogenic syndromes - genetic mutations causing obesity, very rare Environmental factors - metabolic rate, exercise, food intake, culture Genes - strong factors as BMI of biological parents more predictive than adoptive parents but still cannot explain obesity epidemic

Primer on managing weight disorders

Options: hypocaloric diet, behavioral modification, intense exercise regimens, pharmacotherapy, weight reduction surgery Hypocaloric diet: deficiency of 500 kcal diet per day, will last for 6 mths but almost 0 likelihood of maintaining weight after 5 yrs, regardless of composition of macronutrients in the diet Pharmacotherapy - very little available or effective • Orlistate - 10 lbs per yr, phentemine - only 12 wks, sibutramine - off market due to increased CV events, tesofensine - better? Clinical trials... Bariatric surgery - successful! Lose lots of weight and even tho gain some back, still maintain huge weight loss • Restrictive - band around stomach to promote satiety signals • Mixed malabsorptive & restrictive - proximal stomach removed and satiety levels rise and feel full more quickly, mild am't of malabsorption

Postnatal growth

Phases: rapid in first 2 yrs of life, steady childhood, growth spurt during puberty Non-endocrine factors influencing growth: genetics, socioeconomic status - nutrition & better health care, normal emotional and psychosocial environment, absence of chronic disease - which limits availability of nutrients & resources for growth Hormonal factors influencing growth:: • Growth hormone (IGF-1) most imp - control postnatal growth • Functions: increase muscle mass - increase aa uptake& protein synthesis & decrease glucose uptake Liver - increase secretion of IGF-1 and binding protein IGF-1: increases linear growth of bone IGF-2 - less imp't postnatally - affects other organs to grow Increase RNA synthesis & glucocorticogenesis Adipose tissue - decrease adiposity - decrease glucose uptake and increase lipolysis • Patterns of secretion - daily episodic w/ major peak during sleep and lifetime - increases birth to infancy, quiescent during childhood, peaks during puberty, then declines Girls hit puberty early than boys but boys have a higher peak • Thyroid hormone - next most ipt • Hypothyroidism postnataly will have profound growth failure & arrest of skeletal maturation • Functions: direct effects on epiphyseal cartilage (facilitates GH effects, permissive effect on GH secretion • If replace it, will go back to growing normally • Sex hormones - for puberty, estrogen for skeletal maturation • Androgens: accelerate bone age maturation more rapidly than linear growth Facilitates actions of GH and IGF, increases stimulation Excess can promote bone growth as opposed to chronological age - so grow but then stop too early • Estrogen: increases cartilaginous linear growth, lateral growth in pelvis and accelerates bone age - closes epiphyseal plate in M and F (males - through aromatase which if lack will keep growing) Biphasic - stimulate growth at low levels but inhibit at high levels • Insulin • PTH & Vit D - skeletal development & ossification Evaluate & monitor growth carefully - track on curve • Chronological vs bone age will help differentiate early/late developers from pathology • Evaluation: pattern of growth, steady growth at normal rate, change in percentile, growth/height velocity, genetic background, heights & ages of sexual maturation of family members, PE

Ramifications of obesity

Psychological: eating disorders, poor self-esteem, depression, body image disorder, social isolation, depression Pulmonary: decrease in exercise tolerance, obstructive sleep apnea, asthma GI: non-alcoholic fatty liver disease, insulin resistnace Renal - FSGS MS - osteoarthritis Neurological - HTN CV - major killer - HTN, dyslipidemia, coaguloapthy, chronic inflammation, endothelial dysfunction, metabolic syndrome - insulin resistance, dyslipidemia, HTN, impaired glucose tolerance test Endocrine - insulin resistanced, impaired fasting glucose,T2DM, precocious puberty menstrual irregularities, PCOS Risk - as BMI increases, risk of HTN, coronary heart disease, cholelithiasis & T2DM increases Location of fat stores - subcutaneous fat is much healthier than central/visceral fat

Hyperthyroidism

Symptoms: • Hot - too much heat, body temp upper limit, direct blood to skin to radiate and perspire • Irritable, cannot focus, attn span shortened • Tremors, muscle weakness Lab values: high T4, extremely low TSH Causes: • Grave's disease - autoimmune antibodies to TSH receptor which constitutively stimulate it • TSI - thyroid stimulatin immunoglobulin • Specific signs: eyes bulging out, non-pitting edema (around eyes?), bruit above thyroid • Radioactive iodine test - extremely high percentage 90% gets into thyroid, homogenously distributed • Tx: Methimisol - binds to TPO so that can no longer make as much thyroxin, disease may then go away and eventually stop drug Surgery or radioactive iodine to get rid of thyroid, then need supplements • Nodules/Lumps • Tumor, most benign, which make too much thyroxin • Radioactive iodine scan - shows distribution excessive only in 1 area • TSH low due to neg feedback tho tumor doesn't respond • Evaluation - ultrasound, biopsy if large or suspicious, if suspicious or cancer - surgery to remove or radioactive iodine If benign - can ignore or remove • Thyroiditis • Inflammation of thyroid due to some insult, immune, viral • Thyroid disorganized and painful • Thyroglobulin leaks into circulation, too many symptoms • Self-limiting so wait it out but treat symptoms, may have pds of overactive and underactive

Posterior Pituitary - ADH/Vasopressin (& Oxytocin)

Termination of axons - not necessary except for some am't of axon to allow for polypeptide hormonal processing to mature hormones • Large engorged stalk cause abnormal function Oxytocin- mediates uterine contractions during delivery + helps breast milk let down, not essential ADH = Vasopressin • Production: gene w/ 3 exons • Precursor split to make ADH + neurophysin - binding protein which stabilizes it and prevents intracellular/intragranular degradation • Function/Receptors of ADH • VP1 - vascular/vasoconstriction • VP2 - kidney - increases permeability of collecting duct to allow free water (w/o electrolytes) pass diffuse back into body Dilutes urine to maintain water in body • VP3 - stimulates release of ACTH from anterior pituitary - ADH will stimulate to max am't

Osteomalacia - too little mineral

Vit D deficiency - not lack of intake but Vit D doesn't work properly • Secondary hyperparathyroidism - decreased absorption of Ca from gut drives up PTH • PTH increases to increase activation of Vit D which lacking but also liberates Ca and P from bone, causes kidney to reabsorb calcium & excrete phosphorous, leads to low serum phosphorous Kids - rickets, adults - osteomalacia X-ray findings: bowing of legs, changes in skull, stunted growth, widening of bones Symptoms: generalized bone pain, proximal muscle weakness Complications: bowing, fractures All forms of osteomalacia lead to excess of FGF-23 which leads to kidney spilling phosphate out

"Storm HITS girls cAMP":

"Storm HITS girls cAMP": Thyroid storm due to: Hyperthyroidism Infection or Illness at childbirth Trauma Surgery · girls: Thyroid storm more common in females. · cAMP: Tx involves high dose of beta blockers (beta receptors work via cAMP) · Alternatively: "S#IT storm": Surgery, Hyperthyroidism, Infection/ Illness, Trauma.

Health Consequences of Obesity

(BMI) as the weight (in kilograms) divided by the square of height (in meters2). - Is independent of gender. - Overweight = BMI of 25 +, obesity= BMI > 30 kg/m2. - coronary artery disease accounting for most of the increase in death rate as the BMI starts to exceed 30 kg/m2. Upper body obesity (also referred to as "male pattern" or "android" obesity) confers a far greater cardiovascular risk than obesity in the hips and thighs ("female pattern" or "gyneoid" obesity). The harmful component of upper body obesity is excess abdominal visceral (mesenteric and omental) adipose tissue with venous drainage directly into the portal vein. Fat in this location promotes insulin resistance (a precursor of diabetes), hypertension, and lipid abnormalities; a combination of conditions often called "Syndrome X" or the "Insulin Resistance Syndrome". Body fat distribution may be assessed clinically by using specially designed calipers to measure skinfold thickness in a variety of locations or by measuring the ratio of waist diameter to hip diameter. A "waist hip ratio" greater than 1.0 is worrisome, with a ratio of less than 0.90 in men or 0.80 in women considered to be safe.

Describe the general mechanism of steroid hormone action in the cell.

* "binding" to specific intracellular receptor proteins. * "activation" - steroid-receptor complex then undergoes a transformation, enabling the complex to bind tightly to appropriate DNA recognition sites. -- For glucocorticoids, involves 1) dimerization, the binding and unbinding of specific heat-shock proteins, and 2) phosphorylation, promoting receptor binding to glucocorticoid response elements, or GRE's in the DNA sequence. This stabilizes the downstream binding of a large # of TF's to RNA polymerase, increasing or decreasing the transcription of specific mRNA's that are subsequently translated into specific proteins which elicit the steroid's physiologic effects Steroid hormones may also have actions via "non-classical" cell membrane receptors. Not yet determined exactly. Summary: Mechanism of action of steroid hormones in mammalian cells. The steroid hormone (S) binds reversibly to an intracellular receptor (R), and the steroid-receptor complex undergoes an activation process that enables it to increase or reduce transcription of specific genes into RNA. After processing in the nucleus, the corresponding mRNAs code for ribosomal synthesis of the specific proteins that mediate the steroid response

Describe the role of transport proteins in thyroid hormone function; what changes in physiologic states or medications can affect these proteins.

* The principal plasma binding hormone is thyroxine-binding globulin (TBG). - one binding site per molecule. - Roughly 80% of T4 binding occurs to TBG. The remaining 20% of T4 is bound to albumin and transthyretin, a prealbumin molecule which also plays a role in the transport of retinol-binding protein. * The binding affinity of TBG for T4 is 10 times that for T3. The proportion of T3 that circulates in the free state is, therefore, higher than that of T4. The plasma TBG concentration, and consequently the total level of thyroid hormone in the blood, is strongly influenced by the functional status of the liver, the nutritional status of the individual, and the presence of estrogens and certain drugs. The effect of these various conditions on TBG concentration leads to certain difficulties in the measurement of total thyroid hormone levels. Conditions That Affect Serum Binding of Thyroid Hormones * Causes of increased TBG - Estrogens (e.g., pregnancy, birth-control pills) - Acute hepatitis - X-linked disorder - Certain drugs (e.g., phenothiazines, clofibrate) * Causes of decreased TBG - Androgens - Glucocorticoids - Protein loss - Malnutrition, wasting - Liver failure - Nephrotic syndrome - X-linked disorder - Certain Drugs (e.g., phenytoin, phenylbutazone) * Substances that compete with thyroid hormones for binding to TBG - Phenytoin - Salicylates

Know the pathognomonic findings associated with Graves' disease.

*** Pathognomonic findings - ophthalmopathy (cytokines), bruit/thrill in thyroid gland, pretibial myxedema (NOT that myxedema) * Increased blood supply for diffuse enlargement Turbulent blood flow makes noise Bruit and Thrill are pathognomonic for Graves'!!!! Lid Retraction and Lag: Common to ALL forms of thyrotoxicosis!!! Proptosis is only found in Graves' disease - eyes in primary position In Graves' disease, an aberrant immune response leads to the production of an IgG molecule (called TSI) which can activate the TSH receptor and lead to unrestrained stimulation of thyroid hormone synthesis. - a large, highly vascular, diffuse goiter. - Microscopically there are numerous small follicles lined by extremely hyperplastic epithelia with papillary infoldings on the lumenal surfaces. Only small amounts of colloid are present since the gland is actively resorbing rather than storing colloid. - Lymphocytes are present. * occurrence of ocular pathology and dermopathy caused by inflammatory infiltration accompanied by deposition of glycosaminoglycans in the retroorbital tissues or the subcutaneous tissues of the lower leg. The ocular process results in protrusion of the eyes (exophthalmos) and occasionally entrapment of the extraocular muscles and optic nerve. - Graves' dermopathy is manifested by shiny, erythematous, occasionally painful nodules overlying the tibial or ankle regions anteriorly. This dermopathy has also been referred to as pretibal myxedema, an unfortunate choice of terms since the process is distinct from the myxedema of hypothyroidism.

Secondary Adrenal Insufficiency - Lab Evaluation

*Hyponatremia Cortisol deficiency - major effect Cortisol is required to excrete free H20 Cortisol suppresses AVP release Lack of cortisol removes suppression of AVP *Hypoglycemia More prominent for unknown reasons *Hypotension Inability to maintain vascular tone from cortisol deficiency Less prominent *Eosinophilia

Primary Adrenal Insufficiency - Lab Evaluation

*Hyponatremia Cortisol deficiency - mild effect Cortisol is required to excrete free H20 Cortisol suppresses ADH release Lack of cortisol removes suppression of ADH Aldosterone deficiency - salt wasting *Hyperkalemia and Metabolic Acidosis- specific to Primary Hypoglycemia *Hypotension Salt wasting with concomitant volume depletion Inability to maintain vascular tone from cortisol deficiency *Eosinophilia

(GUNNER) - Hyperaldosteronism

*The most common cause of hyperaldosteronism is primary hyperaldosteronism, also known as Conn's Syndrome Either a single benign adrenal tumor (adenoma) or bilateral hyperplasia of the adrenal glands which result in overproduction of mineralocorticoid aldosterone * Elevated aldosterone levels → hypertension (due to Na/H2O retention) and hypokalemia. Elevated aldosterone → ↑ K+ and H+ wasting in the cortical collecting ducts → alkalosis and hypokalemia Hypokalemia → metabolic alkalosis due to increased transcellular exchange of K+/H+ Alkalosis causes the -COOH side groups of serum albumin → -COO- → causes increased binding of Ca2+ → decreased free Ca2+ concentration Hypokalemia can also lead to symptoms of muscle weakness as well as cardiac changes visible on EKG (classically described as U-waves) * Diagnosis is often based on measurement of serum renin levels High aldosterone suppresses the secretion of renin. In primary hyperaldosteronism, low levels of renin are seen. By contrast, a high renin level suggests secondary hyperaldosteronism as in reno-vascular hypertension. *treatment: Spironolactone: aldosterone antagonist diuretic, that is also K+ sparing Surgical adrenalectomy

ENDOCRINE CAUSES OF SHORT STATURE

- Growth hormone deficiency - Hypothyroidism - Glucocorticoid excess endogenous or exogenous - Diabetes mellitus under poor control - Diabetes insipidus - untreated - Hypophosphatemic Vit-D- resistant rickets

Growth Hormone Deficiency- Causes

- Idiopathic Genetic Congenital Structural defects Midline facial defects -Acquired Perinatal or postnatal trauma Hypothalamic Pituitary tumors Surgery or cranial irradiation Psychological deprivation

Renin-angiotensin-aldosterone system Hormones: Renin

- a proteolytic enzyme produced (JG) cells which encircle the afferent arteriole to the glomerulus. - The JG cells are stimulated by increased -adrenergic sympathetic activity / fall BP. - Short T1/2or by a fall in the flow of blood to the kidney (decreased perfusion pressure). - Cells of the macula densa near DCT respond to a fall urinary Na+ to the JG cells to release renin. - Low Na diet makes low Renin - low BP. There is an inverse relationship between dietary potassium intake and plasma renin activity levels. - Why would a high potassium diet be better than a low potassium diet for a hypertensive patient? Renin cleaves AG to AGI. AGI is then cleaved by ACE (lungs) to active AGII. two major actions: (1) induces the ZG to release ALDO (sustained) (2)vasoconstriction.

(GUNNER) - Type IIa: Familial hypercholesterolemia

- autosomal dominant absence or ↓ in LDL receptors ↑ cholesterol and ↑ LDL → marked ↑ risk of atherosclerosis and CAD Xanthomas on the tendons - classic locations → Achilles' heel, elbows Corneal arcus - gray or white arcs visible around the entire cornea → lipid deposits at edge of cornea Treatments: Cholestyramine and other drugs that ↑ bile salt synthesis from cholesterol → ↓ cholesterol concentration within hepatocytes → ↑ LDL receptor expression → ↑ cholesterol removal from circulation. Statins ↓ de novo synthesis of cholesterol → increases LDL receptor expression Prevalence: heterozygotes = 1/500 (cholesterol ≈ 300 mg/dL); homozygotes = 1/106 (cholesterol ≈ 700+ mg/dL) Homozygous condition usually lethal before age 20 from MI

Turner's syndrome

1 in 2500 live female births Short stature Streak ovaries with premature ovarian failure Autoimmune disorders

(GUNNER) - Regulation of aldosterone secretion:

1) Aldosterone is under tonic control by ACTH, but is separately regulated by the renin-angiotensin-aldosterone system and by potassium. 2) Angiotensin II stimulates aldosterone synthase in the zona glomerulosa, leading to increased conversion of corticosterone to aldosterone. 3) Hyperkalemia increases aldosterone secretion. In response, renal K+ secretion increases and blood [K+] returns to normal.

(GUNNER) -Signs of hyperlipidemia:

1) Atheroma - lipid plaques in blood vessel walls 2) Xanthomas - lipid laden histiocytes in the form of plaques or eyelid skin nodules 3) Tendinous xanthoma - lipid plaques in tendon, e.g. Achilles tendon 4) Corneal arcus - cornea lipid deposits

Adrenal Cortex - Evaluating for Cushings Syndrome

1) Does the patient display an excess of cortisol? (i.e. do they have Cushing's Syndrome?) 2) If Yes - what is the source of the cortisol excess? ACTH dependent vs. ACTH Independent If ACTH dependent - pituitary vs. ectopic source of ACTH

Be able to describe the key steps in thyroid hormone metabolism, from iodine uptake to final synthesis and storage of T4 and T3.

1) From BL surface: Na+/Iodide symporter (using ATP) from circulation into the thyroid cells. (this also in breast tissue). Acts as a trap for Iodide. - When Iodide levels low, the symporter upregulated - When Iodide high, need to protect against making too much; downregulated. 2) Transport protein (Prendin) brings up to apical surface which allows to TPO to act. - Regulation same as 1) 3) Iodide transport is also dramatically increased by thyroid-stimulating hormone (TSH). 4) The next step in thyroid hormone synthesis is the "oxidation" of iodide by thyroid peroxidase, which is located at the apical cell membrane. In the highly reactive oxidized form, iodine immediately binds to tyrosyl groups within the thyroglobulin molecule. This protein represents about 50% of the protein synthesized by the thyroid and it forms a scaffold upon which thyroid hormone is synthesized. Iodine binds to the carbon in either the 3 positions within the tyrosine phenol ring to form monoiodotyrosine (MIT), or to both the 3 and 5 phenol carbons to form diiodotyrosine (DIT). The oxidation of iodide and subsequent binding to tyrosyl residues is collectively called "organification." 5) The final step in the assembly of thyroid hormone molecules is the "coupling reaction" (also under TSH regulation) that occurs at the interface between the apical cell border and the colloid space. In this reaction, which is also catalyzed by thyroid peroxidase, two DIT moieties can join to form a T4 molecule, or else one DIT and one MIT moiety can join to form a T3 molecule. A minor amount of reverse T3 is formed at this step. These reactions, which involve a significant rearrangement of the thyroglobulin molecule, are poorly understood, but they are known to require oxygen. The modified thyroglobulin molecule is stored within the colloid space.

(GUNNER) Clinical manifestations of hyperthyroidism are referable to:

1) Hypermetabolic state (e.g., ↑ Na+/K+ ATPase activity): due to ↑ T4 and T3 2) SNS (sympathetic nervous system) overactivity: ↑ T4 and T3 → ↑ synthesis of β adrenergic receptors → ↑ β adrenergic tone

Differentiate between "replacement" and "pharmacologic" glucocorticoid therapy. When is each used?

1) Replacement therapy= treatment of deficiency of endogenous adrenal steroids. Patients whose adrenals have been destroyed or removed require replacement of both glucocorticoid and mineralocorticoid activities. - Either cortisol (hydrocortisone) or synthetic glucocorticoid (prednisone) can be used. for replacement. The latter has longer duration of action than hydrocortisone (good b/c one dose/day) but individual variability in their potency. In patients with primary adrenal insufficiency, ACTH levels can be useful for monitoring dosing but there is no ready test for the possibility of overdosing synthetic steroids in patients with secondary adrenal insufficiency. Hydrocortisone-relatively uniform effects among individuals. Since hydrocortisone has a shorter duration of action than synthetic steroids, most patients take it twice a day—mimics the normal diurnal pattern. In deficiency of glucocorticoids caused by deficiency of ACTH, administration of ACTH would theoretically be the logical treatment. However, ACTH must be given by injection and is short-acting, so replacement of steroids is more practical. In this situation, mineralocorticoid activity usually is not deficient. Therefore, treatment with a synthetic glucocorticoid or cortisol ordinarily suffices. 2) Pharmacologic glucocorticoid therapy: glucocorticoids as treatment for conditions other than their deficiency. The doses are supraphysiologic—i.e., in excess of the amount required to substitute for the secretion of glucocorticoids by normal adrenals. Beneficial for: (1) diseases manifested by a severe inflammatory response, and (2) immunologically mediated disease processes. The anti-inflammatory and immunosuppressive effects of large doses of glucocorticoids provide the rationale for treatment.

Describe the central Hypothalamic - Pituitary control of thyroid hormone synthesis and release, including the critical role that TSH plays in these processes.

1) TRH synthesized as part of a larger molecule (pro TRH) in the supraoptic and paraventricular nuclei of the hypothalamus. TRH is transported down the pituitary portal system to the thyrotrope cells of the anterior pituitary. 2) Here TRH stimulates the secretion of TSH through a mechanism involving phosphatidylinositol bisphosphate hydrolysis and activation of protein kinase C. 3)TSH in turn stimulates most of the thyroid metabolic processes by binding to a receptor on the thyroid cell membrane and causing the formation of cyclic AMP. TSH is a 28,000 molecular weight glycopeptide consisting of a specific beta subunit and an alpha subunit that is common to LH, FSH, and hCG. In response to TSH stimulation the thyroid secretes both T4 and T3. * Normally, T3 feeds back directly to the pituitary to inhibit TSH secretion. In part, this inhibitory effect of T3 is mediated through a reduction in the number of thyrotrope receptors for TRH. Although hypothyroidism in rats leads to an increase in paraventricular pro TRH mRNA, there is no compelling evidence for an important hypothalamic feedback loop in humans. T4 is also capable of inhibiting TSH secretion, but only after it is converted to T3 in the pituitary. The high activity of the T4-5'-deiodinase enzyme which leads to T3 production in the pituitary (the Type 2 5'-deiodinase) may account for the lack of TSH elevation despite the low circulating T3 level associated with malnutrition and other stressful conditions.

(GUNNER) - Congenital hypothyroidism is most commonly caused by thyroid dysgenesis due to thyroid aplasia/hypoplasia/ectopy. Congenital hypothyroidism may present with:

1) hoarse cry, weak cough, slow respiratory effort 2) abdominal distention (protuberant abdomen), potbelly with umbilical hernia 3) prolonged neonatal (physiologic) jaundice 4) poor feeding, neonatal hypotonia 5) macroglossia (protruding tongue) 6) enlarged fontanelles, delayed dentition, retarded bone age 7) coarse facial features, widely set eyes, broad flat nose, dry skin with scarce lanugo, pale body with mottled cool extremities 8) S/Sx of hypothyroidism—eg, constipation, somnolence

(GUNNER) -Treatment of hyperthyroidism:

1) β-blocker to control symptoms of ↑ SNS tone 2) Thionamide — e.g., PTU (propylthiouracil), methimazole: - may induce remission by blocking new thyroid hormone production via inhibition of the organification and coupling steps of thyroid hormone synthesis - PTU (not methiazole) also inhibits peripheral conversion of T4 to T3 3) High-dose iodine → blocks release of T4 and T3 into the circulation 4) High-dose radioactive iodine 131I (versus the low-dose of 131I used in imaging studies) → becomes concentrated in the thyroid gland → ablation of thyroid function

(GUNNER) Signs and symptoms of hyperthyroidism:

1) ↑ BMR (basal metabolic rate); ↑ O2 consumption 2) Weight loss despite ↑ appetite 3) Negative Nitrogen balance (catabolic) → thyroid myopathy: proximal muscle weakness and ↓ muscle mass 4) ↑ Heat production; ↑ sweating; heat intolerance 5) Peripheral vasodilation to get rid of heat → warm flushed skin 6) ↑ Synthesis of cardiac β1 receptors → - ↑ HR (sinus tachycardia) - ↑ contractility → ↑ SV (stroke volume) ∴ ↑ PP (pulse pressure) - ↑ HR and ↑ SV → ↑ CO (cardiac output) → cardiomegaly, systolic hypertension, high-output heart failure - Arrhythmias (especially atrial fibrillation) secondary to ↑ HR and/or cardiomegaly 7) ↑ RR (tachypnea) due to ↑ O2 consumption 8) Neuromuscular: ↑ SNS → - Fine tremor (eg, of the hands) - Anxiety - Insomnia - Emotional lability - Inability to concentrate 9) Eyes: - ↑ SNS → overstimulation of levator palpebrae superioris (a muscle which receives SNS innervation from the internal carotid plexus & contracts reflexively to elevate the upper eyelid) → wide-eyed staring gaze and lid lag - Note: true thyroid ophthalmopathy with exophthalmos (proptosis) is only seen in Graves disease [1] 10) GI (gastrointestinal): - ↑ SNS → ↑ GI motility, malabsorption → diarrhea [2] 11) Brisk DTRs (deep tendon reflexes) 12) ↑ Bone turnover → osteoporosis → ↑ risk of fractures 13) Oligomenorrhea

(GUNNER) - Actions of mineralcorticoids (eg, aldosterone):

1) ↑ renal Na+ reabsorption at the principal cells of the late distal tubule and the collecting duct. 2) ↑ renal K+ secretion at the principal cells cells of the late distal tubule and the collecting duct. 3) ↑ renal H+ secretion at the α-intercalated of the late distal tubule and the collecting duct.

(GUNNER) - Signs and symptoms of hypothyroidism:

1) ↓ BMR (basal metabolic rate); ↓ O2 consumption 2) weight gain 3) positive Nitrogen balance (anabolic) 4) ↓ heat production; ↓ sweating; cold intolerance 5) peripheral vasoconstriction to maintain body heat → cool, pale, dry skin 6) coarse, brittle hair/nails; yellow/orange skin 7) ↓ synthesis of cardiac β1 receptors → - ↓ HR (bradycardia) - ↓ contractility → ↓ SV (stroke volume) ∴ ↓ PP (pulse pressure) - ↓ HR and ↓ SV → ↓ CO (cardiac output) → ↓ exercise capacity, shortness of breath 8) blunted EKG (electrocardiogram) voltages 9) ↓ RR (respiratory rate) due to ↓ O2 consumption 10) ↓ GI motility → constipation 11) slow DTRs (deep tendon reflexes) with prolonged relaxation phase 12) fatigue, lethargy, mental slowness 13) myxedema (non-pitting edema due to interstitial accumulation of osmotically active mucopolysaccharides) of the hands, face, periorbital region 14) growth retardation; (perinatal) mental retardation 15) carpal tunnel syndrome 16) atherogenic profile: ↑ total cholesterol, ↑ LDL 17) hyperprolactinemia (if primary or secondary hypothyroidism): ↓ T3, T4 → ↑ TRH → ↑ prolactin

Pathology of the adrenal zona glomerulosa

1o hyperaldosteronism (Conn's syndrome) - Autonomous hypersecretion of mineralocorticoids from the adrenal cortex. - Causes: 1) an adenoma 2) or hyperplasia of ZG. - Levels: Renin ↓ ALDO ↑ o Mineralocorticoid production is also increased in some cases of CAH a (11- or 17--hydroxylase deficiency). Can cause HTN, ↓K, and Alkalosis. Need to reduce Na. - Tx: aldosteronoma = surgery. Bilateral adrenal hyperplasia= medically; low sodium diet, diuretics, aldosterone antagonists (spironolactone or eplerenone), and agents that ↓ ALDO (e.g., verapamil). - 2o hyperaldosteronism - occurs when renin levels ↑ (usually b/c ↓ in RBF) o Cause:, hemorrhage, renal artery stenosis, cardiac failure, or dehydration. - Other causes: secondary hyperaldosteronism include JG cell hyperplasia (Bartter's syndrome) and renin-secreting renal tumors. ----- Mineralocorticoid deficiency - results in Na+ loss, volume depletion, hypotension, hyperkalemia, and acidosis. - Causes: (Addison's disease), some cases of CAH (severe 21-hydroxylase deficiency), congenitally decreased production of ALDO (defects in corticosterone methyloxidase), and resistance. - Renin ↑ A. Hyporeninemic hypoaldosteronism. a. Pts . w/DM & CRI (sometimes NSAIDs) b. Renin ↓. (but prorenin increased)

Auto-immune Adrenalitis

75% of these patients will have detectable antibodies, predominantly against enzymes which mediate steroid production May be isolated (50%) or occur in conjunction with other auto-immune phenomenon (thyroid, parathyroid, ovarian) APS I (rare) or II (more common) I - hypoparathyroid, chronic mucocutaneous candidiasis, gonadal failure and AI II -AInsufficiency!!!! Also thyroid, T1DM, gonadal failure Conversely, auto-immune thyroid disease or T1DM are associated with adrenal Ab and AI only 1-2% of the time. Inappropriate attack on multiple endocrine glands.

PROLACTINOMA Diagnosis

A blood test, measuring the level of prolactin, usually establishes the diagnosis. Not all cases of elevated prolactin are due to prolactinomas. Other possible causes include: Pregnancy Stress Low thyroid function Kidney failure Liver failure A large pituitary tumor (or other tumor occuring in the same area) that causes compression of the pituitary stalk (the connection between the brain and the pituitary gland). Compression of the pituitary stalk interferes with dopamine from the brain reaching the pituitary gland. Because dopamine normally inhibits prolactin release, the normal pituitary gland produces more prolactin (prolactin levels are usually less than 200) The blood prolactin level is usually proportional to the size of the tumor. Large tumors may have prolactin levels in the thousands In some cases, very high prolactin levels can overwhelm the blood test, resulting is a falsely measured prolactin level (typically reported as only slightly above normal). If a prolactinoma is suspected based on clinical symptoms, it is important to have the test repeated using a diluted sample of blood (the so-called "Hook Effect")

Clinical Relevance of Height Velocity

A drop in height velocity in a normal child may represent pathology such as a brain tumor or hypothyroidism and requires investigation Baseline height SDS: -2.75 What about height velocity? Clinical judgment is important in determing the clinical relevance of height velocity in the diagnostic approach to the short statured child. For example, a decline in height velocity pattern of a previously normally growing child may signal the development of pathology (e.g. brain tumor, hypothyroidism) that requiress further investigation. However, in an already very short child, height velocity may be less useful and may delay diagnosis oand treatment. =

Cushings Syndrome

A groups of diseases whose common theme is excess glucocorticoid exposure Pathophysiology includes an exacerbation of the underlying actions of glucocorticoids.... Pathophysiology Excess central adiposity with peripheral lipolysis - Signs/Symptoms: Centripetal obesity, Moon Facies (cheeks), Buffalo Hump (T-C spine) Excess catabolism - muscle breakdown - Muscle weakness / Fatigue, Poor wound healing Osteoblast apoptosis - increase bone turnover- Osteoporosis Increased HGP and decrease insulin sensitivity- Diabetes Mellitus Weakened collagen fibers in the dermis: Violaceous striae/Easy Bruising, Thinning of skin Co-secretion of adrenal androgens -Hirsutism Suppression of GnRH pulsatility - Amenorrhea Immune suppression - Infections - fungal skin and O/P Apparent Mineralocorticoid excess (it's the cortisol!!) - HTN, metabolic alkalosis, hypokalemia ??? Depression/Psychosis

Be able to evaluate patients with symptoms and signs of thyrotoxicosis - lab and imaging if needed - including the relevance of antibody testing and uptake and scan.

A medical condition of excess thyroid hormone levels... Not all, but most causes, are mediated by endogenous overproduction of TH by thyroid gland (aka hyperthyroidism) SYMPTOMS Palpitations Nervousness Agitation or irritability Heat intolerance Tremor Easy Fatigue Muscle weakness Weight loss with good appetite Blurry or Double Vision Frequent bowel movements Oligomenorrhea SIGNS Tachycardia (ST most commonly) Atrial arrhythmias - esp. A Fib Goiter Warm, moist skin Proximal myopathy Eye lid retraction Gynecomastia (rare) Systolic Murmur - high output CHF Wide pulse pressure Circulating T3 levels: - T3 is the active hormone mediating hyperthyroid symptoms. - Also ratio of T3 to T4 secretion by the thyroid increases in states of thyroid overactivity. TSH best screening test: - it takes advantage of the patient's own biological system as a bioassay for effective tissue action of thyroid hormone, - extremely sensitive and has a broad dynamic range. Subtle decreases or increases in thyroid gland function are reflected first with reciprocal, compensatory changes of TSH, even before alterations of circulating T4 and T3 can be detected. These conditions are called "subclinical" hypothyroidism and hyperthyroidism, respectively. * thyroid radioiodine uptake test. T - Administering a known dose of radioiodine and then quantifying radioactivity over the thyroid gland at specified time points after administration. In all cases of hyperthyroidism,the thyroid radioiodine uptake is elevated. (except dopers or to destruction of the gland with release of preformed hormone) An imaging scan of the thyroid gland, which is often done in association with a radioiodine uptake determination, may also give helpful anatomic information about the thyroid.

** Diagnosis of Cushing's syndrome

A) Is the patient hypercortisolemic? = " overnight dexamethasone suppression test (DST)" Test HPA by giving a bedtime dose of a strong synthetic glucocorticoid (dexamethasone). Normal Pt: the dex will suppress endogenous cortisol levels in AM. in a blood sample taken the next morning. (note: dex is sufficiently different from cortisol that it does not show up in the cortisol assay). No suppression - suggests Cushing's. 1) CONFRIM: take many 24 hour urine specimens and measure cortisol. Since excess cortisol saturates CBG/transcortin, so urine cortisol-rises rapidly. Since plasma cortisol levels are pulsatile, this urinary "integrated" measurement is more sensitive to small changes than single plasma cortisol measurements 2) Cause of the hypercortisolism? B/n pituitary, adrenal, and ectopic ACTH use "Liddle test"= extended dex test. Twenty-four urine hydroxysteroids (or cortisol) are measured for 2 days each: • in the baseline state • with 2 mg dexamethasone/day (0.5 mg every 6 hours) "low dose" • with 8 mg dexamethasone/day (2 mg every 6 hours) "high dose" * Pts with stress-related elevation: dex causes 50% reduction in urine hydroxysteroids (or an 80% reduction in cortisol). * Pts with pituitary tumors will usually be suppressed high (not low) dose of dexamethasone, which exceeds the right-shifted set-point of their adenomas. * Pts with ectopic ACTH syndrome unresponsive. 2a) Another useful test is to give synthetic CRH and measure the ACTH response—either in peripheral blood, or in bilateral inferior petrosal sinus sampling (IPSS), an angiographic procedure in which catheters inserted via the femoral veins are advanced through the jugular veins to collect blood as it leaves the pituitary. If all goes well, results sort out as follows: 1. Exogenous glucocorticoids or adrenal tumors: ACTH is suppressed to low levels and does not rise after CRH. 2. Pituitary Cushing's: ACTH levels may be normal or high, but respond to CRH with a further rise. Since the ACTH is coming from the pituitary, central levels sampled from the petrosal sinuses are higher than peripheral. 3. Ectopic ACTH: ACTH levels are normal or high, but usually do not respond to CRH. If IPSS is done, there is no difference between central and peripheral levels of ACTH, because the normal pituitary is suppressed and the extra ACTH is secreted somewhere else by the ectopic tumor.

Renin-angiotensin-aldosterone axis and the regulation of intravascular volume

ALDO: - RLS: conversion of cholesterol to pregnenolone. o ZG only makes ALDO b/c no 17-OH pregnenolone or 17-OH progesterone - Stimulated by: AGII. Also from high K, low Na/ACTH. (Hyperkalemia also increases the sensitivity of the adrenal response to AGII). - Binds receptors, in DCT increase Na+ reabsorption and secretion of K+ and H+ o These receptors show equal affinity for aldosterone and cortisol, but select for ALDO in the DCT b/c of presence of 11-hydroxy-steroid dehydrogenase type 2, which converts the more abundant steroid cortisol to an 11-keto metabolite that does not bind to the mineralocorticoid receptor. o After binding with the intracellular receptor, aldosterone stimulates DNA-dependent mRNA synthesis to form one or more proteins that enhance Na+ transport. Both renin and aldosterone measurements bear an inverse relationship to urinary Na+ excretion.

The Adrenal Cortex - Role in Homeostasis

ALL STEROID-BASED; NEED RECEPTORS Aldosterone -Sodium and ECF volume -Potassium secretion -Renin-ATII mediated Cortisol -Fuel metabolism - Preserve glucose availability for the brain. Does this by : -inhibit insulin effects in the periphery - decrease glucose uptake -Increase Hepatic Glucose Production (HGP) -Protein catabolism - Increase N excretion, make substrates available for HGP -Help mobilize lipid stores to increase fatty acid supply - lipolysis -Physiologic effect on bone - unknown - but in excess inhibit linear growth, suppress osteoblasts and cause ostepoenia/osteoporosis (GIO) -Inhibition of collagen synthesis -Immune modulation tones down inflammatory response (can be useful or pathologic)- anti-inflammatory, vascular responsiveness, stress reponses -Water balance - increase free water clearance -mineralicorticoid like receptorlike properties - salt retention -CNS - mood stabilization Adrenal Androgens -Minimal effect in males - testis predominates -Secondary sexual characteristics in females -ACTH (not LH) mediated -DHEA, DHEAS, Androstenedione

Acromegaly /Gigantism

Acromegaly is a serious condition that is nearly always caused by a tumor of the pituitary gland (an adenoma). The tumor cells secrete an excessive amount of growth hormone (GH). The pituitary gland (or in this case, the tumor) releases growth hormone into the blood stream. Growth hormone acts on special liver cells, causing the release into the blood stream a hormone called Insulin-like Growth Factor (IGF-1). IGF-1 is also called Somatomedin-C.

(GUNNER) - Infectious note: Waterhouse-Friderichsen syndrome

Acute adrenocortical insufficiency associated with meningococcal septicemia May see massive hemorrhage within adrenal glands Characterized by overwhelming bacterial infection meningococcemia, hypotension, and shock with widespread purpura. Can progress into disseminated intravascular coagulation.

Energy Storage in Adipose Tissue

Adipose tissue is unique in its ability to expand almost indefinitely when energy intake chronically exceeds energy utilization. - So, in obese: both larger adipocytes (hypertrophy) and greater numbers of adipocytes (hyperplasia) from a pool of mesenchymal precursor cells. These processes are reversible by reversing energy equation. - Hyperplasia mech: involves TF's including PPAR2, C/EBP, and ADD1/SREBP1. PPAR2., the "master switch" for adipocyte development, is a member of the nuclear steroid hormone receptor family. When PPAR2 is activated by a ligand, proteins necessary for a preadipocyte to use TG made; PG is a ligand. Pts w/ mutation of PPAR2 t are very obese. Adipose tissue serves a mechanical function, provides flotation, and aromatization of gonadal and adrenal androgens into estrogens. Also secretes polypeptides including TNF-A, precursor to AG, a hormone promoting insulin resistance called resistin, a hormone that enhances insulin action called adiponectin, and leptin. The excess of energy intake over expenditure that must be sustained chronically in order to develop obesity is very small. For example, a positive daily energy balance of only 18 kcal, the energy content of a single soda cracker, would result in a weight gain of about 2 pounds per year

Explain why skin pigmentation occurs. in Addison's disease. How might this be reversed?

After >90% of both adrenal cortices destroyed, Addison's disease develops as an insidious, ill defined clinical picture. - The first indications are often vague weakness and fatiguability. As the negative feedback to the hypothalamus and pituitary is abolished, ACTH and MSH levels rise, with consequent increase in pigmentation of the skin and mucous membranes. = Most patients also develop gastrointestinal disturbances, including anorexia with weight loss, nausea, vomiting, or diarrhea. = Reduced cardiac contractility and sodium losses lead to decreased blood pressure; salt losses and inability to excrete water lead to low serum sodium. = When mineralocorticoid synthesis is affected, serum potassium may be increased. Although patients can often tolerate these symptoms for a long time, an infection, injury, or major stress can cause rapid deterioration with low blood pressure, shock and death if this "adrenal crisis" is not diagnosed and treated in time.

Thyrotoxicosis - The Antibodies

Anti-TPO - anti-peroxidase antibody Not so specific Very sensitive for auto-immune related thyroid disease Have a low threshold for ordering when considering any thyroid disease TSIg - Thyroid stimulating immunoglobulin Very specific But often not necessary "Use the Force Luke" Not so sensitive Can have TSIg negative Graves' disease

Thyrotoxicosis syndrome: signs and symptoms "A Penny For Every Symptom That Hyperthyroidism Will Make Grossly Evident":

Anxiety Palpitations/ Pulse rapid Fatigability Emotional lability Sweating Tremor Heat intolerance Weight loss with good appetite Muscular weakness/ Menstrual changes Goitre Eye changes

What are the major functional roles of apoproteins? Give examples of each.

Apoproteins are the protein component of lipoproteins and aid in this transport and delivery process in three ways. 1) They may have a major role in the structural formation of the particle. * Ex: apo B-100 is the major structural protein of VLDL, IDL, and LDL and apo A-I is the major structural protein for HDL. 2) They may act as ligands for receptors. * Ex: apo B-100 which allows recognition and binding by the LDL receptor on the liver and peripheral tissues. 3) They can act as cofactors for enzymatic processing of the particle. *Ex: apo C-II which is necessary as a cofactor for activation of lipoprotein lipase (LPL). Some apoproteins may have more than one function.

The Obesity Epidemic

Approximately one third of all adult Americans are now obese. Why? 1) food supply is being driven by market forces to be ever more palatable, and that highly palatable food reinforces its own intake through the same neurological pathways that reinforce the use of addictive drugs. According to this hypothesis, reward circuitry in the brain can modify or even override the operation of the satiety. 2) connectivity of the arcuate nucleus, paraventricular nucleus, and related hypothalamic structures can be modified by exposure to dietary fat or caloric excess during fetal or neonatal life. This hypothesis is supported by the finding of increased body weight in the adult offspring of pregnant rats that were overfed or made hyperinsulinemic during gestation. It has also been shown recently that leptin administration to neonatal leptin-deficient mice promotes the growth of neuronal projections from the arcuate nucleus.

Acromegaly symptoms ABCDEF:

Arthralgia/ Arthritis Blood pressure raised Carpal tunnel syndrome Diabetes Enlargemed organs Field defect

Acromegaly Co-morbidities

Arthritis High blood pressure Diabetes mellitus Heart disease -heart failure colon polyps and colon cancer Depression Loss of sex drive Abnormal menstrual cycle, galactorrhea

Adrenal Insufficiency - Primary - Etiology

Auto-immune adrenalitis (USA) Occasionally a component of APS I or II Most common. Infectious adrenalitis Tuberculosis (Developing world) HIV and associated OI's - CMV, Kaposis, atypical mycobacteria, etc. Fungal - histoplasmosis, blastomycosis, cryptococcus Bacterial - meningococcus (Waterhouse-Friedrichson Sx) Carcinomatous infiltration Carcinoma of lung (!), renal and breast Hemorrhage or thrombosis Sepsis - Meningococcus, Pseudomonas, Staph, S Pneumo Warfarin mediated Anti-phospholipid syndrome Rarely - drugs (ketoconazole), CAH, adrenoleukodystrophy

Addison's disease: features ADDISON:

Autoimmune DIC (meningcoccus) Destruction by cancer, infection, vascular insufficiency Iatrogenic Sarcoidosis, granulomatous such as TB histiomycosis hypOtension/ hypOnatermia Nelson's syndrome [post adrelectomy, increased ACTH]

Laron syndrome

Autosomal recessive disorder Characterized by insensitivity to GH caused by defects of the GH receptor The syndrome is known to cause grossly impaired growth despite normal levels of serum GH

Describe the clinical presentation of hyper- and hypocalcemia

B. Hypocalcemia Clinical Manifestations Hypocalcemia is generally much more symptomatic than hypercalcemia, although again the symptoms and signs of hypocalcemia are related to the rate of change in calcium levels as much as the severity of hypocalcemia (Table 4). Differential Diagnosis Hypocalcemia is not a common diagnosis partly because calcium homeostatic mechanisms are so effective. However, hypoparathyroidism (many possible etiologies) largely prevents mobilization of the massive supply of calcium in the bones and is the most common cause of low serum calcium. A large number of non-hypoparathyroid states, i.e. Vitamin D deficiency, in which compensatory PTH secretion may be inadequate can also cause Hypocalcemia (Table 5). partly because calcium homeostatic mechanisms are so effective. However, hypoparathyroidism (many possible etiologies) largely prevents mobilization of the massive supply of calcium in the bones and is the most common cause of low serum calcium. A large number of non-hypoparathyroid states, i.e. Vitamin D deficiency, in which compensatory PTH secretion may be inadequate can also cause Hypocalcemia (Table 5).

(GUNNER) - Actions of glucocorticoids (eg, cortisol)—mnemonic: cortisol is "BBIG"

Bone formation due to inhibition of osteoblasts and decreased intestinal Ca2+ absorption. Maintenance of Blood Pressure: cortisol upregulates α1 receptors on arterioles, increasing their sensitivity to norepinephrine (NE). Accordingly, cortisol excess causes ↑ arterial pressure, while cortisol deficiency causes ↓ arterial pressure. Glucocorticoids exert anti-Inflammatory effects through several mechanisms: 1) induction of synthesis of lipocortin, a phospholipase A2 inhibitor—glucocorticoids are used to prevent rejection of transplanted organs because of this function. 2) inhibition of IL-2 production, and 3) inhibition of histamine and serotonin release. ↑ Gluconeogenesis, lipolysis and protein catabolism

Explain the interaction between osteoclasts and osteoblasts through RANKL, RANK and osteoprotegerin.

Bone is a specialized connective tissue with both structural and metabolic functions, i.e. the protection and locomotion roles of the skeleton, and the reservoir function for calcium, phosphate, and organic buffers. It is composed of cells, organic matrix (called osteoid) and mineral. Most of the matrix protein is collagen. The cells in bone are osteoblasts, osteoclasts, lining cells (former osteoblasts), and osteocytes (also former osteoblasts). Osteoclasts come from the monocyte/macrophage lineage of hematopoietic cells. Osteoblasts are derived from fibroblast-like mesenchymal precursor cells. The lining cells are responsible for the minute-to-minute regulation of serum calcium in response to PTH. The osteoblasts form new bone and tell the osteoclasts when to reabsorb old bone. The osteoblasts contain receptors for most of the endocrine factors that affect bone turnover while the osteoclasts have few surface receptors. The signal whereby osteoblasts tightly control the activity of osteoclasts has recently been identified. Many cells from the osteoblast lineage as well as osteoclasts and stromal cells secrete RANKL (receptor activator of nuclear factor B ligand) a cytokine-like molecule in the tumor necrosis factor (TNF) family. The RANKL activates RANK on the cell surface of osteoclast precursors, a sufficient signal to take these cells through differentiation, fusion and activation as well as protecting active cells from apoptotic (cell death) signals (Fig. 6). The third part of this system is osteoprotegerin (OPG), a molecule secreted by osteoblasts. OPG functions as soluble RANK and is able to bind RANKL and prevent it from binding to and activating RANK on the surface of osteoclasts. By altering the amount of OPG being released, osteoblasts can fine-tune the amount of osteoclast activation. All of the many hormones, cytokines and growth factors that affect bone turnover do so by affecting the ratio of RANKL and OPG being released by osteoblasts.

(GUNNER) Signs/Symptoms of hypercalcemia: "moans, groans, stones, and bones"

CNS - confusion, coma, seizures, psychiatric disturbances Renal - 20% have nephrolithiasis Musculoskeletal: weakness and pathologic fractures Cardiac: heart failure and arrhythmias GI: abdominal pain, nausea, constipation

Describe the main factors that influence calcium absorption by the gut.

Calcium in food is absorbed by the intestines, enters the bloodstream and is then distributed to cells throughout the body, stored in/exchanged with bone or excreted by the kidneys. When the supply of calcium in the environment is inadequate for sufficient gut absorption, more calcium is resorbed from the bones and reabsorbed from the renal tubules in order to make up the deficit. Vitamin D increases the efficiency of absorption of calcium by the small intestine. Many Vitamin D responsive genes are activated in the gut, helping to increase the flux of calcium ions into and across intestinal cells. Glucocorticoids can interfere with gut calcium absorption by blunting the effect of Vitamin D on intestinal gene transcription. Vitamin D also increases the efficiency of the absorption of phosphorus.

(GUNNER) - Pheochromocytoma: neuroendocrine tumor of adrenal medulla chromaffin cells that secretes catecholamine

Called 10% tumor because 10% malignant, 10% found extraadrenal, and 10% are bilateral Associated with MEN (multiple endocrine neoplasia) II and III and neurofibromatosis. (Note: MEN II is also referred to as MEN IIa; MEN III as IIb) Treatment: alpha blockers (e.g. phenoxybenzamine or phentolamine)

Regulation of Energy Expenditure

Calorimetry: w/O2, This decay rate is proportional to integrated carbon dioxide production, which can be used to calculate energy expenditure. The "doubly-labeled water" technique is the only method for accurately measuring energy expenditure in completely unconfined subjects. Total daily energy expenditure, or thermogenesis, is traditionally divided into three components: 1) resting metabolic rate= represents the minimal ongoing energy utilization required to sustain cardiac activity, respiration, neurological function, and all the metabolic activities of the body's tissues. Meaured during sleep. a. Best measure: Body's FFM. Value which ↑ in obese. = Total Mass- BFM. b. Fat mass, which largely represents metabolically inactive triglyceride, 2) the thermic effect of exercise = energy utilization due to both voluntary and involuntary physical activity a. As dictated by the laws of physics, the energy required to perform physical activity increases in proportion to body mass. This phenomenon accounts in part for the positive relationship between energy expenditure and body fat mass. 3) dietary thermogenesis = "energy tax" required to digest, absorb, and ultimately to store the nutrients derived from food. A relatively constant 10% of calories ingested. The ability of fat-free mass to predict resting and total daily energy expenditure among subjects at their usual body composition was mentioned above. It turns out that when an individual has deviated below baseline body fat content, these energy expenditure values are even lower than predicted for the new fat-free mass (which is also diminished). These exaggerated compensatory responses to fat loss and gain production of triiodothyronine from thyroxine that occurs during caloric deprivation appears to be one explanation for the fall in energy expenditure with weight loss.

Pulsatility of circulating GH levels in adult men and women.

Circulating GH levels are pulsatile, with high peaks separated by valleys where the GH is undetectable by conventional RIAs or IRMAs (Figure 6). The recent development of sensitive chemiluminescent assays for GH with high frequency sampling and deconvolution analysis has allowed the detailed study of GH secretion. This shows that there are detectable levels of basal GH secretion in the 'valleys' (243). On average, there are 10 pulses of GH secretion per day lasting on average 96.4 mins with 128 mins between each pulse (244). There is a dynamic interplay of pulsatile GHRH and somatostatin secretion: Via crosstalk: GHRH neurones receive inhibitory inputs from somatostatin neurons, whilst somatostatin neurones receive direct stimulatory inputs from GHRH neurones (see Lechan and Toni). Via synergistic actions on somatotrophs: Pre-exposure to somatostatin enhances GHRH-stimulated secretion of GH (245).

Understand the anatomy of the thyroid and how to perform a physical examination of the gland.

Comes from pharynx. Bilobed gland. Isthmus connects the two. Exam: Take index and middle finger until find crichoid cartilige. Once find that, move down trachea until find rubbery stuff. Swallow if needs.

Nonfunctioning pituitary tumors Summary

Common Presentation: headaches > tumor found by imaging Clinical malaise > hypogonadism > panhypit Astute clinician can make the diagnosis before imaging - Signs and symptoms of hypopituitarism and abnormal visual fields Diagnosis: Imaging and Pituitary Function Treatment related to: mass effect >surgery and RT pituitary function >preservation - replacement Urgent therapy in: acute optic nerve compression apoplexy

Side effects of GH treatment:

Common: early edema, joint pain, local bruising at the site of injection Rare: slipped capital femoral epiphyses, gynecomastia, pseudotumor cerebri (or benign intracranial hypertension) Worsening of scoliosis Hyperinsulinemia Diabetes and leukemia: not increased Concerns: No specific safety issues identified in ISS Exacerbation of insulin resistance may be a concern in SGA Long-term cancer risk remains a concern Side effects may be GH dose- and/or IGF-I concentration-dependent

Growth Evaluation: Blood Analysis

Complete blood count (CBC) Sedimentation rate (ESR) Celiac screen Chemistry (electrolytes, LFT, BUN, creatinine) Karyotype (girls) Growth factors (IGF-I, IGFBP-3) - Random GH not useful TSH, free T4 GH stimulation

Tall Stature

Constitutional tall stature Genetic tall stature Syndromes of tall stature Cerebral Gigantisim Marfan's syndrome Homocystinuria Beckwith-Wiedemann syndrome XYY syndrome Klinefelter's syndrome

Hypothyroidism - Treatment Myxedema

Controversial - no studies to support specific therapy Levothyroxine - LT4 - 100 - 500 mcg IV times one then 50 - 100 mcg daily Liothyronine - LT3 - 10 - 25 mcg IV q 8 hours then 10 mcg IV q 8 hours ICU care is mainstay of therapy Antibiotics Steroids Ventilator Support Warming if indicated Volume resuscitation

List the four major causes of Cushing's syndrome and describe your approach to differentiating these clinically.

Cushing's syndrome = sx/sgns of chronic glucocorticoid excess. - protein-depleted as a result of excess protein catabolism. - think skin, muscles, tissues, hair. - poor wound healing. are thin, and the muscles are - some virilization - Body fat is redistributed to collects centrally in the abdominal wall, face, and upper back . Stretched abdominal skin ruptures to form reddish-purple ("violaceous") striae. (In normal individuals, the striae are usually inconspicuous, narrower (<1cm) and are "silver") - diabetes from converted catabolized proteins to glucose in the liver, and the resultant hyperglycemia may be sufficient to precipitate diabetes mellitus. - osteoporosis by decreasing bone formation and increasing bone resorption. - Increased ADH: salt and water retention can cause edema, and there may be significant K+ depletion and weakness. - About 85% have high BP. - can have CNS effects ranging from mental aberrations, increased appetite, insomnia, and euphoria, to frank toxic psychoses. Causes of Cushing's syndrome 1) Exogenous Cushing's : due to glucocorticoid administration (may be after tx for immune/inflammatory disorders). Path: potent negative feedback effects on HPA, ZF & ZR become atrophic. Thus, this is paradoxically also the commonest cause of secondary adrenal insufficiency when treatment is stopped. 2) Pituitary or ectopic ACTH-dependent Cushing's: Excessive ACTH secretion produces adrenocortical hyperplasia. Both adrenals are enlarged, either diffusely or in the form of multiple nodules. - Over 50% in adults are from ACTH-producing pituitary adenomas= "Cushing's disease". --> tumors are usually small (vs acromegaly ones), benign, and well differentiated. Have some (-) feedback, so only a little increase in ACTH. "Shift to the right" allows hypercortisolism to develop, leading to normal pituitary inhibition. Thus, patients with Cushing's disease are also at risk for adrenal insufficiency after their pituitary tumors are removed. - about 15% of the endogenous cases from Tumors from neuroectoderm can also produce excess ACTH ("ectopic ACTH syndrome"). Small-cell lung tumors, carcinoid tumors, and thymomas are commonest. Since they arise from tissues which do not usually express the machinery for glucocorticoid negative feedback regulation, the ectopic ACTH secretion can reach very high levels w/o (-) feedback response. Thus, it may cause max. adrenal stimulation and very high levels of adrenocortical hormones. 3) Adrenal Cushing's: (20%) Adrenocortical (origin) neoplasms may produce various adrenocortical hormones. - Histology: adenomas have normal adrenocortical cells w/o normal cortical architecture. - spherical/encapsulated. Yellow to slightly tan. often show hemorrhage and necrosis. - These carcinomas less efficient production of hormones so by the time they become clinically apparent, they are usually quite large and heavy . 4) "incidentalomas": non-functioning adrenal adenomas which increase in frequency with age, usually require no specific treatment other than follow-up. Larger= more likely hormonally active/malignant; evaluate any larger than 4 cm diameter.

(GUNNER) Secondary Adrenocortical Insufficiency

Decreased production of pituitary ACTH [1] Diagnosis: No hyperpigmentation with decreased ACTH, but increased cortisol response to ACTH. Contrast with Primary (Addison's disease) which has hyperpigmentation with increased ACTH

Adrenal Insufficiency - Secondary Pathophysiology - Secondary

Deficiency of CRH/ACTH Mineralocorticoid intact no issue with potassium balance.

Adrenal Insufficiency - Primary

Defining this disorder Destruction of the glucocorticoid producing capabilities of the adrenal cortex. All three layers gone. Invariably involves loss of mineralocorticoid production and adrenal androgen production as well The adrenal medulla is usually spared. Must be bilateral and involve destruction of 90% of the gland prior to development of signs or symptoms

(GUNNER) - Dexamethasone suppression test:

Dexamethasone suppression test: - Dexamethasone is a synthetic glucocorticoid that can inhibit ACTH secretion from the anterior pituitary - Dexamethasone suppression test may be used to diagnose and differentiate Cushing syndrome from Cushing disease If the patient suppresses ACTH in response to low-dose dexamethasone → the patient may look like they have Cushing syndrome (bummer indeed), but their ACTH-cortisol axis is probably normal. If the patient fails to suppress ACTH in response to low-dose dexamethasone, but they suppress ACTH in response to high-dose dexamethasone → likely an ACTH-secreting pituitary adenoma (Cushing disease) If the patient fails to suppress ACTH in response to either low-dose or high-dose dexamethasone → Cushing syndrome, either due to: - Cortisol-producing tumor in the adrenal cortex (high serum cortisol, low serum ACTH) or - Ectopic ACTH-secreting tumor (high serum cortisol, high serum ACTH), most commonly caused by small cell carcinoma of the lung. The ectopic ACTH-secreting tumor will have much higher ACTH levels than the tumor in the adrenal cortex. If the results of the dexamethasone suppression tests are equivocal → perform a CRH stimulation test with inferior petrosal sinus ACTH sampling

Acromegaly Gigantism Summary

Diagnosis of gigantism -obvious Diagnosis of Acromegaly -often made by abnormal imaging Acromegalic features are insidious, an astute physician can make the diagnosis clinically Diagnosis: Clinical > Imaging > IGF-1 and GH suppression Treatment: Surgery, -concomitant medical and or RT are also necessary

Give the two most common causes of hypercalcemia and explain how to differentiate between them.

Differential Diagnosis In North America more than 90% of patients with hypercalcemia will have either primary hyperparathyroidism or a malignancy and often can be distinguished clinically (Table 3). Primary hyperparathyroidism is described above. Malignancy can lead to hypercalcemia by at least four different mechanisms; 1) paraneoplastic PTHrP; 2) systemic or local cytokine (i.e. IL-6) release by tumoral or peri-tumoral cells; 3) lytic bone metastases (i.e. multiple myeloma, breast cancer); 4) 1-hydroxylase expression in lymphomas leading to excess 1,25-(OH)2-Vitamin D. Milk-alkali syndrome occurs when large amounts of CaCO3 are ingested that simultaneously cause increased calcium absorption and decreased calcium excretion due to the alkalosis. The alkalosis buffers increases in ionized calcium but this syndrome can nonetheless result in symptoms. This disorder is increasing due to people that think that if 1500mg/day of calcium is good for you 15000mg/day must be better. In the setting of hypercalcemia, measuring calcium and phosphate together with PTH and PTHrP is the best way to begin making the diagnosis.

Adrenal Insufficiency - Secondary - Etiology

Drugs - Exogenous glucocorticoid administration Oral, systemic and inhaled. Megestrol use. Many imperfect algorithms - duration and dose play a significant role Any cause of Hypopituitarism Tumors, craniopharyngioma, radiation, pituitary surgery Infiltrative diseases - Sarcoid, HH, Histiocytosis X Predominantly hypothalamic infiltration Lymphocytic hypophysitis - Auto-immune, pregnant women Post-partum pituitary necrosis Head trauma

The Adrenal Cortex - Meet the Family

Each layer has a specific set of enzymes needed to make its hormones.

(GUNNER) - Iodine deficiency:

Endemic dietary iodine deficiency is the most common cause of hypothyroidism worldwide Cretinism: - children with mental retardation, pot-bellied stomach, protruding umbilicus and protuberant tongue. Faces are pale and puffy. - testing of all newborns for hypothyroidism (elevated TSH) is standard of care because mental retardation can be minimized when thyroid hormone is administered in neonatal period.

Factors influencing fetal growth are:

Environmental factors maternal size maternal nutrition placental function absence of infection or substance abuse Altitude Fetal: Hormonal factors Chromosomal abnormalities Inborn errors of metabolism Malformations Infections

Adrenal Insufficiency - Diagnostic Goals

Establish low glucocorticoid production for a given clinical scenario - use cortisol levels Establish the level of defect - use ACTH Primary Secondary Diagnostic tools Basal measurements ACTH stimulation tests -1-mcg versus 250-mcg -Duration Critical thinking - this is my favorite one...will be on the test

Adrenal Insufficiency Pathophysiology - Primary

Excess ACTH Mineralocorticoid deficiency High levels of serum K+

(GUNNER) - Graves disease: most common cause of endogenous hyperthyroidism (85% of cases)

F > M (females are 10x more frequently affected than males); peak incidence between 20-40yo Associated with HLA-DR3 and HLA-B8 Caused by a ↓ in self-tolerance to thyroid auto-antigens → autoantibodies: - TSI (thyroid-stimulating immunoglobulin) = IgG that binds and activates TSH receptor ∴ TSI mimics the action of TSH via type II hypersensitivity. TSI is relatively specific for Graves disease. - anti-Tg (thyroglobulin) and anti-TPO (thyroid peroxidase) antibodies are often present TSI & other autoantibodies cross-react with and stimulate orbital preadipocyte fibroblasts (which express TSH receptors) to synthesize hydrophilic glycosaminoglycans (e.g., hyaluronic acid, chondroitin sulfate). Accumulation of glycosaminoglycans (along with infiltration of fat and mononuclear cells (mostly T cells)) in the retro-orbital space → exophthalmos (proptosis). Triad of clinical findings: 1) Hyperthyroidism secondary to diffuse, symmetrical, nontender hyperfunctional enlargement of the thyroid 2) Infiltrative ophthalmopathy: - exophthalmos (proptosis) due to accumulation of glycosaminoglycans and adipose in retro-orbital tissue; this occurs in ~50% of patients - extraocular muscle weakness 3) Infiltrative dermopathy: - pretibial myxedema: scaly thickening and induration of the skin overlying the shins with nonpitting edema; this only occurs in 1-2% of patients Triad of histologic findings: 1) Diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells → abundant tall columnar cells lining the follicles 2) Colloid appears pale with scalloped (moth-eaten) margins due to ↑ absorption 3) Lymphocytic infiltrate → germinal centers are common (germinal centers should NOT be in the thyroid ; they are normal in lymph nodes)

Post natal growth

Factors influencing growth Evaluate growth Monitor growth Problems associated with growth

Understand the actions of PTH to prevent hypocalcemia.

Factors that increase secretion of PTH include low serum calcium and 1,25-(OH)2-Vitamin D and a high serum phospate. Low serum magnesium also may have a small effect on stimulating PTH production. Calcium signaling through the CaR is the most important regulator, as low serum calcium affects PTH at multiple sites depending on the duration and severity of hypocalcemia by 1) increasing release of pre-formed hormone (30-90sec); 2) decreasing intracellular pro-PTH degradation (30-60min); 3) increasing PTH gene expression (several hours); and 4) enhancing parathyroid cell proliferation (days) (Fig 4). Although low serum magnesium can stimulate PTH production, magnesium is also a co-factor for the processing and release of PTH. Severe hypomagnesemia can cause a low serum PTH. High serum calcium and 1,25-(OH)2-Vitamin D as well as low phosphate decrease PTH synthesis and release (all easy to remember as negative feedback from PTH effects) Biological Activity All of the actions of PTH on mineral homeostasis (Figure 5) are mediated through a G-protein coupled transmembrane receptor (PTH-1R). The receptor is found in many tissues in adults and even more widely during fetal development and appears to mediate signals related to growth in addition to effects on calcium homeostasis (described below). Bone PTH increases the release of calcium and phosphate from bone by stimulating osteoblasts to activate osteoclasts. When PTH action on bone is continuous (i.e. hyperparathyroidism) the net effect is loss of bone minerals and hypercalcemia, however when PTH action on bone is intermittent, the net effect is one of bone growth especially in the bone most susceptible to metabolic bone disease (see below under treatment of osteoporosis). Kidney The kidney is the essential organ where PTH action differentially regulates calcium and phosphate homeostasis by promoting calcium reabsorption while decreasing phosphate reabsorption. The mechanism of increased phosphate excretion occurs by a specific down regulation of a sodium/phosphate co-transporter. PTH also stimulates 1,25-(OH)2-Vitamin D production by the kidney as discussed above. DCT main site of calcium regulation PTH in the kidney. PTH increases the number of open ca channel/calcium reabsorbed. Remember that hypercalcemia (even if the cause is primary hyperparathyroidism) will increase the amount of calcium filtered and will easily overwhelm this distal mechanism resulting in (appropriately) higher levels of calcium in the urine (hypercalciuria) even though a smaller percentage is being excreted . This concept is especially important in the treatment of hypocalcemia from hypoparathyroidism where attempts to normalize serum calcium with calcium supplements and Vitamin D can result in renal calcification and kidney failure.

Hypothyroidism - Symptoms

Fatigue and listlessness Weight gain - usually with a poor appetite Edema Cold intolerance Proximal muscle weakness Constipation Hoarseness - accumulated fluid in the vocal cords Slowed mentation Menorrhagia, Irregular menses or amenorrhea Decreased sweating

Adrenal Insufficiency Clinical Manifestations Non-specific symptoms for both 1st and 2ndary:

Fatigue, listlessness, *fever, *abdominal pain, nausea, poor appetite,* emesis (keep food down), generalized weakness, dizziness * very important to treat ASAP. Sexual dysfunction or loss of libido Weight loss Orthostatic hypotension Concerning symptoms -fever, emesis and abdominal pain

Metabolism of catecholamines

Following secretion, catecholamines either: 1) bind to receptors or 2)are quickly metabolized since they have a very short half-life in the circulation - Metabolism occurs via two main pathways: - (1) circulating catecholamines are sequentially acted upon by the hepatic and renal enzymes (COMT) to produce the intermediate metabolites, metanephrine and normetanephrine, and then by MAO to produce (VMA); (2) intracellular catecholamines are metabolized sequentially via MAO plus COMT to 3,4 dihydroxymandelic acid as a very transient intermediate metabolite that is quickly converted to VMA as the final product. In normal patients, most of the circulating catecholamines are excreted as urinary VMA (~65%).

Describe some of the pathways leading to increased glucocorticoid secretion following a heart attack

Follwoing "stressors," there is an increased secretion of ACTH and, consequently, a rise in circulating glucocorticoid levels. These same stressful stimuli also activate the sympathetic nervous system and catecholamines in the adrenal medulla, and part of the function of circulating glucocorticoids may be maintenance of metabolic and vascular reactivity to catecholamines. During severe stress, the amount of ACTH secreted exceeds the amount necessary to produce maximal glucocorticoid output. Increases in ACTH secretion to meet emergency situations are mediated through the release of corticotropin-releasing hormone (CRH) from the median eminence of the hypothalamus, and its transport via the portal-hypophyseal vessels to the anterior pituitary to stimulate ACTH secretion. * If the median eminence is destroyed, some basal glucocorticoid secretion continues, but increased secretion in response to many different stresses is blocked. Afferent nerve pathways from many parts of the brain (limbic responses, barorecptors when low BP and niciceptors) converge on the median eminence. * Interleukins triggered by infection and other circulating modulators reach the hypothalamus via the bloodstream and activate CRH and ACTH Glucocorticoids are necessary for the catecholamines to exert their full free fatty acid (FFA) mobilizing action, and the FFAs are an important emergency energy supply. However, sympathectomized animals tolerate a variety of stresses with impunity. Another hypothesis holds that glucocorticoid secretion is essential because the rapid steroid-induced movement of fluid into the vascular system helps to prevent shock.

Adrenal Insufficiency - Dynamic Testing

For whom the cosyntropin tolls.... All patients with indeterminate basal cortisol levels All patients for whom time is of the essence There is no diurnal variation in response to ACTH Therefore the test may be performed at any time of day Terminology Short ACTH stimulation test - plasma cortisol at 0, 30, 60 min Prolonged ACTH stimulation test - plasma cortisol at 0, 4 and 48 hrs High dose ACTH stimulation test - 250 mcg cosyntropin Low dose ACTH stimulation test - 1 mcg cosyntropin How to interpret an ACTH stimulation test... For the high-dose test... Peak cortisol must reach >18 - 20 mcg/dL Failure to reach this peak cortisol is diagnostic of AI But you are still not completely sure of the type of AI Thankfully you sent off that ACTH level... A cortisol >18 - 20 rules out all primary AI and MOST, but not all, of secondary AI Why does this test not rule out all of secondary AI? Consider new onset secondary AI

Approved indications for GH

GH deficiency Chronic Renal failure with short stature Turner Syndrome Prader Willi Syndrome Also: Children with small for gestational age [SGA] who have not reached a normal height range by age 2 years Children with idiopathic short stature who are >2.25 SD below the mean Adults with GHD Short gut syndrome Adults with AIDS wasting

Regulation of GH secretion-feedback loop

GHRH from the hypothalamus attaches to a specific GHRH receptor on the somatotroph The somatotroph cells release GH into the systemic circulation where it travels to many sites and attaches to specific GH receptors causing release of Insulin-like Growth Factor-1 (IGF-1). Almost all the circulating IGF-1 comes from the liver. IGF-1 inhibits further release of GHRH and GH by a negative feedback loop. There are at least two other important regulators of GH secretion, however. Somatostatin, made in the hypothalamus, inhibits release of GH. Additional receptors have been found on somatotroph cells, distinct from GHRH receptors. These receptors are the site of action for a recently discovered 28 amino acid peptide called ghrelin. Ghrelin is abundant in the stomach and is a GH secretogogue, raising the possibility of nutritional regulation of GH The physiological importance of ghrelin is not yet fully understood, it has a role in stimulating appetite. Orally active analogs of ghrelin are under development and may be used to stimulate GH secretion pharmacologically. There is also a lot of interest in developing ghrelin antagonists as a potential appetite suppressant for the treatment of obesity.

(GUNNER) - Regulation of glucocorticoid secretion

Glucocorticoids secretion oscillates with the circadian rhythm. For most people, this amounts to cortisol levels being highest just before waking and lowest in the evening. Glucocorticoid secretion is controlled at the level of hypothalamus, the anterior pituitary and at the adrenal cortex. These components make up the hypothalamic-pituitary-adrenal axis The paraventricular nuclei of the hypothalamus synthesizes the releasing factor CRH (corticotropin-releasing hormone) and secretes it into the hypothalamic-hypophysial portal system when stimulated. CRH stimulates corticotrophs in the anterior pituitary to synthesize POMC (the precursor to ACTH) and secrete ACTH. The second messenger for CRH is cAMP. ACTH increases steroid hormone synthesis in all zones of the adrenal cortex by stimulating cholesterol desmolase and increasing the conversion of cholesterol to pregnenolone. The sensitivity of the adrenal cortex to ACTH is increased by ACTH itself due to upregulation of the ACTH receptor. Chronic stimulation of the adrenal cortex by ACTH causes cortical hyperplasia. The second messenger for ACTH is cAMP. Cortisol exerts negative feedback on the HPA axis by inhibiting the release of CRH from the hypothalamus and ACTH from the anterior pituitary.

(GUNNER) - After confirming thyrotoxicosis with TSH and free thyroid hormone level assays, 131I uptake may help determine the etiology of the thyrotoxicosis:

Graves disease: diffusely ↑ 131I uptake in the whole thyroid gland Toxic multinodular goiter: uneven 131I uptake with occasional autonomous "hot" nodules demonstrating ↑ 131I uptake Thyroiditis: ↓ 131I uptake Patient taking exogenous thyroid hormone: ↓ 131I uptake - iatrogenic hyperthyroidism — e.g., patients with hypothyroidism may take too much of their prescribed thyroid hormone replacement medication - euthyroid patients may surreptitiously take exogenous thyroid hormone for secondary gain — this excess thyroid hormone negatively feeds back on the pituitary → ↓ TSH → ↓ thyroid activity (∴ ↓ 131I uptake) with thyroid gland atrophy

ENDOCRINE CAUSES OF SHORT STATURE

Growth hormone deficiency 1:4000 children, or 1% of short children Congenital malformations of hypothalamus and pituitary Genetically determined disturbances Tumors Chronic inflammation Idiopathic Following radiotherapy and chemotherapy for neoplastic disease Growth hormone resistance Growth hormone receptor defect Post receptor defect

(GUNNER) - Cushing syndrome

Hallmark: ↑ cortisol—increased 24 hour urine free cortisol level Signs/Symptoms: buffalo hump, weight gain, moon facies, hypertension, hyperglycemia, osteoporosis, amenorrhea, impotence, and striae Causes: A) Cushing disease: ACTH-secreting pituitary adenoma with resultant increase in cortisol levels B) Only the primary pituitary adenoma is referred to as Cushing disease. The other etiologies collectively reflect a Cushing syndrome. A high dose dexamethasone suppression test can be used to distinguish Cushing disease— cortisol levels are inhibited (levels unchanged in Cushing syndrome caused by adrenal or ectopic ACTH tumor). C) Ectopic ACTH production: small cell lung cancer with increased ACTH D) Iatrogenic: a patient taking cortisol for therapy, a decreased ACTH due to negative feedback to pituitary E) Adrenal hyperplasia or neoplasia → ↓ ACTH due to negative feedback to the pituitary : Tumor excision with postop glucocorticoid replacement Drug Therapy: Mitotane: antineoplastic agent, selectively inhibits adrenal cortex Ketoconazole: antifungal, also inhibits steroid synthesis, inhibits P450

(GUNNER) - Causes of primary hypothyroidism:

Hashimoto thyroiditis (chronic autoimmune thyroiditis) Post ablation: surgical or I-131 radiation Iodine deficiency Drugs: - lithium - amiodarone - sulfonamides Subacute lymphocytic (painless) thyroiditis Myxedema coma

Symptoms caused by space occupying lesion:

Headaches Compression of the optic chiasm, visual defects Might also have issues with the pituitary.

Measuring growth

Height Weight Head circumference Body proportions: span / height upper / lower segment degree of sexual maturation.

Acromegaly Diagnosis

History and physical findings Laboratory tests: IGF-1 Random GH and after an OGTT (< 1 (ng/ml) Imaging MRI of the pituitary (90%) are macroadenomas

The major causes of thyroid enlargement (goiter) may be categorized as follows:

I. Overstimulation of thyroid A. TSH-driven 1. Hormone biosynthetic defect a. Iodine deficiency b. Inborn error of hormone synthesis c. Drug or diet-induced impairment of hormone synthesis B. TSI (thyroid-stimulating immunoglobulin)-driven: Graves disease II. Neoplastic processes A. Uninodular B. Multinodular III. Infiltrative processes A. Lymphocytic (Hashimoto's thyroiditis) B. Amyloid C. Fibrous (Riedel's struma)

Etiology of Obesity

In obese individuals, a greater body fat mass to suppress appetite and to stimulate energy expenditure to the point that energy balance is achieved. No truth in lower metabolism. It has already been pointed out that obesity is a polygenic (multiple gene) trait in humans, rather than being a simple dominant or recessive condition involving single identifiable genes. Nevertheless, a number of investigators have screened large populations of obese individuals for defects in the human homologs of the cloned rodent Mendelian obesity genes. An alternative interpretation of the positive relationship between plasma leptin and body fat mass shown is that human obesity is a disease of "leptin resistance". In this view, thrifty genes promote obesity by diminishing the normal response to leptin at any of a number of points including transport into the central nervous system, binding to the leptin receptor, or post-receptor signaling events. The leptin resistance hypothesis would explain the fact that exogenously-administered recombinant leptin is not a particularly effective treatment for human obesity.

Hormones and Growth

Increase in GH increases growth Increase in Thyroid hormone increases growth Increase in Sex steroids, increase growth initially and ULTIMATELY STOP growth

Adrenal Insufficiency - Making the Diagnosis

Initial Evaluation Basal (8 AM) cortisol and ACTH Cortisol <3 mcg/dL is ~100% specific 36% sensitive Cortisol <10 mcg/dL is 77% specific 66% sensitive Cortisol >18 mcg/dL rules out AI ACTH levels >100 pg/ml seen uniformly in primary AI ACTH levels are variable in secondary AI

Describe the reciprocal effects of PTH on renal excretion of calcium and phosphate

Kidney 25-OH-Vitamin D undergoes a second hydroxylation reaction in the kidney (Fig 3). The 1-hydroxylase converts 25-OH-Vitamin D into 1,25-(OH)2-Vitamin D the active hormone. The activity of this renal enzyme is precisely regulated. PTH and low phosphate increase activity of the enzyme while 1,25-(OH)2-Vitamin D and high phosphate decrease activity. In addition, growth hormone and prolactin may play a minor role in activating the 1-hydroxylase. The half-life of 1,25-(OH)2-Vitamin D is 4-6 hours. Chronic kidney disease decreases the production of 1,25-(OH)2-Vitamin D by reducing the amount of the enzyme and by decreased phosphate clearance causing hyperphosphatemia which suppresses the enzyme. Inactivating mutations of the 1-hydroxylase result in Vitamin D dependant rickets type 1 (VDDR1) which causes deformities of bone in young children. The kidney also has the highest concentrations of another enzyme that acts on Vitamin D, namely 24-hydroxylase. This enzyme is the first step in the inactivation and degradation of Vitamin D.

Hypothyroidism - Treatment

Levothyroxine - LT4 1.6 mcg/kg body weight administered orally = full replacement Slow replacement for at risk populations Elderly CAD or CAD equivalent patients (DM, etc.) Long half life - 7 days Liothyronine - LT3 Not used as replacement therapy - short half-life - fluctuating levels LT4/LT3 combinations - not recommended Synthetic / compound pharmacy Dessicated animal products Lab parameters for follow-up 2 month TFT after any dose change Goal - Primary hypothyroidism - normal TSH and FT4 Goal - Secondary hypothyroidism - upper limit of normal FT4

(GUNNER) -Thyroid storm: abrupt-onset severe thyrotoxicosis

Likely caused by sudden release of catecholamines, as may occur as a result of an acute stress such as: - infection - surgery - trauma Most commonly occurs in patients with underlying Graves disease S/Sx: - high fever (hyperpyrexia) - tachycardia out of proportion to fever - tachyarrhythmias (e.g., atrial fibrillation; ventricular fibrillation) — common cause of death in patients with thyroid storm - shock due to heart failure and/or vomiting-induced volume depletion - coma

Why is Lp(a) thought to have a potential role in fibrinolysis?

Lipoprotein (a),is assembled extracellularly from ApoA and LDL. Due to the structural homology to plasminogen, Lp(a) interferes with fibrinolysis by competing with plasminogen binding to fibrinogen and fibrin. This results in impaired plasminogen activation, and decreased thrombolysis. Lp(a) has also been shown to bind to macrophages, possibly promoting foam cell formation and development of the atherosclerotic plaque.

Where is lipoprotein lipase found, and what is its role in triglyceride catabolism?

Lipoprotein lipase is synthesized in adipose tissue and muscle and then transported to the luminal surface of the endothelial lining of the adjacent capillary where it acts on triglyceride-rich lipoproteins. These chylomicrons and VLDL contain the substrate triglyceride and co-factor apo C-II necessary for normal lipoprotein lipase enzyme activity. The fatty acids that are released during the processing of triglyceride-rich particles can be used for energy by muscle or re-esterified into triglyceride in adipocytes for later use.

Non-Functioning Pituitary Tumors, space occupying effect

Majority are macroadenomas Symptoms -tumor expansion: Headache -stretches sellar dura Optic nerve compression -visual loss, bitemporal hemianopsia Eye muscle paralysis -invasion to cavernous sinuses Acute hemorrhage or infarction of the tumor ("pituitary apoplexy") Sudden headache, visual loss, double vision, and/or pituitary failure Medical Surgical emergency

Adrenal Insufficiency Clinical Manifestations Associated Symptoms of Secondary AI - think hypopituitarism.

Manifestations of hypopituitarism Sexual dysfunction, loss of libido, ED Loss of sexual hair DI - polyuria, thirst Headache Visual field deficits

Describe the relationship between bone loss, aging and fractures.

Many women with low bone mineral density who meet osteoporosis criteria never go on to have a fracture. Many factors other than just the bone density are involved in determining whether a bone will break when exposed to a given force and some of these factors are outlined below. Whether a bone will fracture depends on the trauma sustained as well as the strength of the bone, which in turn depends on the quantity of bone and the so-called quality of bone. In elderly persons, hip fractures usually occur after a fall, but every fall does not result in a fracture. The force of the impact also contributes to a fracture. Young people who fall often soften their impact much more effectively than the elderly. Padding of the bone may also reduce the impact, so that subcutaneous fat over the hips adds some protection. The size, shape and quantity of bone are the key factors that give bone strength, especially when bone is tested ex vivo. Male bones are often stronger than female bones simply because the diameter of the diaphysis is greater. Recent longitudinal studies have demonstrated that both bone density and age are independent significant risk factors for fractures (age being the strongest risk factor). Age is also the most important factor in predicting bone density Finally, the quality of the bone helps determine whether it will fracture. The micro-architecture of normal trabecular bone consists of connected plates. In osteoporotic bones these turn to disconnected plates and rods, and the bone loses its structural integrity. Women with equal bone density but more intact trabecular architecture are less prone to fracture. Other aspects of bone quality are not well understood but include ability to repair microfractures, strength of the crystalline structure, and integrity of the underlying collagen matrix.

What are the signs and symptoms of the chylomicronemia syndrome?

Marked hypertriglyceridemia (triglyceride levels > 2000 mg/dl, normal levels are usually < 200 mg/dl), in which both chylomicron and VLDL particles accumulate, is associated with a constellation of symptoms and signs including abdominal pain (often due to pancreatitis), eruptive xanthomas, and milky plasma (lipemia retinalis). This disorder has been named the chylomicronemia syndrome because it is thought that the high, prolonged circulating levels of chylomicrons are a leading culprit in the clinical manifestations. Although triglyceride levels may be elevated in patients with pancreatitis due to other common etiologies (such as alcoholism or pancreatic duct obstruction), these levels do not exceed 1000 mg/dl and are not thought to be a cause of the pancreatitis. Laboratory evaluation of patients with the chylomicronemia syndrome can reveal a number of artifactual abnormalities that are due to the accumulation of the triglyceride-rich particles. These include a low arterial oxygen level, falsely normal amylase in someone with pancreatitis, low hemoglobin, an increased bilirubin, low serum sodium, and abnormal thyroid function tests

Adrenal Insufficiency - Treatment At Home Precautions

Medic-Alert Bracelet Dexamethasone emergency 4 mg IM injection kit at home Double or Triple dose rules If unable to take PO pills - call for emergency assistance

Nonfunctioning pituitary tumors- Medical treatment

Medical Therapy hypersecretory tumors effectively treated with dopamine agonists (eg. bromocriptine, cabergoline). Medical treatment using somatostatin analogues or dopamine agonists has varying degrees of efficacy for treating GH adenomas. The growth hormone receptor anatagonist, pegvisamont, may prove more effective and can be used in combination with other agents Ketoconazole and/or metyrapone therapy can normalize serum cortisol levels in patients with Cushing's disease preoperatively. Somatostatin (growth hormone-inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF) Regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone and has a much longer half- life (approximately 90 minutes, compared to 2-3 minutes for somatostatin). Since it is absorbed poorly from the gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndrome, acute variceal bleeding, and acromegaly. It is also finding increased use in polycystic diseases of the liver and kidney. Lanreotide (INN) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, like octreotide.

(GUNNER) - Hashimoto thyroiditis (chronic autoimmune thyroiditis):

Most common cause of hypothyroidism in iodine-sufficient areas (developed countries) Nontender thyroid, which often becomes diffusely enlarged → insidious development of hypothyroidism, most commonly in women age 30-50 Anti-thyroid antibodies: - anti-Tg (thyroglobulin) antibodies - anti-TPO (thyroid peroxidase) antibodies -- TPO was formerly known as microsomal antigen Caused by failure of self-tolerance to thyroid auto-antigens → thyroid cell death due to: 1) CD8+ T-cell mediated cell death 2) Cytokines activate TH1 → IFN-γ recruits and activates macrophages → follicle damage 3) anti-thyroid autoantibodies (anti-Tg and anti-TPO) → ADCC (antibody-dependent cell-mediated cytotoxicity) Histology: - 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 ↑ risk of developing other autoimmune diseases, for example: - DM 1 (Type 1 Diabetes Mellitus) - SLE (Systemic Lupus Erythematosus) - SS (Sjögren's syndrome) - MG (Myasthenia Gravis) ↑ risk of primary thyroid lymphoma: - B-cell non-Hodgkin lymphomas, especially extranodal marginal zone lymphomas of MALT (mucosa-associated lymphoid tissue) type Treatment: levothyroxine

Hypothyroidism - Hashimotos Hypothyroidism

Most common cause of primary hypothyroidism More common in women. In general population - antibody + prevalence can range from 8 -27% Risk of hypothyroidism increases with TPO+ Ab, but is still low - 2-4% per year Lymphocytic (CD4+ and CD8+ T cells, B cells) infiltration of the gland on histology Genetic risk factors include HLA-DR3, 4 and 5 Associated with other autoimmune disease - T1DM, Addisons disease, vitiligo, pernicious anemia and alopecia areata Can see other thyroid antibodies such as TSH-receptor antibodies

(GUNNER) - Pediatric note: Neuroblastoma

Most common extracranial solid cancer in infancy Neuroendocrine tumor derived from neural crest of sympathetic nervous system. Most often found in adrenal medulla but can also be found anywhere along sympathetic chain. Associated with spinal cord compression, weakness, bone lesions, swollen neck and abdomen 90% of cases have elevated catecholamines or its metabolites (dopamine, homovanillic acid, metanephrines and vanillylmandelic acid) Diagnosis aided with MIBG scan Association with n-myc oncogene

Prolactinoma symptoms

Most common pituitary adenoma Prolactin role in pregnancy and breastfeeding In women: irregular menstrual periods or amenorrhea (lack of periods) Galactorrhea Reduced sex drive In men pituitary failure more common Loss libido "Gynecomastia" Mass effect: Hypopituitarism, visual loss, and headache Chronic hyperprolactinemia Low sex steroids > osteoporosis

Discuss the effects of glucocorticoids on glucose metabolism.

Most glucose is mobilized from the liver= gluconeogenesis & breakdown of glycogen. *Acute Glucocorticoid excess increases blood sugar. This leads to insulin resistance, increased insulin levels, and eventually to hyperglycemia. On the other end, adrenal insufficiency can impair glucose production during fasting and lead to (usually mild) hypoglycemia. *Chronic glucocorticoid excess leads to mobilization of glucose from other sites—muscles, fat, skin, and connective tissues—which can lead to muscle atrophy if severe and prolonged. However, adequate normal levels of glucocorticoid are needed for normal functioning of these tissues, so adrenal insufficiency does not cause muscle hypertrophy. * Fat: Acutely, a rise in glucocorticoids promotes lipolysis, with a release of free fatty acids and glycerol to be converted from fat into glucose. On the other hand, chronic glucocorticoid excess increases the deposition of fat in certain areas of the body - especially the abdomen, liver and trunk.

What is "reverse cholesterol transport", and what is the role of HDL?

Most organs make access of cholesterol and then go back to the liver to use it. HDL plays several roles in lipid metabolism including acquiring redundant surface lipids from processed chylomicrons and VLDL and aiding in the removal of excess cholesterol from tissues (the "reverse cholesterol transport system") Following hydrolysis of triglyceride in chylomicrons and VLDL by LPL, the core lipid content in these lipoprotein particles becomes smaller. Because surface components are not affected by lipoprotein lipase, redundancies occur in the surface layer. These redundant surface components are transferred to HDL by the activity of phospholipid transfer protein. Direct pathway - Reverse Cholesterol transport ♦ Slight excess of cholesterol in most organs which ABC1 transporter puts on nascent HDL particles ♦ LCAT esterifies free cholesterol to cholesterol ester - now HDL ♦ Anti-therogenic ♦ Taken up in liver by SRBI or HDL receptor

What is the pathophysiology of familial hypercholesterolemia, and what is the estimated frequency in the population?

Mutations of the LDL receptor, or less commonly mutations in the apo B-100 molecule, lead to impaired interaction of LDL with its receptor. Familial hypercholesterolemia results from mutation in the LDL receptor and lack of recognition of LDL particles, marked elevations in cholesterol levels in the blood, and accumulation of cholesterol in tendons (tendon xanthomas). Presentation: severe hypercholesterolemia - LDL >250 • Mutation: LDL receptor so cannot clear LDL - get doubling w/ mutation in 1 receptor ♦ Dominant, heterozygous - double, homozygous - 4-6x - full knockout or leaky mutation • Clinical: atherosclerotiv vascular disease premature, premature CHD, family history, arthritic joint pain ♦ Corneal arcus - cholesterol deposition in sclera of eye - normal as age but not when younger ♦ Xanthelasma - cholesterol deposition in inner corner of eye ♦ Tendon xanthomas - Achilles xanthoma pathognomic for FH - thickening of tendon more common

Constitutional delay of growth

No history of malnutrition or systemic illness Family history of a similar pattern of growth and puberty Normal PE and body proportions Height at or below -2 SD Growth velocity above 3.5 cm/year Delayed puberty Delayed BA with predicted height appropriate for family Normal TFTs, CBC, ESR, UA, and chemistries Normal growth factors and GH stim test

POSTNATAL GROWTH

Non-Endocrine Factors: Genetic factors-one of the most heritable traits recognized in man Socioeconomic status. Nutrition. Better health care. Normal emotional, psychosocial environment. Absence of chronic disease.

(GUNNER) - Subacute lymphocytic (painless) thyroiditis:

Nontender thyroid Histology: - lymphocytic infiltrate - prominent germinal follicles - Hürthle cell metaplasia is not prominent (versus Hashimoto thyroiditis, in which Hürthle cell metaplasia is a prominent feature) Roughly one third of patients become hypothyroid within 10 years

Obesity- Evolutionary Considerations

Obesity is not inherited in a simple Mendelian dominant or recessive pattern, implying that a number of genes must operate together to determine body fat mass. Two types of studies have proven that the familial tendency of obesity is due more to the genes shared by family members than to their shared diet and activity patterns. - Twins & Adoptive show this. "Thrift Genes" - Indians. Favors a greater storage of energy than that permitted by the genotypes of other individuals. Thrifty genes are beneficial when food is limited but lead to obesity-related health complications such as diabetes and coronary artery disease when food is abundant.

Thyroid Cancer

One of a few cancers still increasing in prevalence (reasons not clear) Four major Types Papillary Follicular Medulary (more on this later....) Anaplastic Risk Factors include... Radiation exposure Family history More commonly seen in woman, but worse prognosis in men

(GUNNER) - TBG (thyroxine-binding globulin) binds most T3 or T4 in peripheral blood

Only free T3 or T4 is active. TBG bound T3 or T4 is inactive. Conditions where TBG is increased or decreased can affect total T3 or T4 levels. For example, increased estrogen during pregnancy causes increased TBG, which results in increased total T3 and T4 levels. However, the free T3 and free T4 levels are actually normal (therefore, pregnancy is not a hyperthyroid state).

The Physiology of Appetite Regulation / Energy Intake

Orexigenic/Anabolic molecules in the Central Nervous System Neuropeptide Y (NPY) Agouti-related Peptide (AgRP) Anorectic/Catabolic molecules in the Central Nervous System Pro-opiomelanocortin (POMC) Melanocortin receptor 4 (MCR4) α - melanocyte stimulating hormone (α - MSH)

Understand the etiology of osteomalacia

Osteomalacia is characterized by excessive unmineralized osteoid. This means that the building blocks (calcium and phosphate) or building conditions (enzymes, pH) do not allow for optimal mineralization. Whereas normal bone has less than 5% osteoid, in some cases of osteomalacia this can increase up to 40 or 50%. Unmineralized osteoid reduces strength of the bone, causes bony pain and increases fracture rate. In growing children, the growth plates of bones are particularly affected, and children develop rickets with bowed legs, and deformed skulls and ribs. Many diseases can result in osteomalacia (Table 7), but usually involve either problems with Vitamin D production or function (not enough calcium and phosphate), excess renal excretion of phosphate, bicarbonate or protons (not enough phosphate, wrong pH) or enzymatic defects (i.e. alkaline phosphatase deficiency). Osteomalacia is commonly treated using calcium supplementation and vitamin D treatment. The type of vitamin D prescribed differs for age-related osteomalacia (Vitamin D2 or D3), liver disease (25-OH-VitaminD), renal disease and VDDR1 (1,25-diOH-VitaminD).

Describe reciprocal regulation of PTH and Vitamin D

Parathyroid gland Vitamin D potently decreases the production and secretion of PTH by parathyroid chief cells by acting as a negative transcriptional factor. This inhibition only occurs if serum calcium levels are normal or high. Low calcium levels stimulate the production of an intracellular protein called calreticulin that binds the PTH promoter in such a way that the VDR cannot access the VDRE and therefore PTH mRNA production is not inhibited. Both Vitamin D and various Vitamin D analogs are used to prevent and treat secondary hyperparathyroidism.

What enzymatic defects causing congenital adrenal hyperplasia are associated with virilization?

Partial blockade of any step on the pathway to cortisol due to a mutation in one of the enzyme genes causes the syndromes of congenital adrenal hyperplasia (CAH). - Decrease in cortisol synthesis b/c of block increases ACTH secretion, resulting in hypertrophy and hyperplasia of the cortex and excessive production of steroids which are proximal ("upstream") to the blockade, and their metabolites. - So, CAH pts have normal/low cortisol, but too much precursors and their metabolites (androgens and sometimes mineralocorticoids if lesion at site). FORMS OF CAH: *1) Most common from deficiency of 21-hydroxylase (esp. in AshJews and Yupik Inuit). When blocked, ACTH overcompensates and high levels of progesterone and (especially) 17-hydroxyprogesterone where no block accumulates - so androgens (and estrogens) can be greatly increased. - In utero will result in female infants with ambiguous genitalia (e.g., fused labia, large clitoris). Male children will virilize early and have an early acceleration of growth due to the sex hormone excess, but then the epiphyses of their long bones fuse early and they end up shorter than normal. 1a) About 30% also have the enzyme deficiency in the AG, and produce so little mineralocorticoid (deoxycorticosterone and aldosterone) that they cannot conserve Na; they are said to have the "salt wasting form" of CAH. - Leads to hypotensive shock then death a few days after birth. Test: measure blood 17-OH progesterone, the compound just "upstream" from 21-hydroxylase. Will be very high. 2) Milder forms of 21-hydroxylase deficiencies can account for some cases of hirsutism, POS, or virilization in women who had no symptoms at all in childhood. While baseline levels of 17-hydroxyprogesterone can sometimes be close to normal, they rise far above normal when the adrenal cortex is stimulated with a dose of ACTH. RX: adequate glucocorticoid replacement to reduce the stimulus to elevated ACTH (and androgen overproduction). With the salt-wasting form, mineralocorticoid replacement may also be needed, and even in non-salt wasting patients, adding mineralocorticoid helps suppress ACTH and reduces the dose of glucocorticoid needed.

GH DEFICIENCY TREATMENT

Patient diagnosed with GHD Idiopathic short stature Adults: Panhypopituitarism Reduced QOL Adverse CVD profile and/or osteopenia The elderly ADVERSE EFFECTS COSTS VERSUS BENEFITS

Prolactinoma - Lab Values

Physiological (ng/ml) Normal values 5-20 Pregnancy 20-350 Functional Causes Hypothyroidism 5-60 Renal Failure 5-100 Drugs Anti-Dopaminergics <350 Tumors Suprasella lesions <350 Microprolactinomas 30-500 Macroprolactinomas 100-30,000

Tall Stature due to Endocrine Disorders

Pituitary Gigantism Sexual Precocity Thyrotoxicosis Infant of Diabetic Mothers

(GUNNER) Acromegaly vs. Gigantism

Pituitary adenoma that secretes growth hormone Signs/Symptoms: coarsening of skin/facial features, thickening hands and feet, prognathism, and peripheral neuropathies due to nerve compression GH secretion in childhood prior to skeletal epiphyseal closure = Gigantism GH secretion in adulthood after epiphyseal closure = Acromegaly Diagnosis: increased insulin like growth factor and MRI/CT imaging of pituitary neoplasm Treatment: 1) Surgery or radiation 2) Octreotide: somatostatin analogue that inhibits GH release from the anterior pituitary [1] 3) Pegvisomant: growth hormome receptor antagonist blocking the production of IGF-1

Causes of Hyperprolactinemia

Pituitary tumor Nursing Drugs Estrogen Exercise Emotional stress Nipple stimulus Chest wall disease

Pituitary Tumors

Pituitary tumors are common (25-30%) Benign (adenomas) slow growing can invade adjacent structures (cavernous sinus) Spontaneous, inherited pituitary adenomas present in 25% of MEN-1 Classification by size microadenoma (<1 cm in diameter) macroadenoma (> 1 cm in size) Classification by function Functioning Non-functioning

Regulation of Appetite

Plasma ghrelin levels have been found to rise immediately prior to a meal and to fall within 30-60 minutes after the meal. During the early phase of a meal, feeding is maintained through the operation of central neurochemical pathways that positively reinforce ingestive behavior. As the meal progresses and food starts to enter the stomach and small intestine, a new set of neural and circulating signals is generated that sharply reduces appetite = ie. CCK. (in gut to prevent GI Damage). These meal-related signals are all very short-lived and, with the exception of ghrelin, do not reflect body fat stores. So CCK admin will just result in more meals. Study: Leptin is secreted by adipocytes into the circulation and transported to the brain where it binds to a specific hypothalamic receptor. When recombinant leptin is administered to an ob/ob mouse, food intake and body fat mass decrease to normal. Recombinant leptin has no effect when given to a db/db mouse (b/c receptor is the problem). - So Leptin acts as a key negative feedback signal that diminishes aggregate appetite when body fat stores are excessive and vv. May potentiate CCK. After going through BBB, leptin, insulin, and ghrelin bind specifically to receptors in the arcuate nucleus and other areas of the hypothalamus. - One population of neurons makes neurotransmitters named neuropeptide Y (NPY) and agouti-related protein (AgRP). The other is POMC- then made into MSH. o NPY stimulates feeding. o MSH inhibits feeding by its interaction with MC4r. AgRP antagonizes the binding of MSH to MC4r and, therefore, promotes feeding. o With expansion of adipose tissue, stimulate POMC, inhibit NPY/AgRP neurons in the arcuate nucleus. The PVN integrates POMC and NPY/AgRP input. When plasma leptin and insulin levels increase, PVN elicits anorexia. Gherlin can also stimulate the reverse

(GUNNER) All individuals with hypercalcemia should be evaluated for hyperparathyroidism. Causes.

Primary causes: Single benign adenoma: majority of cases Hyperplasia of parathyroid glands: rare incidence MEN (multiple endocrine neoplasia) I and IIA Secondary causes: occurs when parathyroid glands are chronically stimulated by hypocalcemia to release PTH 1) Chronic renal failure: PTH is elevated due to decreased levels of calcium or 1,25 dihydroxy-vitamin D3. CRF (chronic renal failure) results in decreased conversion of active vitamin D and inadequate excretion of phosphate. Both processes lead to hypocalcemia and thus, a stimulus for secondary hyperparathyroidism. 2) Malabsorption syndromes (chronic pancreatitis, small bowel disease): fat soluble vitamin D cannot be reabsorbed, which leads to hypocalcemia. Tx : Calcitriol (vitamin D) and phosphate binders such as aluminum hydroxide or calcium carbonate 3) Rickets - Vitamin D or calcium deficiency which results in increased PTH secretion Tertiary causes: Long standing hyperparathyroidism: progresses into autonomous hypersecretion of PTH even after correction of chronic hypocalcemia

Pathology of ADH secretion or action Diabetes insipidus

Refers to the passage of copious amounts of dilute, unsweetened urine. - Occurs with: o 1) ADH deficiency (central or hypothalamic diabetes insipidus) Major causes: familial or acquired etiologies such as neoplastic, granulomatous or infiltrative diseases of the hypothalamus or posterior pituitary, neurosurgery, severe head injury. o 2) decreased renal response to the action of ADH (nephrogenic diabetes insipidus). may be inherited or acquired from chronic renal disease or drugs such as lithium. Hypokalemia and hypercalcemia also a cause. o 3) Dipsogenic diabetes insipidus (also called psychogenic polydipsia) is a disorder of excessive water drinking that results in hypotonic polyuria, but it is does not cause hypernatremia or hyperosmolarity. - DX: Polyuria (w/ eventual hypernatremia). o Osmotic diuresis (e.g., glucosuria), hypokalemia and hypercalcemia are also causes of polyuria and should be excluded before making the diagnosis of DI. o The diagnosis of diabetes insipidus requires the measurement of serum and urine osmoles and serum ADH when the patient is hyperosmolar (hypernatremic). The diagnosis often requires blood and urine sampling before and after a period of water deprivation or an infusion of hypertonic saline. Measurement of serum ADH levels can usually help discriminate between hypothalamic diabetes insipidus (low ADH levels) and nephrogenic diabetes insipidus (normal or high ADH levels. - Tx; adequate water intake. HDI may also use exogenous ADH therapy.

Pathology of ADH secretion or action Syndrome of inappropriate ADH hypersecretion (SIADH)

SIADH describes the syndrome of hypoosmolar serum and inappropriately concentrated urine due to inappropriately normal or elevated ADH levels. - Pt needs to be euvolemic because in the setting of hypovolemia. Can't diagnosie in hypothyroidism or hypoadrenalism because thyroid hormone and glucocorticoids are both necessary for normal free water excretion. - Causes: malignant tumors that produce ADH , pulmonary disorders (e.g, pneumonia), CNS disorders, and certain drugs. - Hyponatremia usually is the initial clue. Patients with SIADH have impaired excretion of a water load. - Although the diagnosis of SIADH may be confirmed by demonstrating a failure to excrete a water load, a risk of administering a free water load for diagnostic purposes may precipitate life-threatening hyponatremia. Measurements of ADH reveal persistent elevation. - Tx: correct the underlying cause, limit intake of solute-free water.

Sex steroids (growth)

Sex steroids contribute to growth during puberty Androgens: accelerate bone age maturation more rapidly than linear growth. Increase GH and IGF secretion Estrogen increases cartilaginous linear growth increase lateral growth of the pelvis. accelerate bone age. Their action is however, biphasic. They stimulate growth at low levels and inhibit growth at high levels.

(GUNNER) - Acute thyroiditis:

Signs and Symptoms: - fever - painful thyroid - painful cervical lymphadenopathy Often secondary to bacterial infection Gland destruction → initial thyrotoxicosis, with labs including: - ↑ serum T4 - ↓ serum TSH - ↓ I-131 uptake

(GUNNER) Prolactinoma

Signs/Symptoms: impotence, amenorrhea, gynecomastia, galactorrhea, headache High Yield Point: enlargement of the pituitary gland → compression of optic chiasm → bitemporal hemianopsia (loss of peripheral vision) May have mass effect on surrounding pituitary gland, causing general hypopituitary symptoms Prolactin increases dopamine secretion from hypothalamus. Subsequently, dopamine inhibits further prolactin secretion. Prolactin also inhibits GnRH. Treatment for prolactinoma: 1) Bromocriptine or cabergoline: dopamine agonists. Dopamine normally inhibits PRL release. High Yield Point: This is also why dopamine antagonists (ex: antipsychotics) cause galactorrhea (loss of inhibition) NOTE: Bromocriptine can also be used in the treatment of Parkinson's disease. 2) Transsphenoidal surgical resection for large tumors

Prolactinoma -Ophthalmology

Since changes in vision are often early signs of tumor progression, ophthalmological investigations are useful in the primary diagnosis as well as during follow up. Goldmann perimetry is most frequently performed to document visual field defects though computerized perimetry (Octopus) is more reliable. Sometimes visual evoked potentials (VEP) can be helpful in demonstrating lesions located along the optic pathways. VEPs may be useful in discriminating simple compression from severe demyelinating lesions of the optic pathways.

Discuss the different mechanisms of hyperparathyroidism

Single parathyroid adenomas are the most common cause of excess, inappropriate PTH secretion (primary hyperparathyroidism) and this is the most common diagnosis for patients in whom hypercalcemia is incidentally discovered. Four-gland hyperplasia can also cause primary hyperparathyroidism, either sporadically or in genetic conditions such as multiple endocrine neoplasia type 1 or 2a. Very rarely parathyroid carcinomas are found that produce excess PTH. Primary hyperparathyroidism due to an adenoma is usually treated by surgical removal of the adenoma, especially if it can be visualized by a nuclear medicine scan (Sesta-MIBI). Patients with mild hyperparathyroidism without complications are often followed without specific therapy. Hypercalcemia in these patients may be worsened by correction of vitamin D deficiency, high-dose oral calcium supplementation or thiazide diuretics. Patients with four-gland hyperplasia will sometimes undergo resection of 3 ½ glands to treat their hypercalcemia but this treatment is rarely curative. Chronic renal failure and chronic Vitamin D deficiency (see above) can result in hyperplastic parathyroid glands that produce high PTH levels (secondary hyperparathyroidism). In patients with renal disease, active vitamin D (1,25 diOH- Vitamin D, calcitriol), vitamin D analogs (paracalcitol), phosphate binders and CaR agonists (Cinacalcet) are used to prevent and treat secondary hyperparathyroidism. Long-standing secondary hyperparathyroidism can result in autonomous parathyroid function, so-called tertiary hyperparathyroidism (i.e. it continues even if the renal failure is corrected)

(GUNNER) Vitamin D

Sources: Sunlight - Vitamin D3 (cholecalciferol) in the skin Diet - Vitamin D2 (ergocalciferol) Conversion to active form pathway: Vitamin D3 and Vitamin D2 → 25OH vitamin D (in liver) → 1,25 OH2 vitamin D (kidney) Conversion of 25-Oh vitamin D to 1,25-OH2 vitamin D relies on 1α-hydroxylase. 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. Increase intestinal Ca2+ absorption via induction of vitamin-D dependent Ca2+-binding protein (calbindin-D-28K) Increase intestinal phosphate absorption Increase reabsorption of Ca2+ and phosphate in kidneys Increase bone resorption of Ca2+ and phosphate [1] Regulation of Vitamin D depends on the activity of 1α-hydroxylase. Factors that increase 1α-hydroxylase activity: ↓ serum [calcium] ↓serum [phosphate], ↑ PTH levels 1,25-OH2 vitamin D also inhibits its own production by inhibiting 1α-hydroxylase.

Hyperthyroidism - Treatment

Symptomatic Relief for all Patients High doses of beta-blockers First line therapy for young, low risk patients - or - Depletion therapy in elderly, high risk patients prior to I-131 Antithyroid drugs: Methimazole (daily) or PTU (TID) Agranulocytosis precautions for high dose PTU - 3rd most common cause of liver toxicity by medication, rarely indicated Definitive Therapy for Resolution of Disease RAI - 131 - most common treatment choice in the US Surgery - becoming more common - total thyroidectomy Tidbits on Diagnosis and Therapy Using a thionamide only inhibits production of new hormone; it does not interfere with pre-formed hormone release. Beta-blockers, in high doses, are the drugs of choice for symptomatic relief and suppression of tachyarrhythmia. Thionamide use in a patient with thyroiditis will only lengthen the hypothyroid phase and cause confusion in interpreting TFTs. Therefore... Utilize beta-blockers up front and titrate aggressively. Establish the etiology of thyrotoxicosis before initiating drug therapy Do not treat thyroiditis with thionamides; use beta-blockers and pain medication prn.

Renin-angiotensin-aldosterone axis and regulation of serum potassium levels

System also plays a key role in K+ homeostasis. disturb cell resting potentials and can lead to arrhythmias. - Hyperkalemia= directly ↑ ALDO. In addition to the direct effect of K+ upon the ZG, K+ increases its AGII response. (So w/low K+, more AGII needed to stim. ALDO) - Also K+ has direct effects upon renin secretion. When BP low, K becomes low after RAA activation. The resultant fall in plasma K+ further stimulates renin secretion. However, the fall in plasma K+ also acts on the ZG to make AGII a less effective stimulator of ALDO so that this positive feedback cycle does not cause severe, life-threatening hypokalemia.

(GUNNER) - Synthesis of thyroid hormones

T3/T4are synthesized on a large, tyrosine-rich glycoprotein called thyroglobulin. Thyroglobulin resides in the colloid. Iodide (I-) is transported across into the follicular cell via the Na-I transporter and then into the lumen. Thyroid peroxidase , which is found on the luminal surface of the follicular cell, oxidizes I- to I2. Organification: I2 is conjugated to tyrosine residues on thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. Thyroid peroxidase catalyzes this reaction. Coupling of MIT and DIT (catalyzed by thyroid peroxidase): DIT + DIT = T4 MIT + DIT = T3 Secretion: Iodinated thyroidglobulin is stored in the follicular lumen. Upon stimulation by TSH, follicular cells endocytoses thyroglobulin and lysosomal enzymes digest thyroglobulin, releasing T3 and T4 into the circulation. Residual MIT and DIT are deiodinated by thyroid deiodinase. The I2 that is generated is recycled to synthesize more thyroid hormone. The Na-I transporter is inhibited by thiocyanate and percholate anions. Thyroid peroxidase is inhibited by propylthiouracil and methimazole. Wolff-Chaikoff effect : High levels of I- inhibit thyroid hormone synthesis by blocking the organification step.

(GUNNER) - Thyroid hormones:

T4: main secretory product of thyroid gland T3: in peripheral tissues, T4 is deiodinated to T3 by 5'-deiodinase. T3 is significantly more potent than T4. rT3 (reverse T3): found in blood, has no biologic activity

(GUNNER) - Regulation of thyroid hormone secretion

TRH from the hypothalmus stimulates the secretion of TSH by the anterior pituitary. TSH: ↑ synthesis and secretion of thyroid hormones. Mechanism: adenylate cyclase-cAMP Negative feedback: T3 down-regulates TRH receptors in the anterior pituitary leading to inhibition of TSH secretion. Thyroid-stimulating immunoglobulins (TSI) are auto-antibodies (IgG) against TSH receptors. Binding to TSH receptors on follicular cells stimulates T3/T4 release. Patients with Graves' disease exhibit high concentrations of TSI.

(GUNNER) - Subacute granulomatous thyroiditis (DeQuervain thyroiditis):

Tender thyroid; in fact, subacute granulomatous thyroiditis is the most common cause of thyroid pain Preceded by flu-like illness with sore throat and fever, jaw pain, tender thyroid, and a markedly elevated ESR (erythrocyte sedimentation rate) Histology: - lymphocytic infiltrate - multinucleate giant cells surrounding fragments of colloid Early phase can manifest as hyperthyroidism, as damaged gland spills T4 Usually self limiting, resolves after weeks Treatment: aspirin, in severe disease can supplement with cortisol

Evaluation of short stature

The evalaution of a child with short stature involves the careful integration of endocrine, auxologic and biochemical data. Important clues from the child's medical history and physical examination indicating an endocrine cause for short stature include: Microphallus, hypoglycemia, prolonged jaundice Septo-optic dysplasia, midline defects, S/P pituitary injury. History of brain tumor, irradiation Abnormal pituitary MRI, intracranial lesion Family history of genetic syndrome

How does the difference in activity between the type 1 and type 2 5'-deiodinase enzymes allow the T3 level to fall during illness and starvation?

The half-life of T3 is only one day as opposed to seven days for T4. Thus, in situations which impair the peripheral production of T3, the level of this hormone declines rapidly. This may also be an adaptive mechanism permitting rapid adjustment to the stresses of caloric deprivation or illness. Both T4 and T3 normally circulate tightly bound to serum binding proteins. Only 0.02% of the circulating T4 and 0.3% of the circulating T3 exist unbound in the serum. It is the small concentration of the free hormones, however, which is metabolically active. The extensive binding of thyroid hormones provides both a reservoir of thyroid hormone and prevents excretion of these small molecules by the kidney.

Describe the function of the parathyroid calcium sensing receptor.

The membranes of parathyroid cells and renal tubular cells express calcium sensing receptors (CaR) that closely monitor the level of ionized serum calcium. At the parathyroid gland, serum calcium functions as a negative feedback signal. If serum calcium is high, PTH secretion is inhibited while, if calcium is low, PTH secretion is rapidly stimulated. At the kidneys, the CaR helps regulate calcium excretion, extracting more calcium from the renal tubules if the serum calcium has decreased and less when the serum calcium is high. However, when serum calcium levels rise, CaR signaling interferes with the functioning of anti-diuretic hormone in the collecting ducts and causes partial nephrogenic diabetes insipidus, which paradoxically makes hypercalcemia worse by causing dehydration and increased passive calcium reabsorption in the proximal convoluted tubule. The CaR receptor was discovered and cloned in 1993 by expression cloning of bovine parathyroid mRNA (Brown et al. Nature 1993; 366:575) and the CaR gene was subsequently localized to chromosome 3q11. A clinically relevant disorder, arising from inactivating mutations of the CaR on one allele (heterozygous), is familial hypocalciuric hypercalcemia (FHH). The mutated receptor is defective such that cells with CaR do not adequately sense the true serum calcium levels. Therefore the parathyroid glands produce PTH levels that are relatively high and kidney tubule cells in the loop of Henle extract more calcium out of the urine. In these patients, throughout life, the set point for calcium homeostasis is increased and serum calcium levels are maintained at a higher level. Chemical compounds that either stimulate (agonist) or block (antagonist) the CaR have been developed and a CaR agonist (Cinacalcet) has recently been shown to be an effective treatment of secondary hyperparathyroidism.

What is the metabolic syndrome and how is it related to the development of atherosclerosis?

The metabolic syndrome refers to the clustering of several cardiovascular risk factors that frequently occur together and greatly increase the risk for coronary events. The recently updated NECP recognized it as a secondary target of risk reduction therapy. The metabolic syndrome consists of a central distribution of adiposity, or visceral obesity; insulin resistance; elevations in plasma free fatty acids; inpaired glucose tolerance; hypertension; dyslipidemia; and an abnormal procoagulant state. *Risk Factors Abdominal obesity: (waist circumference) Elevated triglycerides Low HDL cholesterol Raised blood pressure Fasting glucose > 110 mg/dl * individuals with the metabolic syndrome are at high risk for atherosclerotic complications.

Treatment of Obesity

The most frequently attempted treatment for obesity is restriction of dietary energy intake, often to an extreme degree or by means of a grossly unbalanced food selection. weight returns to baseline over a period of months to years - fat diet with regular aerobic exercise. o Caloric intake is not intentionally reduced in this strategy. Substituting foods of lower energy density (complex carbohydrates and fiber) for foods of high energy density (fats and simple sugars) causes a relative increase in satiety at the baseline fat mass. The consequent spontaneous reduction in energy intake combined with a sustained increase in energy expenditure, causes regulation to occur at a somewhat reduced fat mass. Among the medications currently approved to treat obesity, only orlistat (an inhibitor of gastrointestinal fat absorbtion) appears to be somewhat effective (approximately 4 kg weight loss at one year) and safe. Orlistat can cause diarrhea and malabsorbtion of fat soluble vitamins.

(GUNNER) -Myxedema coma:

The only emergent hypothyroid condition Can be spontaneous onset or precipitated by cold exposure, infections, drugs (CNS depressants), or hypoxia S/Sx: hypothermic stupor/coma, hypoventilation with CO2 retention, hypotension Treatment: respiratory support, intravenous levothyroxine, cortisol

Correlate the various histologic areas of the adrenal gland with the hormone(s) produced.

The outer zona glomerulosa is made up of whorls of cells 1 to 3 cells across (i.e., "glomeruli") that are continuous with the bundles ("fascicles") of cells which form the zona fasciculata. These columns are separated by venous sinuses. The inner portion of the zona fasciculata merges into the zona reticularis, where the cell columns become interlaced in a network - All layers are lipid since will be made into steroid hormones, especially in the outer ZF. - All 3 secrete corticosterone (see below), but the enzymatic mechanism for converting corticosterone to aldosterone is limited to the ZG. - while the enzymatic mechanism for forming cortisol and sex hormones, 17α-hydroxylase is only in ZF & ZR ZF & ZR under control of pituitary. ZG has independent trophic action of angiotensin II. Thus in hypopituitarism, the ability to conserve Na+ is usually normal. Injections of ACTH, and stimuli that cause endogenous ACTH secretion cause hypertrophy of the zona fasciculata and zona reticularis, but produce only transient stimulation of aldosterone and do not increase the size of the zona glomerulosa.

Complications of Transsphenoidal Surgery

The overall mortality rate for transsphenoidal surgery is less than 0.5% (Table 6). Major morbidity (cerebrospinal fluid leak, meningitis, stroke, intracranial hemorrhage, and visual loss) occurs in between 1 and 2% of cases. Less serious complications (sinus disease, nasal septal perforations, and wound issues) occur in approximately 6.5%. Larger invasive tumors and giant adenomas are associated with a higher morbidity.

Plasma IGF-1 Levels

The pattern of pulses becomes more prominent during the active phase of growth during late childhood and early adolescence, in part due to rising levels of sex hormones. These normal patterns are susceptible to disruption by psychogenic, nutritional and metabolic disturbances Emotional deprivation > growth failure in children Uncontrolled diabetes and starvation paradoxically lead to increases in GH secretion In children who develop diabetes in childhood with poor control results in a small reduction in the overall height

Is Fat Mass Regulated?

The stability of body weight over long periods of time - physiologically regulated and not behavior? When tried to make ppl Gain: worsening feelings of satiety and nausea; weight eventually reached a plateau despite ongoing consumption of food in excess of their baseline caloric intake. This observation implied that energy expenditure must have increased in order to dissipate the extra energy consumed. Taken together, the Vermont study and the Minnesota study demonstrate that body fat mass is regulated to resist displacement either above or below its ordinary value, and that this regulation involves active modulation of both appetite and energy expenditure. "set point" for body fat mass. An increase in BMI would be resisted by development of a proportional negative energy balance, whereas a decrease in BMI would be resisted by development of a proportional positive energy balance.

Hormone-producing pituitary adenomas

The three most common hormone-producing (called endocrine-active) adenomas are: -Prolactin-secreting pituitary adenoma (prolactinoma): over-production of prolactin by the pituitary tumor causes loss of menstrual periods and breast milk production in women. -Growth hormone-secreting pituitary adenoma: excessive growth hormone (GH) production causes acromegaly in adults or gigantism in children. -ACTH-secreting pituitary adenoma: excessive ACTH hormone produced by the pituitary gland causes Cushing's disease. -Other hormone producing pituitary tumors are very rare Thyroid stimulating hormone (TSH) producing pituitary adenomas cause hyperthyroidism

How are the processes of inflammation and hyperlipidemia interrelated in atherosclerosis

There is also an association of the metabolic syndrome and inflammation. Increases in proinflammatory cytokines such as interleukin 6, tumor necrosis factor α, and C-reactive protein reflect overproduction by the expanded adipose tissue mass. Insulin resistance in the liver, muscle, and adipose tissue is not only associated with increased levels of proinflammatory cytokines (and the relative deficiency of the anti-inflammatory cytokine adiponectin), but may actually be a result of this inflammatory state. The inter-relationships between insulin resistance, inflammation, and cardiovascular disease are complex, but our understanding of these intertwined processes is rapidly evolving.

Adrenal Insufficiency Diagnostic Considerations

There may not be a true gold standard Recall...circadian rhythm

Actions of catecholamines

They released if BV/BP fall, in stress. Activation is mediated through a brainstem center. - Usually, peripheral sympathetic system responds before o exception with hypoglycemia when medullary CATS normalize BG by stimulating gluconeogenesis, glycogenolysis, and inhibiting insulin secretion. Note: there is an overlap in the plasma epinephrine levels of patients with moderate to severe stressors and patients with pheochromocytomas. Actions of catecholamines are mediated by two major classes of receptors ( and ) on the surface of target cells; receptors initiates distinctive physiological responses that are specific for each tissue type. Catecholamines have several actions on the vascular system to increase CO & BP: . Sympathetic and catecholamine stimulation increase blood pressure by effects

Neurohypophysis (ADH) Synthesis & Mechanisms to Maintain Plasma Osm:

Thirst= when serum osmolarity ↑even slightly. A thirst center in the VM, near to the supraoptic and paraventricular nuclei ADH made. It should be noted that the osmostat for thirst is set at a higher level than for ADH release. Synthesis and secretion of ADH - ADH made in the hypothalamus and transported within neurosecretory granules in the axons of the hypothalamic neurons to nerve endings in PP. Synthesis of ADH is made w/neurophysin II, which binds ADH during transport to PP. When ADH is secreted, neurophysin is also released. - Secreted when: o A decrease in blood volume causes ADH release. However, the blood volume must fall by 10% to 25%, compared to the 1-2% rise in osmolarity needed to stimulate ADH secretion. Note: Non-osmotic stimulation of ADH release may predominate over hypo-osmolar suppression, resulting in water retention and hypoosmolarity. o Fall in BP o Stress/Heat/Nicotine (not Alcohol) o This neural regulation of ADH appears to be via both cholinergic and adrenergic pathways; cholinergic and -adrenergic activity stimulate while -adrenergic activity alone inhibits.

Be familiar with how thyroid hormones are metabolized in the peripheral target tissues, and their actions on different organ groups (ie skeletal muscle, cardiac muscle, gut, bone, etc.)

Thirty-five percent of the circulating T4 undergoes 5'-deiodination to form T3 and 45% of T4 normally undergoes 5-deiodination to form reverse T3. The peripheral deiodination reactions occur largely in the liver and kidney, although deiodination appears to occur to some extent in the target cells themselves. As noted earlier, the balance between T3 and reverse T3 production determines the overall state of thyroid activity. One factor which strongly influences the ratio of T3 to reverse T3 production is the caloric intake of the individual. In states of nutritional deprivation the inactivation pathway of reverse T3 formation is favored by a decrease in the activity of the peripheral, or Type 1 (5'-deiodinase) enzyme. This may be viewed as an adaptive mechanism of the organism to avoid excessive energy utilization in states of nutritional depletion. A variety of illnesses not necessarily associated with starvation also favor the inactivation of T4 as reverse T3. Only 20% of serum T3 comes directly from the thyroid, the remaining 80% being produced by peripheral conversion from T4.

What pathologic findings in the adrenal may be associated with cortical failure?

This diagnosis can currently best be made by observing a failure of plasma cortisol to increase following an exogenous ACTH stimulus (Figure 17), or by demonstrating a low or normal plasma cortisol in the face of great stress. In an emergency situation, it is often prudent to send off a serum sample for cortisol determination and then start steroid replacement therapy immediately without waiting for the results. Both the patient's rapid response to therapy and ultimately the plasma cortisol level may confirm your initial impression. Since cortisol is not stored, and the adrenal cortex rapidly atrophies when ACTH stimulation decreases, the cortisol response to ACTH is decreased in both primary and secondary adrenal insufficiency (see Figure 6). Repeated stimulation or continuous infusion of ACTH over several days can partially reverse this atrophy and induce a cortisol response in secondary, but not in primary, adrenal insufficiency. A quicker test to distinguish between primary and secondary adrenal insufficiency is to measure ACTH levels (Figure 18). These are elevated in primary adrenal insufficiency, as feedback attempts to compensate for low cortisol, but low (or inappropriately normal) in secondary adrenal insufficiency.

Bone X-Ray to Determine Bone Age

This slide shows a sample hand and wrist x-ray that is taken to determine bone age. The bones indicated in the white box are those used in the determination of bone age, including the phalanges, where the epiphysis can be seen.

Which lipoprotein disorders are associated with xanthomas?

Three cutaneous manifestations are pathognomonic of various lipid disorders resulting in hyperlipidemia. 1) Eruptive xanthomas occur with marked triglyceride elevations in chronic chylomicronemia. 2)Tendon xanthomas (particularly in the Achilles tendon and the extensor tendons of the hands) are pathognomonic of genetic defects in LDL receptor interactions with apo B (familial hypercholesterolemia or familial defective apo B). 3) Palmar (planar) and tubo-eruptive xanthomas occur with remnant accumulation in remnant removal disease. Lipid deposits around the eyes (xanthelasma) or in the cornea (corneal arcus) are less specific

Non-Functioning Pituitary Tumors -Causes

Tumors: MOST COMMON: Adenoma, Craniopharyngioma, other parasellar tumors, metastatic tumors Vascular: Sheehan's, Apoplexy, Aneurysms Inflammation, infiltrative, infection: charachterized by invading both pituitaries. Primary - Lymphocytic hypophysitis Sarcoid, TB, Langerhans cell histiocytosis (Histiocytosis X), Wegner's granulomatosis, Hemochromatosis Congenital: Genetic and developmental defects Trauma, Radiotherapy

Osteoporosis Tx

Tx: biomarkers to follow disease • Prevention: weight bearing exercise, smoking cessation, avoid excessive alcohol intake, calcium supplementation, Vit D supplementation • Anti-resorptive therapies • Bisphosphonates - turn off resorption by inducing apoptosis in osteoclasts so more balanced resorption and formation but concern of totally dysregulation turnover so that cannot make new bone properly and at risk for atypical fractures , 1x per yr, increases bone density & suppresses bone turnover, decreases fractures • Calcitonin - helps vertebral fractures • PTH - only anabolic therapy, daily injection to promote bone formation above resorption, till peaks and cannot increase any more, helps w/ both types of fractures • Estrogen replacement therapy - effective but side effects of MI, stroke, blood clots • Raloxifene - selective estrogen receptor modulator - prevents vertebral fractures, bone promotes estrogen but can also cause clots in venous circulation • Denosumab - like osteoprotegerin so dampens RANK ligand and dampens osteoclast activation

Be familiar with the molecular biology of a thyroid follicle, including orientation within the thyroid gland, actions at each membrane interface and the role of colloid.

Unlike most endocrine glands, the thyroid has great storage capacity. It's stored in the colloid. The BL membrane in contact with blood supply. Next to follicle, C- cells secrete calcitonin. No role in thyroid.

Understand the tests (laboratory and imaging) used in evaluating patients with thyroid disease. What are the expected serum levels of these hormones in states of disease excess or deficiency.

Use T4 & TSH together always. NOT JUST TSH. Tests of Thyroid Autoimmunity -TPO - thyroid peroxidase antibody - commonly seen in Hashimotos, but a general marker for thyroid autoimmunity -Thyroglobulin-Ab - as above, but less commonly positive -TSIg - Thyroid Stimulating Immunoglobulin - specific marker of Graves' disease Anatomical Thyroid testing -Ultrasound - assess for echogenicity, nodularity, vascularity Functional Anatomical testing (for hyperthyroidism) -Uptake and Scan In all cases of hyperthyroidism, except those due to exogenous administration of synthetic thyroid hormone or to destruction of the gland with release of preformed hormone, the thyroid radioiodine uptake is elevated.

Describe the consequences of vitamin D deficiency.

Vitamin D deficiency is an extremely common diagnosis and often a combination of low sunlight exposure, age and inadequate dietary Vitamin D coexist in patients. The deficiency is often not recognized because it is can be asymptomatic, may take years to develop and symptoms are insidious and non-specific (bony pain, neuromuscular weakness). Vitamin D deficiency can usually be corrected easily by oral replacement. Replacement regimens vary, but for severe deficiency (<5ng/ml) a combination of 50,000 IU of ergocalciferol weekly for 8 weeks followed by 800-1000 IU of Vitamin D daily is often used. Vitamin D deficiency is also a common diagnosis in toddlers that are exclusively breastfed and that have little (unblocked) sun

Treatment of Cushing's syndrome

W/o is fatal from hypercortisolism. Tx depends on cause. Pituitary: TSA. As much preoperative information as possible (MRI, IPSS) is helpful to guide the surgeon, since these tumors may be very small. (adrenal adenomas and carcinomas is also surgical). Usually it is not practical to remove just the tumor, and adrenalectomy is performed. Unless the tumor is very large, adrenalectomy can be done by laparoscopy, with more rapid surgical recovery. And tumors producing ectopic ACTH can either be excised (carcinoids), if they can be found, or treated with chemotherapy (small cell lung carcinomas). Unfortunately, small tumors producing ACTH can sometimes be very difficult to locate, and the physician may have to follow these patients for an extended period of time until the tumors become manifest on radiography or by selective venous sampling. To reverse the symptoms of Cushing's syndrome in the meantime (or in a patient who is not a surgical candidate), drugs which block cortisol synthesis (such as ketoconazole, o,p'-DDD, or aminoglutethimide) or glucocorticoid action (RU486) may be used. Adrenalectomy is a last resort.

In evaluating a child's growth:

What has been the pattern of growth? Has the child been growing steadily and at a normal rate? Has there been a change in percentile position? What is the growth or height velocity? What is the genetic background of the child? What are the heights and ages of sexual maturation in the family members? On examination: Are the body proportions normal? What is the stage of puberty? Has the child begun the adolescent growth spurt?

AcromegalyTreatment

When surgery fails... Medical Somatostatin analog (Octreotide, Lanreotide) Pegvisomant (Somavert) Dopamine agonists (cabergoline Dostinex) Radiation Stereotactic

What are the two defects required for remnant removal disease?

Where are the remnants coming from? Both chylomicron and VLDL remnants acquire apo E from HDL before they can bind to hepatic receptors for either uptake and degradation or further processing to LDL. Three alleles of the apo E gene have been described (apo E2, apo E3, and apo E4) which result in six potential combinations. The apo E4 allele product has the greatest affinity for hepatic receptors, followed by apo E3, with the apo E2 allele product having markedly reduced receptor affinity. Most of the population has the apo E3 and/or E4 allele with normal remnant uptake. Individuals who are homozygous for the rare E2 allele have marked impairment of hepatic uptake and accumulation of remnants in the plasma with very low levels of LDL. Interestingly, the majority of these individuals have either normal or low lipid levels If an individual who is homozygous for the E2 allele (E2/E2) , however, has simultaneous occurrence of a defect causing excessive input of VLDL, either inherited or acquired, then excessive accumulation of remnants and hyperlipidemia occurs. * You also need a second hit (too much lipids, clearance defect, estrogen) This disorder has various names including type III hyperlipidemia, remnant removal disease, and dysbetalipoproteinemia. Because chylomicron and VLDL remnants contain roughly equal amounts of triglyceride and cholesterol, the hyperlipidemia of remnant removal disease is characterized by both hypercholesterolemia and hypertriglyceridemia. Strias Palmaris - cholesterol deposition in creases of hands & fingers • Tubular xanthoma - cholester on tendons, esp knees and elbows • Eruptive xanthomas

Understand the physiologic basis for treatment of osteoporosis.

Women taking estrogen replacement at the time of menopause can prevent cases of hip fracture, but this therapy has become increasingly controversial for many women. An adequate calcium intake and VitaminD levels should be assured, although calcium and VitaminD alone cannot substitute for the loss of estrogen. Exercise is probably beneficial but has not been completely studied, and of course smoking and excess alcohol should be avoided. Most experts recommend treatment of established osteoporosis. Possible treatments include, bisphosphonates, estrogen, selective estrogen receptor modulators, calcitonin, rhPTH and a monoclonal antibody against RANK-ligand. Most of these treatments are anti-remodelling and only slow the rate of bone loss. However, the rhPTH treatment increases the rate of bone formation, and intermittent injections of rhPTH have resulted in increased bone mass and decreased fractures in osteoporotic patients. Although hyperparathyroidism preferentially wastes cortical bone, cyclic PTH therapy appears to be effective in forming trabecular bone, and constant vs. intermittent PTH exposure has very different effects on osteoblast RANKL/osteoprotegerin secretion (see above). Monoclonal therapies directed at the RANK-ligand have shown effectiveness in improving bone density and reducing bone fracture

(GUNNER) - The cortex is further divided into three zones:

Zona glomerulosa: mineralocorticoid aldosterone, involved in sodium reabsorption Zona fasciculata: mostly produces glucocorticoids (eg, cortisol); also produces some sex hormones (eg, DHEA, androstenedione) Zona reticularis: androgen DHEA (dehydroepiandrosterone) and androstenedione

Ionized Ca -

active form, ~50% of total serum Ca which measure - other protein albumin bound or organic complexes - relevant w/ elevated phosphate and changes in serum protein lead to changes in total serum calcium (Ca can be high if low serum protein even tho appears normal)

Diagnosis of Cushings

all phenotypes look the same • Detect cortisol when should be there: Late night salivary cortisol, 24 hr Urine production, Suppression of cortisol w/ dexamethasone and test morning cortisol (which should be <2) • Results of Dexamethasone Suppression test: • ACTH dependent pituitary tumor - suppresses by 50%, high ACTH • ACTH dependent ectopic tumor - no reduction, high ACTH • ACTH independent adrenal adenoma - no reduction, low ACTH

(GUNNER) Addison's disease

causes include: 1) Adrenal atrophy or autoimmune destruction (most common) 2) Granulomatous infection (eg, tuberculosis) of the adrenal gland 3) Infarction of the adrenal gland 4) HIV (human immunodeficiency virus) 5) Waterhouse-Friderichsen syndrome 6) DIC (disseminated intravascular coagulation) Absence of hormone production in all 3 cortical divisions Primary deficiency of aldosterone and cortisol production Result is hyponatremic volume contraction, hyperkalemia, constipation, diarrhea, fatigue and skin hyperpigmentation. Melanocyte-stimulating hormone MSH shares the same precursor molecule as ACTH Primary Hypoaldosteronism Diagnosis: 1) Hyperpigmentation (buccal mucosa, skin creases, skin) due to ↑ ACTH levels 2) Abnormal cosyntropin (ACTH) stimulation test: subnormal response of plasma cortisol following cosyntropin (synthetic ACTH) is definitive and diagnostic of adrenocortical insufficiency—vs. normal patients who have a brisk increase in cortisol after cosyntropin administration. 3) Abnormal metyrapone test: ↑ ACTH, but no ↑ in 11-deoxycortisol—vs. normal patients who have ↑ ACTH and ↑ 11-deoxycortisol in response to metyrapone administration. Metyrapone test (no longer used clinically, but still frequently tested concept): - normal cortisol synthesis pathway: cholesterol → → → 21-hydroxylase converts 17-hydroxyprogesterone into 11-deoxycortisol → 11-β-hydroxylase converts 11-deoxycortisol into cortisol - metyrapone inhibits 11-β-hydroxylase In a patient with functional adrenal glands, the metyrapone test is normal: inhibition of 11-β-hydroxylase by metyrapone → ↓ cortisol and ↑ 11-deoxycortisol. The decreased cortisol level negatively feeds back to the hypothalamus and anterior pituitary → ↑ ACTH (indicating intact function of the hypothalamus and anterior pituitary) → ACTH stimulates the adrenals, further increasing 11-deoxycortisol (indicating intact function of the adrenal cortex), yet cortisol levels remain low due to metyrapone inhibition. In a patient with adrenal insufficiency, the metyrapone test is abnormal: patients with adrenal insufficiency make subnormal amounts of cortisol, so administering metyrapone → slight decrease in the already low level of cortisol, which negatively feeds back to the hypothalamus and anterior pituitary → ↑ ACTH (indicating intact function of the hypothalamus and anterior pituitary) → ACTH stimulates the adrenals, however the adrenals aren't functioning properly ∴ there is a subnormal ↑ in 11-deoxycortisol, or perhaps no ↑ at all if the adrenal insufficiency is severe. Tx: Glucocorticoids

(GUNNER) Regulation of PTH:

controlled by serum Ca2+ and Mg2+ ↓ free serum Ca2+ causes ↑ PTH secretion and vice versa. Ca2+-sensing receptors on chief cells mediate these effects. Mild decreases in Mg2+ stimulate PTH secretion, while severe decreases in Mg2+ inhibit PTH secretion and produce symptoms of hypoparathyroidism. Common causes of ↓ Mg2+: diarrhea, aminoglycosides, diuretics, and alcohol abuse.

(GUNNER) Actions of PTH:

coordinated to ↑ serum [Ca2+] and ↓ serum [phosphate]. ↑ bone resorption of calcium and phosphate: binding the PTH receptor on osteoblasts → in response, osteoblasts secrete M-CSF and RANK-L, which stimulate osteoclasts to break down bone and release calcium. ↑ hydroxyproline excretion reflects bone resorption due to the actions of PTH. ↑ intestinal absorption of Ca2+: PTH stimulates 1α-hydroxylase in the kidney → increased 1,25-(OH)2 vitamin D production. ↑ renal Ca2+ absorption in the distal convoluted tubule. ↓ kidney reabsorption of phosphate → ↑ phosphate excretion (phosphaturic effect). Mnemonic: PTH = Phosphate Trashing Hormone PTH action at the proximal tubule results in ↑ urinary cAMP.

• Tx of prolactinomas

dopamine - inhibits prolactin production even in lactotrophs, generally effective so rarely need surgery but can do transphenoid surgery

Which lipid disorders are associated with premature atherosclerosis?

dyslipidemias.

Aldosterone receptor:

intracellular ligand activated nuclear receptor - steroid hormone binds cytoplasmic ligand and then enters nucleus as transcripton factor • Ligand binding at C terminal, DNA binding in center, transactivation domain at amino terminal • Aldosterone enters from blood through basolateral side,binds to receptors and turns on gene for ENaC • ENaC channels insert on luminal membrane and na flows into cell from urine • Na/K ATPase at basolateral side pumps K into cell w/ Na leaving cell • Aldosterone also stimulates H+ ATPase to secrete H into urinary lumen

(GUNNER) - Pheochromocytoma:

neuroendocrine tumor of adrenal medulla chromaffin cells that secretes catecholamine Called 10% tumor because 10% malignant, 10% found extraadrenal, and 10% are bilateral Associated with MEN (multiple endocrine neoplasia) II and III and neurofibromatosis. (Note: MEN II is also referred to as MEN IIa; MEN III as IIb) Treatment: alpha blockers (e.g. phenoxybenzamine or phentolamine)

Acquired disorders of lipoprotein metabolism

secondary disorders of TG & cholesterol • High cholesterol - hypothyroidism (overproduction), nephritic proteinuria (impaired clearance), thiazide diuretics • TGs - metabolic syndrome - diabetes, obesity, drugs, steroids, estrogen, glucocorticoids

(GUNNER) Hyperthyroidism - Diagnostic lab findings:

serum TSH: - if primary hyperthyroidism: ↓ TSH - if secondary hyperthyroidism: ↑ TSH ; in the rare case that a patient has secondary hyperthyroidism due to a TSH-secreting pituitary adenoma → inject TRH and look for ↑ in TSH - when hyperthyroidism is clinically suspected, serum TSH is usually the most sensitive test ↑ total T4 ; ↑ free T4 Note: up to 5% of patients may exhibit T3 toxicosis (↑ serum T3, 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.

(GUNNER) - hypothyroidism Lab values:

serum TSH: - primary hypothyroidism (caused by thyroid hypofunction): ↑ TSH - secondary hypothyroidism (caused by pituitary hypofunction): ↓ TSH - tertiary hypothyroidism (caused by hypothalamic hypofunction): ↓ TSH When hypothyroidism is clinically suspected, serum TSH is usually the most sensitive test. ↓ total T4 ; ↓ free T4 ↓ T3 resin uptake.

What are the differences in origin and fate of triglycerides in the exogenous vs. the endogenous pathway?

§ Exogenous (Dietary) Pathway - Chylomicron Metabolism * After a meal, within the intestinal cell, free fatty acids are combined with glycerol to form TG; cholesterol is esterified by the enzyme (ACAT). - These are assembled with apo B48 to form chylomicrons and secreted into the intestinal lymphatics. (allows tissues other than the liver to have the first opportunity to remove TG from the chylomicron). Apo B48 is derived from the same gene as Apo B100 but is produced by editing of the mRNA occuring only in the intestine. - NOT contain the LDC receptor binding domain found in Apo B100. Apolipoproteins CII and E are acquired after the chylomicrons enter the plasma. Apo CII serves as a co-factor for lipoprotein lipase (LPL) which resides on the endothelium of muscle and adipose tissue. The LPL hydrolyzes the triglycerides in the core of the chylomicron particle. As the chylomicron shrinks, the surface components are transferred to HDL; the core becomes the chylomicron remnant particle. These chylomicron remnants then acquire apo E from HDL, and are then taken up by the liver binding to receptors that recognize apo E. The hepatic degradation of these particles results in the delivery of dietary cholesterol to the liver. § Endogenous pathway • To supply energy when fasting so not from diet • Liver secretes triglyceride-rich VLDL into plasma, where it, too, acquires apo CII from HDL. • VLDL interacts with LPL in capillary endothelium, and the core triglycerides are hydrolyzed to provide fatty acids to adipose and muscle tissues. - 50% of the catabolized VLDL particles are taken up by hepatic LDL receptors that bind to apo E; - 50% remains in plasma, becoming IDL. IDL is gradually converted by hepatic lipase to the smaller, denser, cholesterol-rich LDL. As IDL is converted to LDL, apo E becomes detached, leaving only one apoprotein, apo B-100. Each particle in this cascade from VLDL to LDL contains one molecule of apo B-100

ACTH independent

• Adrenal adenoma/carcinoma • Tumor in the adrenal gland itself which secretes cortisol NOT in response to ACTH • CRH & ACTH levels go way down, not suppressible • Iatrogenic - exogenous

GH deficiency

• Appearance: decreased muscle mass, increased fat mass, short stature • Causes: lack production of GH, lack normal GH receptor - Laron Dwarf

Pseudohyperaldosteronism - apparent MR excess

• Can be due to mutation in aldosterone receptor where responsive to more ligands than just aldosterone • High cortisol - cortisol can bind to GR and MR w/ equal affinity but enzyme 11, beta hydroxysteroid dehydrogenase inactivates cortisol to cortisone but if too much then overwhelms enzyme or blocking enzyme then appears like lots of aldosterone

17 OHase Deficiency

• Cannot make cortisol so shifts pathway to making lots of aldosterone • Stops at precursor corticosterone which itself has HTN effects

GH Excess - Acromegaly

• Cause: GH secreting tumor • During puberty - very tall - rarely • After puberty - acromegaly - b/c epiphyseal plates already closed • Clinical features of Acromegaly • Age at dx - ~42 yo • Delay to diagnosis 8 yrs - b/c gradual, don't notice • Acral/facial changes - broadening of head, frontal bossing, prognantism, widening hands/feet • Hyperhydrosis - lots of sweating • HTN - directly due to GH Entrapment Neuropathy - due to increased proliferation of cartilage & fat • Arthritis - cartilage overgrowth of joints causing arthritis • Potential diabetes mellitus & DKA - b/c GH excess causes hyperglycemia and rise in serum free fatty acids • Effects of a class pituitary GH secreting tumor: headaches & hypopituitarism • Dx of Acromegaly: GH levels dramatically high (80-100), IGF-1 also high, GH doesn't fall when receive glucose • Tumor - erratic very high levels of GH • Mechanism of action of a GH secreting tumor - GHRH normally binds to cAMP to promote proliferation and transcription of GH but in tumor cAMP is constitutively active • Tx: surgery for tumor, somatostatin analog to inhibit GH, GH receptor antagonist - prevents dimerization of GH receptor

Syndrome of ADH (SIADH) - ADH excess

• Causes: • Tumors producing ADH ectopically • CNS diseases, pulm diseases - acute cause of overproduction of ADH by pituitary • Chronic disease - cirrhosis or CHF - arterial circulation appears to be suppressed so body responds by producing ADH, doesn't respond to keeps producing more ADH • Clinical probs: reabsorb too much water, dilute blood sodium, dilute blood chemistry

Hypophysectomy cures Brattleboro rat of DI

• Central DI - cannot make ADH • Remove pituitary - DI goes away • Why? Thyroid hormone & cortisol necessary for renal free water clearance - they make the free water which is absorbed by ADH • If don't make free water (due to increased proximal reabsorption of free water) • Solution to nephrogenic DI - thiazide diuretic - prevent generationfo free water by inhibiting sodium reabsorption • Reduces magnitude of dieresis and thus DI b/c free water not generated so don't lack prob w/ reabsorbing it • ?? still probs tho b/c still cannot concentrate urine???

Adrenal medulla Comp.

• Chromaffin cells= catecholamine-producing cells of the medulla o embryologically derived from the neural crest. Impt. when searching for a pheochromocytoma outside of medulla; are generally in the midline of the body (e.g., head and neck, heart, around the aorta or vertebra, or in the bladder). • Portal system arises from the adrenal cortex and supplies blood to the medulla where catecholamines are synthesized. o portal blood glucocorticoid levels are 100x higher/gen. circ. o Blood flow to the medulla is neurally regulated; inc. in stress so CATs go in circulation. o preganglionic sympathetic fibers of the splanchnic n.

Hypercalcemia

• Clinical: fatigue, weakness, coma; constipation, anorexia, nausea, vomiting; polyuria, polydipsia, dehydration, nephrolithiasis, nephrocalciosis; palpitations, arthyrhmia, bradycardia, short QT, AV block • Blocks ADH ability to concentrate urine & kidney stone • Vicious cycle - severe hypercalcemia causes polyuria, nausea vomiting which causes more hyperclacemia which causes dehydration... • Diff Dx: • Outpatient setting - primary hyperparathyroidism • Inpatient setting - malignancy (inc humoral hypercalcemia malignancy) • Tx: rehydration, diuretics once rehydrated to remove Ca in ECF, bisphosphonates in osteoporosis to lower serum Ca • Surgery if needed and glucocorticoids for Vit D toxicity and granulomas

Hypocalcemia

• Clinical: numbness, tingling, irritability, brisk reflexes, seizures: muscle cramps, spasms, tetany: long QT, CHF (both Chvostek's and Trousseau's signs) • Diff Dx: • Hypoparathyroid w/ low blood Ca and low PTH Autoimmune, post-surgical, Mg deficiency, neck irradiation, neonatal • Non-hypoparathyroid: Vit D deficiency, Crush syndrome, PTH or Vid D resistant, acute illness... • Causes: deficient PTh secretion or action - leads to hypocalcmia & hyperphosphatemia • Gain of function mutation in Ca sensitive receptor that constitutively active, can never secrete PTH • Tx: give Vit D and Ca (can now give PTH which also helps but Vit D and Ca basically just as good) • Allosteric modulator - binds to Ca sensitive protein receptor modifying response when Ca binds so that does not inhibit PTH • Calcimimetic ex: Cinacalcet - L shift dose response curve to shut down PTH secretion - secondary or intractable primary

Diabetes Insipidus - ADH deficiency

• Common complaint: frequent urination • 2 types: • Central DI (aka neurogenic) Causes Mutations: neurophysin molecule - critical for synthesis & storage Hypothalamic lesion - no longer can produce ADH Cut stalk - no longer make ADH, Wallerian degeneration - transient release of stored ADH so transient recovery followed by permanent DI • Nephrogenic DI Kidney doesn't respond to ADH - prob w/ receptor • Water deprivation Test to evaluate DI - stop ingestion of water & check urine osmolarity • Normal - concentrates urine - 1000 • DI - cannot concentrate urine as lack ADH Central DI - if give ADH will respond immediately and concentrate urine Nephrogenic DI - if give ADH still cannot respond, cannot concentrate urine

Atherosclerosis

• Contributing factors: increased LDL, VLDL or TGs, decreased HDLs • Cigarette smoking, HTN, procoagulant state, diabetes, thrombosis • Excess TG lipoproteins - increased TG, low HDL -- contributes to oathersclerosis • Atherogenic particles - TG rich lipoprotein, w/ ApoB100 on surface • Atherogenic Cholesterol • VLDL + ILD + LDL = Total cholesterol - HDL = non HDl cholesterol • Predictive of CV event rates - more than LDL • Useful when TGs >200 • Goals - add 30 to LDL lecture • More flexible - non-fasting samples

ACTH dependent

• Cushing's Disease - pituitary dependent tumor secreting excess ACTH • Excess ACTH upregulation of cortisol & androgens • Feedback still works, vicious cycle: increase ACTH, increase cortisol feedback to decrease ACTH and decrease cortisol which feeds back to increase ACTH...can keep low for yrs before detected • Slightly suppressible, requires higher levels of cortisol in order to suppress • Ectopic ACTH syndrome - malignancy, prob paraneoplastic • Most commonly small cell cancer of lungs, or renal or breast cancer • Late stage, Usually untreatable, presents more quickly • Generates ACTH which is identical to ACTH from pituitary causing increase in cortisol but NOT responsive to feedback from cortisol Does suppress ACTH from pituitary but essentially irrelevant • Bronchial Carcinoid - generates ACTH but is suppressible by cortisol • Appears like pituitary tumor but none seen on MRI so then likely this • Inferior petrosal sinus sampling - catheter in petrosal sinus and in periphery - if levels of ACTH constant in brain, prob not brain (pituitary) but rather carcinoid elsewhere in body

HDL

• Direct pathway - Reverse Cholesterol transport • Slight excess of cholesterol in most organs which ABC1 transporter puts on nascent HDL particles • LCAT esterifies free cholesterol to cholesterol ester - now HDL • Anti-therogenic • Taken up in liver by SRBI or HDL receptor • Indirect pathway • Cholesterol from periperhy placed on HDL • CETP - cholesterol ester transfer protein switches cholesterol and TG from HDL and VLDL Secondary causes of low HD: smoking, obesity, sedentary lifestyle, high carb or very low fat diet, hypertriglyceridemia, certain drugs

Metabolic consequence of hypertriglyceridemia - increased risk of atherosclerosis

• Due to TG rich particles, decreased HDL, small dense LDL

Thyroid Hormone

• Effects transcriptions of specific gene- including growth hormone • T3 enters cell, binds w/ receptor protein, enters nucleus and binds to thyroid response element • Triggers RNA polymerase - stimulates or inhibits Growth Hormone cell - stimulates TSH producing cell - inhibits it (neg feedback)

Cortisol

• Ensure brain has glucose that it required • Fuel metabolism • Inhibits insulin effects in the periphery - decrease glucose uptake • Increase hepatic glucose production • Protein catabolism - break down proteins and make substrates available for HGP • Increases lipolysis to make fatty acids available to make glucose • Bone - (in excess inhibits linear growth, suppress osteoblast, causes osteoporosis) • Decreases Ca absorption in the gut • Inhibition of collagen synthesis • Immune modulation - anti-inflammatory (excess susceptible to infection) • Water balance - increase free water clearance • Mineralcorticoid-like properties - helps w/ salt retention • CNS - mood stabilization

Thyroid composition:

• Follicles - cuboidal follicular cells lining center of colloid - pink flud filled w/ thyroglobulin - protein which thyroid is synthesized from - large warehouse • Parafollicular cell s- b/w follicles, secrete calcitoni - prevent bones from dissolving while hibernating

Prolactin

• Function: stimulates lactation in a properly sensitized breast - reproductive age, w/ estrogen etc • Inhibition • from hypothalamus - otherwise stimulated to secrete • dopamine - inhibits • Causes of Hyperprolactinemia (normal 5-20) • Pregnancy 20-350 - estrogen stimulates proliferation of lactotroph, pituitary can double and prolactin levels rise • Hypothyroidism? 5-60 • Lack hypothalamus, no inhibition and high prolactin • Renal failure 5-100 • Drugs - Anti-dopaminergics - no longer inhibiting prolactin so rise, usually <350 • Tumors - block portal system so prevent inhibition of dopamine getting down • Microprolactinoma - 30-500 Microadenoma - secrete prolactin Tumor - can have other consequences - destroy tissue... Macroprolactinomas 100-300,000

Primary Aldosteronism

• High aldosterone but low renin as shuts off due to high aldosterone • Na reabsorption and Hypokalemia • Types of tumors: • Aldosterone producing adenoma - excessive aldosterone, directly affects tubule system w/o renin • Idiopathic Hyperaldosteronism aka Bilateral Renal Hyperplasia - bilateral tumors, symmetrical or not Does NOT respond to removing adrenal gland - unclear why not, other factors Adrenal vein catheterization - identify unilateral or bilateral, gradient only in 1 then unilateral • Glucocorticoid Remediable Hyperaldosteronism - chimeric gene b/w promoter of Aldo Synthase and of 11OHase so that promoter for synthesis of 11 OHase (cortisol) which is stimulated by ACTH is found on Aldo Synthase - ACTH stimulate production of aldosterone and ACTH much higher levels to hyperaldosteronism. Can tx w/ cortisol to suppress ACTH • Tx: surgical removal when unilateral - cures or greatly improves HTN unless long-standing cannot cure

Hypo vs hypercalcemia

• Hypocalcemia - membrane depolarization, increased excitability, seizures • Hypercalcemia - hyperpolarization, reduced excitability, coma

• Clinical Manifestations of a prolactinoma

• Hypogonadotropic hypogonadism - prolactin inhibits GnRH, thus decrease LH/FSH, estrogen... Can be corrected by giving GnRH • Can grow up to affects optic chiasm - visual field defects (bitemporal hemivision), blind • Headaches - tumor stretching dura • Hydrocephalus - blocking 3rd ventricle • Cranial nerve palsies - sella turcika lateral to cavernous sinuses w/ no bone b/w so can affects nerves within • CSF rhinorrhea - leakage of CSF into nose if affect sphenoid sinus - high incidence of infection

Regulation of thyroid

• Hypothalamus produces TRH - portal circulation to anterior pituitary • Thyrototrophic cells in anterior pituitary make TSH - secrete when stimulated into blod to bind to thyroid • Levels of thyroid hormone feedback to pituitary to decrease TSH production

Actions of catecholamines

• Increase HR, contractility, cardiac output, BP, blood glucose, lipolysis, skeletal muscle blood flow & contractility • Decrease: visceral blood flow, GI tract motility, urine output

Small Dense LDL - low cholesterol content of LDL particles - increased particle number for given LDL-cholesterol levels

• Increased Tgs and decreased HDL • Associated common genetic treat w/ increased risk of coronary disease • Possible mechanisms of increased atherogenicity • Greater arterial uptake - smaller so gets into atherosclerotic lesion more easily • Increased uptake by macrophages • Increased oxidation susceptibility - TGs more easily oxidized, acted upon by lipases and shrink • Calculating LDL cholesterol • Total cholesterol - HDL - TG/5 - invalid when TG>400 • nonHDL cholesterol = Total cholesterol - HDL • smaller particles greater risk • ApoB100 best marker for goals of therapy and risk • Synergistic effects of diet & drug - successful diet reduces drug therapy by over 50%

Insulin resistance = Metabolic syndrome & dyslipidemia

• Insulin - inhibits lipolysis so insulin resistance leads to excess of free fatty acids which are re-esterified into TGs making extra ApoB and excess VLDL • CETP switches cholesterol from HDL for TGs on VLDL and b/w LDL and VLDL • HDL depleted of cholesterol, more TGs and cleared faster • LDL - depleted cholesterol, enriched TGS - small dense LDL

Renin-AII-Aldosterone

• Liver makes angiotensin, Renin from kidney cleaves to Angiotensin I, ACE from lung cleaves to AII which is active form - short lived, degraded quickly • Effects of AII: overall - salt & water retention, increase in effective circulation volume • stimulates sympathetic system • kidney - tubular reabsorption of Na//Cl and excretion of K w/ water retention • adrenal gland cortex - secretes aldosterone leading to water retention • arteriolar vasoconstriction, increase in BP • pituitary gland - ADH secretion - increase water absorption in collecting duct of kidney • Juxta-glomerular apparatus - secretion of renin • Specialized group of epithelial cells in kidney make renin • Stimuli to make renin: Sympathetic nerves Baroreceptors in afferent tubule sense filling pressure of afferent arteriole, if low will stimulate JGA to make renin Macula densa - in distal convoluted tubule - sense Cl, if dehydrated, proximal tubule reabsorb all NaCl and little comes down and thus stimulate release of renin • AII receptors - Types 1 & 2 - ACEi inhibits both, ARB only inhibits Type 2 which stimulates renin production

Functions of the thyroid

• Metabolism, growth & development • Brain development - if hypothyroid from birth, deficient brain development • Calorigenesis - maintaining body heat - uncouples in brown fat, increases cAMP to catecholamines • CV system changes - sympathetic, contractility • Regulates turnover of materials into and out of the body

Pheochromocytoma - catecholamine secreting tumor from adrenal medulla

• Or sympathetic paraganglia - paraganglioma - sympathetic system uses as neurotransmitters • Clinical significance: potentially life threatening, surgically curable in 90%, sporadic or hereditary, dx may lead to recognition of associated diseases • Clinical presentation: classic symptom triad: headaches, palpitations, diaphoresis • Additionally: anxiety, panic attacks • Pathophysiology of symptoms: • Headaches - vascular smooth muscle contractions - A1 adrenergic • Palpitations - cardiac stimulation - B1 adrenergic • Diaphoresis - activation of sweat glands - a adrenergic and cholinergic • Clinical signs: HTN - paroxysmal, pallor during attacks, postural hypotension, rarely hypotensive episodes, metabolic abnormalities - hyperglycemia as Epi inhibits insulin secretion, stimulates glycogenolysis and gluconeogenesis (looks like diabetes till remove catecholamines) • Dx: biochemical testing - catecholamines and metabolites in plasma or urine • COMT breakdown pathway methylates to normetanephrine - inactivates but can test for • MAO and COMT sequentially then VMA - most abundant urinary metabolite • Can test many of these metabolites, most overlap b/w normal and abnormal bu plasma metanephrine is best • 10%: bilateral, extraadrenal, malignant • Therapy: surgery - high risk yet curable in 90% - must prepare w/ alpha blockers b/c losing catecholamines to prevent shock and deal w/ unintentional release of catecholamines when remove tumor • Minimally invasive, persistent or recurrent HTN in 10%

Calcium Regulation - in bone, GI tract and kidney

• PTH hormone: raises serum Cal levels • Bone - releases Ca and phosphate by activating osteoclasts • Kidneys - favors Phosphorous excretion and calcium reabsoroption • Dosing - excess can lead to holes in bone but small am'ts have anabolic effects to build bones • Receptor on PTH cell - Ca sensitive so if Ca present, shuts off secretion of PTH and vice versa • PTH Related Peptide - malignancies secrete, acts like PTH on receptors • Vitamin D - regulates GI calcium absorption, skeletal mineralization, PTH secretion • Diet and skin have precursors, liver intermediate metabolizes to 25 OH Vit D and kidney to 1,25 OH Vit D active form • Toxicity of 25 OH Vit D when too much, kidney step more regulated through PTH and phosphate • Abnormally in granulomas, macrophages can also activate so can lead to toxicity • If Vit D cause of hypercalcemia, then glucocorticoids (prednisone) will have dramatic lowering effect

• Etiologies of prolactinomas

• Pituitary adenomas - most common • Other dx w/ same symptoms - extrapitutiary lesion, craniopharyngioma (Rathke's pouch), cyst... • Blood borne - likely involves hypothalamus as well - sarcoidosis

Familial (Type I) Hyperlipoproteinemia/Chylomicronemia

• Presentation: TGs >1000 w/ usual diet • Defect: mutation or absence in LPL or ApoCII - cannovert convert chylomicrons or VLDL along pathway so they predominate w lots of TGs, defect in clearance pathways • Rare, recessive, childhood esp puberty • Complications: can be life-threatening • Pancreatitis • Eruptive xanthomas - extensors surfaces ,skin temp lower, blood flow less, pruritic, after fatty meal and goes away after decrease TG intake • Hepatosplenomegaly

Familial Hypertriglyceridemia aka Hyper TG Normal ApoB

• Presentation: increased TGs • Defect: liver overproduces TGs in VLDL, not particles but am't of TG • Common, autosomal dominant • TG 200-500, decreased HDL • CHD risk may or may not be increased - b/c depends on particles which ins't now • ApoB may or may not be increased • Associated w/ obesity, diabetes mellitus, hyperuricemia

Familial Combined Hyperlipidemia aka HyperTG HyperapoB

• Presentation: increased VLDL, IDL and LDL • Defect: liver makes too many VLDL particles - too many particles w/ ApoB100 on surface • VLDL then metabolized to VLDL remnant and then LDL - so can have excess of all 3 - combined • Depending on nutrition can shift and have only excess of 1 - eating lts - predominance VLDL and TGs, fasting then LDL predominate - always ApoB100 • Most common, autosomal dominant, CHD risk increased

Remnant Removal Disease aka Type III Hyperlipidemia

• Presentation: increased chylomicron/VLDL remnant - increased TG and CE 9cholesterol) • Defect: ApoE2 (E2,3,4) hetero or homozygous - low affinity for remnant receptors so cannot clear remnants well and thus accumulate, remnants w/ 50:50 TG:CE so both TG and CE • Any additional stress, then chylomicrons themselves will accumulate • Dx: divide VLDL/TG, should be ~.2 but if >.3 then suspect, broad beta band on electrophoresis • CHD and peripheral vascular disease increased • Strias Palmaris - cholesterol deposition in creases of hands & fingers • Tubular xanthoma - cholester on tendons, esp knees and elbows • Eruptive xanthomas

Familial Hypercholesterolemia

• Presentation: severe hypercholesterolemia - LDL >250 • Mutation: LDL receptor so cannot clear LDL - get doubling w/ mutation in 1 receptor • Dominant, heterozygous - double, homozygous - 4-6x - full knockout or leaky mutation • Same as familial defective ApoB - which is what? • Clinical: atherosclerotiv vascular disease premature, premature CHD, family history, arthritic joint pain • Corneal arcus - cholesterol deposition in sclera of eye - normal as age but not when younger • Xanthelasma - cholesterol deposition in inner corner of eye • Tendon xanthomas - Achilles xanthoma pathognomic for FH - thickening of tendon more common

Hyperaldosteronism - most common endocrine cause of HTN Diff Dx:

• Primary: Adrenal causes: Aldosterone producing adenoma, idiopathic hyperaldosteronism, glucocorticoid remediable aldosterone • High aldosterone, low renin • Secondary: Renal causes: Increased Renin High aldosterone, high renin • Renal-vascular stenosis - decreased perfusion of kidneys due to stenosis so increased renin • Reninoma - tumor secreting renin • Liddle's Syndrome - truncated ENaC protein so that cannot properly remove from membrane and thus constantly activated as if aldosterone constantly stimulating, responds to K sparing diuretic • Apparent MR excess - increased cortisol • Low aldosterone, low renin

Hyperparathyroidism

• Primary: tumor of PTH - excessive PTH which doesn't shut down when Ca high • Causes hypercalcemia & hypophosphatemia • Secondary: s/t causes hypocalcemia and appropriate response by PTH but chronic prob which isn't solved such as end stage renal disease where cannot clear phosphate and leads to hypocalcemia, thus hyperparathyroidism • Diff Dx of hypercalcemia - parathyroid gland or not, check PTH, renal status, Vit D level • Not parathyroid, PTH suppressed - tumor or granuloma • Tx: hyperparathyroidism- treatable and reversible - surgery • Sporadic ¼ glands, familial - all 4 glands • Unclear if should treat asymptomatic hyperparathyroidism • Familial Isolated hyperparathyroidism • Multiple diff genetic diseases, all involve all 4 parathyroid glands • FHH - Familial Hypocalciuric Hypercalcemia aka Familial Benign Hypercalcemia Loss of function mutation in 1 allel fo Ca sensitive receptor so that requires higher levels to shut down receptor to inhibit PTH - esp in kidney where Ca regulates reabsorption of Ca through its own sensitivity and if not as sensitive, reabsorb too much leading to hypercalcemia Fairly asymptomatic, suggested if Ca: creatinine ratio is low • Neonatal Severe Hyperparathyroidism Pediatric emergency Both copes of Ca sensitive receptor mutated so that do not sense Ca at all and PTH constantly secreted leading to increasingly high Ca levels through massive bone resorption Tx: remove all 4 parathyroid glands

• Diseases of the proteins (thyroid)

• Radioactive iodine - taken up by iodine symporter - diagnostic or can destroy • TSH receptor - mutated then underactive • Grave's Disease - autoimmune antibody vs TSH receptor that constantly stimulates it • Hashimoto's Disease - anti-TPO antibodies, thyroid slowly destroyed • Thyroglobulin can be used as a tumor marker if thyroid removed b/c only tissue in the body to make it

• 2 forms of thyroid hormone

• T3 - 4 iodine molecules, majority of what thyroid makes, not biologically ctive • T4 - 3 iodine molecules, 10% of what thyroid makes, biologically active • T4 enters liver, kidney & muscle where iodinates clip off iodine forming T3 which active in circulation 100% T4 from thyroid, 20% of T3 from thyroid

Clinical Thyroid

• TSH - measured directly, sensitive & reproduceable • T4 - thyroid functioning • Thyroxin Binding Globulin TBG - binds most of T4 to enable to circulate in blood as insoluble, extremely high affinity • Free T4 - activein blood - lab measure total T4 • When thyroxin & TBG increase: • Pregnancy - estrogen increases production of both • Nephrotic syndrome - lose lots of protein in urine including TBG, TBG and T4 decrease but thyroid is normal • Am't of free protein remains the same even if binding protein decreases • Clinically useful: TSH and free T4 • Normal lab values: free T4 0.8-2 ng/dL and TSH .4-4.5

• Synthesis of thyroid hormone

• TSH receptor - on basal membrane - TSH binds to receptor and linked to adenylate cyclase to make cAMP which stimulates iodine symporter • Iodine symporter on basal membrane - brings iodine into cell against a strong concentration gradient, anchored in membrane, iodine as I- which is not biologically active • Pendrin - apical membrane - directs I- toward TPO • TPO - thyroid peroxidase - apical membrane - oxidizes iodine to reactive form and inserts onto tyrosine molecules of thyroglobulin (1 or 2) • Projections of apical membrane - pick up iodinated thyroglobulin, phagocytose into phagolysosome where degrade into thyroid hormone and secreted into blood

Dietary hyperlipidemia

• diet high in saturated fat leads to increased chylomicrons and VLDL which are broken down to LDl and so LDl and LDL-C increases and then reduces activity of LDL receptors • Good diet - low in saturated fat - enhances clearance

(GUNNER) - Familial Combined Hyperlipidemia (FCH)

↑ LDL and/or ↑ VLDL, ↓ HDL Affects 1% of the population Mechanism not fully elucidated; may be due to ↑ apoB-100 production → VLDL packaging ↑ → serum VLDL levels ↑ Phenotype expression is variable with multiple risk factors (obesity, diet, drugs, etc.)

(GUNNER) -ther lab findings consistent with thyrotoxicosis include:

↑ bone turnover → ↑ serum calcium (hypercalcemia) ↑ glycogenolysis → ↑ serum glucose (hyperglycemia) ↑ LDL (low density lipoprotein) receptor synthesis → ↓ serum cholesterol (hypocholesterolemia)

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