ERM midterm 2 UCSD SSPPS SOM

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What is the endogenous pathway for lipoprotein metabolism?: Liver makes XOL, packages it in VLDL with apolipoproteins and TGs. In the periphery, TGs are released, leaving IDL and LDL particles, which can either deliver XOL to peripheral cells, or recycle back to the liver and be taken up via LDL receptor. The liver removes 2/3 of all LDL particles.
What is the exogenous pathway of XOL metabolism?: Intestinal epithelial cells form chylomicrons made of XOL, TGs, and apolipoproteins. TGs are delivered to the periphery, and small amount of XOL, but most is delivered to the liver through apoE-mediated LDL reception.
What is reverse XOL transport?: Extra XOL in peripheral cells is taken up by HDL to go back to the liver. â€œNascentâ€ HDL is synthesized by the intestine and contains only apoA-I. ApoA-I picks up XOL from peripheral cells forming HDL. Lecithin-cholesterol acetyltransferase (LCAT) converts free XOL on the HDL surface to XOL freeing up space on the surface of the HDL so it can pick up more XOL and the HDL becomes bigger. HDL is carried back to the liver by 3 possible mechanisms: (1) Cholesterol ester transfer protein (CETP) can transfer its XOL ester to VLDL remnants, IDL, and LDL in exchange for TGs. The VLDL, IDL, and LDL then recycle the XOL ester back to the liver eventually. (2) Some HDL have apoE, attained with transfer from other lipoproteins. (3) Hepatic uptake via the SR-B1 receptor. But SR-B1 does not internalize the HDL. It selectively extracts XOL esters and then releases the HDL.
How much XOL do we need to survive?: Cells need 2.5mg/dL, but there is a 10:1 ratio of plasma to cellular XOL concentration, so serum XOL needs to be at least 25mg/dL.
What are goals for LDL levels in different risk populations?: Moderate risk for CHD goal is <130. Moderate risk means no familial hx and no other risk factors, or young adults with FH, or adults with FH and no other risk factors. Groups with high risk goal is <100. High risk means family hx of CAD or â‰¥2 risk factors, or with Fhand family hx of CAD or other risk factors, or existing CAD, or after CABG (coronary artery bypass graft), or low HDL and family hx of CAD
2 fates for synthesized XOL?: Bile or VLDL
Every 1% decrease in XOL gives how much reduction in chance of having a coronary event?: 2-3%
How do bile sequestrants reduce XOL?: Bile not reabsorbed in gut, so hepatocytes upregulate LDL receptors, reducing serum XOL
How do statins work? Side effects? Used for primary or secondary prevention?: HMG CoA Reductase inhibitors, the rate-limiting step in XOL synthesis. Less XOL means more LDL receptors expressed. Can cause myopathy and increase in liver enzymes (ALT, AST). They have been shown to reduce strokes in primary and secondary prevention.
How is Niacin used in XOL therapy?: Reduces secretion of VLDL, so less XOL in plasma
How do selective XOL absorption inhibitors work?: Ezetimibe blocks XOL absorption by binding to Niemann-Pick C1 like 1 protein in the intestines with no effect on lipid-soluble vitamin absorption. They are particularly helpful with statins because allow reduction in statin dose
How to treat FH refractory to traditional treatments?: All lipid-lowering drug therapies rely on reduction of LDL receptors, but if deficient (as in FH), then can do plasma-phoresis (like dialysis), or liver transplant so new liver has LDL receptors (but immunosupression is a big problem too)
How does Vit D promote mineralization of osteoid?: Raises the blood calcium to the necessary levels for mineralization
What is the disease of vit D deficiency?: osteomalacia
What effect does vit D have on GI?: Increase calcium and phosphorous absorption (upregulation of a calcium binding protein) via binding as a heterodimer on an RXR that promotes transcription of proteins
What effect does vit D have on blood?: Raises blood calcium and phosporous
How are vit D and toll receptors related?: Promote members of the immune system through toll receptor pathway (so vit D deficiency can lead to higher rate of infection)
PTHrP?: There are three forms (by alternate splicing). Parathyroid related protein, and is expressed in many tissues, but is very high in neonates. It shares a receptor with PTH. Itâ€™s very high in malignancy (esp. breast, prostate, squamous), and can lead to hypercalcemia
Whatâ€™s HHM?: Humoral Hypercalcemia of Malignancy. (due to overexpression of PTHrP in malignancy)
What hormones decrease bone resorption?: Calcitonin and estrogen
What hormones increase bone resorption?: PTH, PTHrP, glucocorticoids, thyroid hormone, high dose vit D
What hormones increase bone formation?: Low-dose PTH/PTHrP, growth hormone, vit D metabolism, insulin, androgens (males with hypogonadism have low bone density)
What hormones decrease bone formation?: Glucocorticoids
Whatâ€™s Forteo?: A recombinant PTH analogue to increase bone formation
Two conditions that describe too little bone?: Osteomalacia, osteoporosis
Two conditions described by too much bone?: Osteopetrosis, pagetâ€™s disease
2 conditions that describe too little calcium?: Hypoparathyroidism, osteomalacia
2 conditions that describe too much calcium?: Hyperparathyroidism, HHM
How to determine bone density?: Not x-ray anymore (not sensitive until >30% lost). So, use bone densitometry, or others
What happens in pagetâ€™s disease?: High bone resorption, and overcompensatory bone resorption
What does bone cancer do to bones?: Causes osteoclasts to work more than usual (so eat up bones)
What causes osteopetrosis?: Deficiency in osteoclasts, so overproduction of bone
Whatâ€™s the effect of high PTHrP on PTH?: Decreases it because of neg feedback
Whatâ€™s secreted by the anterior pit?: TSH, ACTH, GH, Gonadotrophic hormones, prolactin
Whatâ€™s secreted by posterior pit?: Oxytocin and ADH
What hormone is secreted by pituitary in response to GnRH from hypothalamus?: Follicle stimulating hormone (FSH), and Leuteinizing hormone (LH)
What hormone is secreted by pituitary in response to GHRF (Growth Hormone Releasing Factor) from hypothalamus? And what is the inhibitory hpituitary hormone?: Growth hormone (GH). Inhibitory is somatostatin
What hormone is secreted by pituitary in response to TRH (thyrotropin releasing hormone) from hypothalamus? And what is the inhibitory hormone?: Thyroid secreting hormone (TSH) and prolactin. The inhibitory hormone is somatostatin. But prolactin is negatively inhibited by dopamine.
What hormone is secreted by pituitary in response to VIP (vasoactive intestinal peptide) from hypothalamus? And what is inhibitory hormone?: Prolactin. Inhibitory is dopamine
What hormone is secreted by pituitary in response to CRH (corticotrophin releasing hormone and vasopressin from hypothalamus?: ACTH (adrenocorticotrophin)
Where is the pituitary gland?: Below hypothalamus, in the sells turcica inside the sphenoid bone, and surrounded by the sphenoid sinus (can access through nasal canal, rather than skull). The optic chiasm is directly in front of the pituitary, so if pituitary has tumor, it can impinge on optic chiasm and cause vision problems.
How is hypothalamus and pituitary connected in their blood and nerve supply?: Blood comes from superior hypophaseal artery and forms a portal system with anterior pituitary. At base of hypothalamus, it becomes a capillary bed (called the median eminence), then forms venules into the anterior pituitary, so hormones go directly to ant. Pit. Ant Pit also gets some direct blood from middle hypophaseal artery.
How is blood supply to post pit?: Inferior hypophaseal artery, and short vessels into ant pit. The post pit receives input to release hormones from neurons from hypothalamus.
When does corticotopin releasing hormone (CRH) cause release of cortisol from adrenals?: Causes ACTH to go up first. Stress, tissue injury, maintenance of BP
What is the CRH receptor?: A 7-TM receptor
How do circadian rhythms affect cortisol?: Causes cortisol to be released in varying amounts throughout day, lowest at night, highest in morning
What stimulates CRH release from hypothalamus?: NE, ACh, 5-HT, IL-1. CRH then stimulates pituitary to release ACTH, which stimulates adrenals to release cortisol
What is cortisolâ€™s role in negative feedback?: Acts on both the anterior pit and hypothalamus to decrease secretion
What molecule does ACTH come from?: POMC (proopiomelanocortin), which is also a precursor to other molecules too. ACTH acts on adrenals to release cortisol
What is Addisonâ€™s disease?: Adrenal insufficiency, no cortisol to provide negative feedback, so CTH and ACTH levels go high. High levels of ACTH also mean high melanin (both come from POMC), which causes pigmentation of the skin, skin creases, nails, and gums
TSH and TRH and TH pathway/axis?: TRH is a tripeptide released from hypothalamus to stimulate TSH secretion from ant. Pit. The TSH (which is made of a common beta subunit with unique alpha subunit) binds TSH receptor (a 7-TH receptor) to stimulate release of TH. TH is either T3 or T4 (# of iodine). T3 is more active, but T4 is higher concentration. TH inhibits TSH secretion.
What regulates TSH secretion? (besides TRH): Cold increases TSH (because TH increases metabolic rate). dopamine inhibits TRH release from hypothalamus. GCs inhibit TSH release.
Gonadotropins (LH and FSH) pathway, regulation?: GnRH from hypothalamus stimulates release of FSH and LH. FSH stimulates ovaries to produce estrogen and testes to poduce testosterone, both of which exert negative feedback on hypothalamus to decrease GnRH release.
What else (besides testosterone and estrogen) regulates GnRH release?: Inhibin is a hormone from follicle cells that inhibit gonadotroph release. The higher cortex also controls GnRH release such as brain trauma can cause early puberty, and elite athletes and anorexics have low GnRH
What is primary hypothyroidism?: A thyroid gland problem, causing low T4 (canâ€™t make it), and high TSH, trying to give neg feedback, but doesnâ€™t work
What is secondary hypothyroidism?: A pituitary ot hypothalamus problem, causing low T4 due to no stimulus. If giving TRH as a diagnostic test, pituitary failure will mean no TSH secretion. If itâ€™s a hypothalamus failure, then delayed or small amount of TSH. But these are not conclusive, just supportive
What is goiter?: Large thyroid, but does not indicate function, can be hypo-normo-, or hyper-thyroid hormone. However, it can press on neck causing difficultly breathing and decreased activity. It can cause short stature, deafness, mental retardation. Can be caused by iodine deficiency or Graveâ€™s disease, but Graveâ€™s disease also causes large eyes
Thyroid follicles and C-cells?: Follicle cells have thyroid hormone inside. C-cells secrete calcitonin, and are distinct from follicle cells. Low TSH causes flat, empty follicle cells.
How is TH made?: Iodine taken up by thyroid cells via Na-Iodine symporter (NIS). The iodine is oxidized by peroxidases, placing them on tyrosine residues on thyroglobulin. 2 iodinated thyroglobulins then become covalently attached (coupled), then transported into colloid space, and later endocytosed back into the T cell where fuse with lysosomes. Proteolytic cleavage of the coupled thyroglobulin releases 3-4 T3 and T4 molecules. Unused iodine is recycled
Stucture of TH?: Tyrosine etherized to 6-carbon ring (so two rings). Iodine is attached to 3 and 5 carbon positions. T3 has no 5â€™ iodine (on second ring) and is the most biologically active version. Reverse T3 has no 5-carbon iodine on tyrosine ring, and has no biological activity.
How does TSH promote TH release?: Activates cAMP pathway to activate NIS by PKA phosphorylation and activates PKC. NIS is a 13-TM receptor only on basolateral side of T-cells. NIS is on other cells in the body, but thyroid is only tissue that expresses thyroid peroxidase needed to make TH.
Dietary iodine?: Required intake is 50mcg per day, but there is an additional 10mcg recycled per day, so daily usage is actually 60mcg. Average American diet has 250mcg. Any excess goes out urine. Out of the 60mcg, 35 go into urine, 15 in feces, and 10 recycled.
What is the Wolf-Chaikoff effect?: High doses of iodine decrease TH production by decreasing peroxidase activity, hydrogen peroxide formation, adenylyl cyclase activity (inhibiting NIS), release of T3/T4. The effect is overcome after 2 days due to increase of NIS activity induced by low thyroid cells iodine concentration.
T4 versus T3 synthesis?: T4 is made exclusively from the thyroid (about 80-100mcg/day), while T3 is made in the thyroid (6-8mcg/day) but mostly by converstion from T4 in ther periphery (24mcg/day)
How is T3 and T4 trasnported around?: >99% bound to protein, with T3 being 5-10 times more active and 10 times higher free concentration. Changes in binding proteins (including displacement by drugs) can affect TH levels, but long-term levels not affected by this.
What is the relative binding affinities of proteins that bind T3 and T4?: TBG (thyroxine binding golbulin) has higher affinity for T4 than T3, and binds 70% of TH. Transthyretin (prealbumin) equally binds T3 and T4, and binds 15% of TH. Albumin has low binding affinity for T3 and T4, but has large binding capacity because there is so much albumin
How is T4 metabolized?: De-iodinases. D1 and D2 remove iodine from outer ring to make active T3. D1 and D3 remove iodine from inner ring to make inactive reverse T3. De-iodinases have seleno-cysteine in active center, and are inhibited by fasting, illness, glucocorticoids, drugs, and during fetal life
Besides de-iodination, how else is TH metabolized?: Sulfination (increase water-solubility), glucuronidation (increases water-solubility), ether bond cleavage, oxidative deamination
How is thyroid involved in development?: TH helps CNS development and increase linear growth. Hypothyroid in mother leads to lower birth weight and IQ. The TH axis starts at weeks 12-16, and TH therapy in hypothyroidism (1/4500 births) can increase IQ
Molecular mechanism of TH action?: Enters cells through ATP receptor, enters nucleus, and binds to Thyroid receptor (TR). TR (either alpha in heart, or beta in liver) heterodimerizes with RXR to induce transcription of genes and activate MAP kinase pathway. Without TH, TR represses transcription
What effect does TH have in energy metabolism?: Increases BMR and core body temp
What are the effects of TH on heart, liver, muscle, and GI?: Heart: increase HR. Liver: decrease XOL synthesis. Muscle: increase strength and turnover. GI: increase motility
What lab values are done for thyroid stuff?: T4, free T3, T4, TSH, thyroglobulin, Antibodies to peroxidase or thyroglobulin antibodies (thyroid immune disease). In hypothyroid, T4 and T3 are low, and TSH is high. In hyperthyroid, itâ€™s opposite.
Procedures to test for thyroid conditions?: Readioactive iodine scan to detect large thyroid in graveâ€™s disease or cold nodule in cancer which can increase or decrease iodine uptake. Thyroid ultrasound or aspiration of thyroid cells can also be done.
Characterisitics of hypothyroidism?: Myxedematous (dry skin, swellings around the lips and nose, mental deterioration, and low BMR), feeling cold, weakness, hoarse, weight gain, mental slowness, constipated, decreased reflexes, missing lateral eyebrows, protruding tongue. Occurs 4:1 women to men, and increases with age. Usually caused by destruction of thyroid, but 5% due to destruction of pituitary. Can be iodine deficiency, autoimmune attack, or from surgery or radioactive iodine
How to treat hypothyroidism?: 0.1-0.15 mg T4 per day, start low for patients with CAD
Characteristics of hyperthyroidism?: Weight loss, sweating, flushing, heat intolerance, increase heart failure, muscle weakness/wasting, amenorrhea, fine skin, hypercalcemia, osteoporosis, protrusion of eyes. Usually causes by Graveâ€™s disease (antibodies that stimulate extra TH production). Toxic nodules also a common cause, or possibly thyroiditis increasing TH release. Incidence 4:1 to 8:1 in women:men
How to treat hyperthyroid?: Antiperoxidase drugs (blocks iodine binding). 1-2 yrs therapy needed in 50%, or lifelong in 50%. Has mild immunosuppresive effect. Can use radioactive iodine. Surgery rare.
Regional anatomy of the pituitary?: In the cavernous sinus, which also contains CN III, IV, V, VI. The sella turcica usually covered by dura to block CSF, but empty sella syndrome has no dura, so CSF can put pressure on pituitary, causing sxs or no sxs
Development of the pituitary? And cell types and their products?: Post from 3rd ventricle, ant. from oral invagination. Produces hormones by week 10-12. Pit1, Prop1, and Hesx1 are growth factors for differentiation of thyrotroph, somatotroph, and lactotroph cells. In the anterior pituitary, there are acidophils (thyrotrophs 3-5% for TSH, gonadotrophs 10-15% for LH/FSH, and corticotrophs 15-20% for ACTH), and Basophils (somatotophs 40-50% for GH, lactotrophs 10-15% for prolactin). Some basophils can secrete both GH and prolactin.
How is growth hormone release controlled?: GnRH stimulates secretion and somatostatin inhibits secretion. Ghrelin from stomach and brain also increase secretion. During sleep is when most is released, and levels vary throughout day. Beta blockers and L-arginine promote secretion, and insulin drops BG, which stimulates secretion of GH, glucagon, cortisol. Obesity decreases GH and may confound diagnosis of GH disorder.
What is action of GH on hypothalamus?: Inhibits GnRH release.
What is effect of GH on liver?: Stimulates to produce IGF-1, which stimulates growth plates, and inhibits release of GnRH and GH. IGF-1 levels are more steady then GH, so good indicator of GH levels.
What is the JAK-STAT pathway?: Growth factors bind to 2 different receptors and cause dimerization to induce this pathway. So, to block excess GH, there are agents to block the receptors.
OGTT and GH?: Test for Gh levels using oral glucose tolerance test, which would cause hyperglycemia and stop GH secretion, but if GH is very high, then it will stay high.
Two major effects of GH excess?: Gigantism (growth plates continue to be stimulated), and acromegaly (bones grow outward causing wide face and hands)
How is prolactin regulated?: Mainly by negative feedback from dopamine. Too much prolactin can interfere with gonadotroph release, so interfere with menstrual cycle, and cacn cause infertility. Is also causes galactorrhea. In men, it can cause galactorrhea (milk secretion), impotence, infertility. If hypersecretion is due to tumor, can impinge on optic nerves, but tumor can be treated very well by dopamine to shrink tumor and decrease secretion.
Whatâ€™s another name for ADH (secreted from the post pit)?: Vasopressin or arginine vasopressin (AVP)
Similarity between oxytocin and ADH?: Both stored and secreted by post pit. Both are 9 AA compounds. They are cyclic with internal disulfide bond. They have short half-lives, and are made by cleavage of neurophysins
How is ADH and oxytocin made from neurophysins?: ADH from neurophysin II, stimulated by nicotine. Oxytocin made from neurophysin I, stimulated by estrogen
What are V1 and V2 receptors for?: ADH receptors. V1 is coupled to PLC, causes vasoconstriction on vascular smooth muscle, liver, platelets, cerebrum, pituitary corticotrophs. V2 is coupled to adenylate cyclaseâ†’PKA and acts in renal CT and TALH to conserve water to insert AQP2 into apical tubular membrane. AQP3 and 4 are constitutively expressed on basolateral mambrane.
What controls ADH release?: Primarily Na osmolarity. But also hyperglycemia in the presence of insulin as well as ura are small stimuli for ADH release. EtOH inhibits ADH release. mOsm<280 = no ADH secreted. â‰¥295mOsm, is maximal antidiuresis, but not max ADH release. At 290mOsm, thirst kicks in too. Also, the NTS (which responds to the baroreceptors) inhibits ADH secretion. Severe volume changes override osmolarity control of ADH
How does thirst center work?: Located in anterior hypothalamus to an unknown stimulus. Osmotic threshold is beterrn 285 and 290 mOsm/kg, and is also stimulated by volume depletion.
How do histamine, nicotine, anesthetics, vincristine, cyclophosphamide, barbiturates, metoclopramide, and clofibrate affect ADH?: Stimulate ADH secretion
How do PGE2, Ang II, ACh, beta agonists affect ADH?: Stimulate ADH secretion
How do hyperkapnia and hypoxia affect ADH?: Stimulate ADH secretion
How do phenytoin, EtOH, ANP, alpha agonists, and halothane affect ADH?: Inhibit ADH secretion
How is synthetic ADH designed?: a.k.a. DDAVP. AAs 1 and 8 altered so it has longer half-life, but same potency. Given intranasally (least proteolysis), but also in oral ans SQ forms.
What is neurogenic diabetes insipidus?: Canâ€™t make ADH (>80% of ADH-secreting neurons arenâ€™t functioning). Usually still have detectable ADH, just low. Patients have to drink a lot, but DDAVP is only real therapy, and goal is slight hypotonicity (hypertonicity is more dangerous).
What is nephrogenic diabetes insipidus?: Either deficient V2 receptor (X-linked, and variably mutated) or AQP2 mutation. Patients donâ€™t respond well to DDAVP therapy
Whatâ€™s SIADH?: Due to CNS injury, release to much ADH, leading to increased ECF, decreased aldo and increased ANP and natriuresis. Therapy is lithium or certain abx to block receptor, and limit fluids
What is the water-deprivation test for ADH? Alternative tests?: Normal patients have high ADH, and itâ€™s good for differentiating between partial and severe ADH deficiency. Nephrogenic diabetes has high ADH, but unresponsive. Can also infuse hyperosmolar saline, which should have same effect. Or can give DDAVP, which should concentrate the urine, but if nephrogenic diabetes, urine wonâ€™t be more concentrated.
3 phases of human growth?: Intrauterine (1.2-1.5cm/week), childhood (6cm/year), adolescence (9-10cm/year)
Length versus height in kids?: Using length (lying down) is more reliable and accurate than height (standing up) for at least the first 3 years.
Height velocity during growth?: Rapid at birth, and slows withl age, then stays about constant until pre-adolescence.
Peak of height groth timing for boys and girls?: Surge in height velocity begins 2 years before peak velocity is reached, and girls start 2 years earlier than boys, but boys peak velocity is higher than girls. Girls stop growing at 14-15, boys at 17-18.
What growth factors promote growth in-utero?: Insulin (big babies in gestational diabetes, with risk of hypoglycemia at birth), and IGF-I and IGF-II
What growth factors promote growth during childhood?: GH (role of Pit1, Prop1 important for this), TH. If GH is deficient, growth will slow or stop at 6mo to 1 yr. If TH is deficient, there will be slow growth immediately at birth.
What growth factors are important in adolescence?: GH and TH, as well as sex hormones. Estrogen causes closure of growth plates. If estrogen receptor mutations, growth doesnâ€™t stop.
Where does GH act on the epiphyseal growth plate?: On non-dividing cells in the resting zone, which is most distal. It causes them to release IGF-I to cause local proliferation of the second zone. To assess growth plate, look at left hand (less likely to be injured), to look for fusing of the growth plate with the bone
What is first sign of puberty in males and females?: Testicular growth and breast growth. Estrogen causes increase in GH
Causes of short stature?: (1) Genetic, so normalize according to mean of parentâ€™s height (MPH), but which doesnâ€™t account for any non-genetic height deficits in parents, (2), constitutional growth delay (late bloomers), occurs in 5% of children, late puberty, will reach normal height eventually. (3) nonendocrine disorders such as turner syndrome (45X) since a gene on X chromosome affects growth. Patients continue to grow until normal time, just slower, GH therapy can add about 5 inches. Down syndrome also truncates height. (4) other reasons such as chronic liver or kidney or pulmonary disease, malnutrition, congenital heart disease (canâ€™t eat enough to keep up with heightened metabolic rate), intrauterine growth retardation, metabolic storage diseases. (5) Psychosocial dwarfism (will become normal if removed from neglected home), and (6) chondroodysplasias (defective growth plate such as fibroblast receptor mutation)
Endocrine disorders leading to stunted growth?: (1) GH or receptor deficiency due to hypothalmic defect (GnRH deficiency commonly due to child radiation treatment on brain) or pituitary defect (GnRH receptor problem or GH deficiency) GH deficiency can be due to GH gene mutation, idopathic, Pit/Prop mutation (no cells to make GH), or destructive lesion of pituitary such as tumor). (2) GH insensitivity
How does glucocortiocoid excess (Cushingâ€™s) affect growth?: Can stunt growth
How does Rickets affect growth?: Stunt due to inability to calify bones
How can sex steroid hormone deficiency affect growth?: Stunt growth due to lack of adolescence growth spurt
What endocrine disorders can cause tall stature?: GH excess (pituitary gigantism), or precocious puberty (taller at first, but growth ends early, so end up shorter than usual
What genetic disorders lead to tall stature?: Klinefelter syndrome (47 XXY males), but have gonadal failure due to fibrosis of testes. Marfan syndrome, a connective tissue and aortic arch problem (Abraham Lincoln). Homocystinuria, and Soto syndrome
Basic job of cortex and medulla of adrenals?: Cortex is ectoderm-derived, makes hormones. Medulla is neuroderm-derived, makes EPI, and hormones made from cortex enhances production of medulla products
What does the zona glomerulosa of the adrenal cortex do?: Produces mineralocorticoids like aldo
What does the zona fasciculata of the adrenal cortex do?: Makes glucocorticoids like cortisone, cortisol, corticosterone. Is very lipid-dense
What does the zona reticularis of the adrenal cortex do?: Produces sex hormones
What stimulates release of cortisol and aldo?: ACTH from pituitary (which is released under the stimulation of CRF from the hypothalamus) stimulates release of aldo from the zona glomerulosa and cortisol from the zona fasciculata. Cortisol, but not aldo or androgens, feeds back to hypothalamus and pituitary to turn off CRF and ACTH
How is blood supply in adrenals arranged?: Blood enters cortex, and goes into medulla, so hormones from cortex can have effects on release of NTs from medulla
Steps of adrenal and gonadal hormone synthesis?: Starts with XOL, acted on my CYP to make pregnenolone, and then through distinct pathways to each hormone. 21-OHase and 11-OHase are needed for both aldo and cortisol. 17-OHase is needed for androgens and cortisol (but not aldo).
Cortisone/cortisol relationship?: Cortisone is precursor to cortisol, but the enzyme that converts it comes in two isoforms. Type 1 (in the liver and adipose) converts cortisone into cortisol to promote fat storage. Type 2 (in the kidney) converts cortisol into cortisone, so it has no effect there. Cortisone has less biological activity.
What happens if 21OHase deficient?: It is the most common adrenal insufficiency. It backs up glucocorticoid and mineralocorticoid synthesis, so ACTH levels go up since there is no cortisol to inhibit it. Therefore, the sex hormones pathway gets very stimulated and in males causes early puberty but shorter stature as an adult. In females it results in ambiguous genitalia (enlarged clitoris). Females are often misdiagnosed as polysystic ovarian syndrome, and some patients have mineralocorticoid deficiency causing hypotension.
What is treatment for 21OHase deficiency?: ACTH suppression by glucocorticoid therapy (cortisone, prednisone, dexamethasone), but too much will impair growth. Can also replace mineralocortoids (fludrocortisone)
How to test for 21OHase deficiency?: Give ACTH. If already maxed out, will not increase production of corticoid precursors
What happens in 11OHase deficiency?: Less common than 21OHase deficiency. 11OHase in required in androgens and cortisol (not aldo/mineralocorticoids). So, high Aldo leads to high retention of Na and water and HCO3-, but excretion of K and H+ (so hypokalemia). and major sx is Hypertension due to 11-desoxycortisol and deoxycorticosterone accumulation (acts like aldo). The high aldo also causes reduced renin secretion, which is normally 90% of control over aldo (while ACTH has 10% control).
What are RAAS-dependent causes of mineralocorticoid excess?: Vomiting, diuretics, edema, renal ischemia, barterrâ€™s syndrome, renin-producing tumors
What are RAAS-independent causes of excess mineralocorticoids?: Aldo-producing adenoma or hyperplasia, congenital adrenal hyperplasia, 11OHase deficiency, 17OHase deficiency (but not 21OHase deficiency), licorice ingestion, glucocorticoid-suppressible hyperaldosteronism
Relationship between EPI and cortisol?: Both are released in response to â€œfight or flightâ€ or stress, and both activate catabolism.
What are the effects of glucocorticoids on the liver?: Cause glycogenolysis by activating enzymes in the pathway
What are the effects of glucocorticoids on adipose?: Lipolysis
What are the effects of glucocorticoids on muscle?: Proteinolysis to provide substrate for glucogenesis
What are the effects of glucocorticoids on glucose?: Maintains levels during fasting and increases during stress
What are the effects of glucocorticoids on pancreas?: Decrease insulin secretion
What are the effects of glucocorticoids on adrenals?: Increase epinephrine synthesis
What are the effects of glucocorticoids on kidneys?: Decrease calcium reabsorption
What are the effects of glucocorticoids on bone?: Decrease bone synthesis
What are the effects of glucocorticoids on GI?: Decrease absorption of Ca++ and Mg++ and PO4
What are the effects of glucocorticoids on skin?: Antiproliferative for fibroblasts and keritinocytes
What are the effects of glucocorticoids on heart?: Increase contractility
What are the effects of glucocorticoids on blood vessels?: Increase reactivity to pressors
What are the effects of glucocorticoids on thymus?: Involution and decrease lymphocytes
What are the effects of glucocorticoids on monocytes?: Decrease proliferation and antigen presentation, decrease IL-1, IL-6, TNF-alpha
What are the effects of glucocorticoids on granulocytes?: Demargination by decreasing adhesion molecules
What are the effects of glucocorticoids on inflammation?: Decrease leukotrienes, PGs, COX2
What are clinical characteristics of cortisol deficiency?: Addisonâ€™s disease. Think JFK. General and muscle weakness, loss of appetite and weight, increased pigmentation (due to high melatonin since ACTH is also made from POMC), hypotension, hyponatremia, hyperkalemia (all due to high ACTH and therefore aldo), anemia.
Causes of glucocorticoid deficiency?: Primary adrenal causes (high ACTH) can be autoimmune, tuberculosis, adrenal hemorrhage, tumor. Or central lesion (pituitary or above) which gives low ACTH, and no pigmentation. It can be a pituitary tumor, radiation to head, head trauma, infections, or isolated ACTH deficiency
How to test for cortisol deficiency?: Cortosyn stimulation test to stimulate cortisol reserve. In normal patients, will increase to >18mcg/dL in 30-45 minutes, but if not, then there is a defect in the pathway.
What is cortisol excess disease called? What are the forms?: Cushingâ€™s disease. It can be ACTH-dependent (70% pituitary, 5% are ectopic production by a tumor) or ACTH-independent (20% adrenal adenoma, 2% adrenal carcinoma, 2% macronodular hyperplasia, 1% surreptitious or factious glucocorticoid administration
Sxs of cushingâ€™s disease?: Extra cortisol causes weight gain, moon facies, HTN, stretch marks, glucose intolerance, proximal muscle weakness, menstrual cycle dysfunction, easy bruising, osteoporosis, hypokalemic alkalosis (rare)
What is glucocorticoid therapy used for? And common complications of their use?: Respiratory conditions, IBD, RA, chronic skin conditions, immunosuppresive. Complications include osteoporosis, HTN, glucose intolerance, skin thinning, central obesity, and usually not fully reversible upon discontinuation
Examples of glucocorticoids used therapeutically?: Prednisone, methylprednisolone, prednisolone, fludocortisone (mineralocorticoid), dexamethasone (20-25x more potent and much longer half-life (about 12-18 hours instead of 6-8 minutes)
How to screen for cushingâ€™s disease?: Overnight dexamethasone suppression test. Give at 11pm-midnight, then measure cortisol at 8am. Normal persons will decrease >20% mcg%. Can confirm with 24hr urine free cortisol
What patients should be suspected if having primary aldosteronism?: Hypertensive with easily provoked hypokalemia. Should measure renin and aldo levels, since high aldo suppresses renin, while other hypokalemic states have high renin. Can be confirmed with 24hr urine aldo production test and suppression using saline for 3 days.
What is pheochromocytoma? Rules of 10? How to screen?: Overgrowth of adrenal medulla and overproduction of epinephrine, leading to HTN, HA, sweating, palpitations. Rules of 10: 10% are extra-adrenal, 10% are bilateral, and 10% are malignant. Screen by measuring plasma metanephrine, confirm by 24hr urine epinephrine metabolite test. Some tumors have only one metabolite elevated.
What is osteogenesis imperfecta?: Malformed skeleton due to disease of collagen, so messes up bones, even though minerals are normal
Primary and secondary hormones to regulate bones and calcium?: Calcitonin, PTH, PTHrP, vit D. secondary are gonadal and adrenal steroids and TH
Functions of calcium?: Cell signaling, neural transmission, muscle contraction, blood coagulation, enzyme cofactor, membrane functions, biomineralization
Which pool of blood calcium is regulated?: The diffusible, non-protein-bound pool. About 30% is bound to albumin and globulins, and 10-15% bound to bicarb, citrate, phosphate, others. About 50% is free ionized. The salt and free forms are regulated, and is near saturated. If too high, can cause tissue calcification and kidney stones (usually CaPO4).
Bone calcium is distributed between what forms?: Inorganic (non-cellular) 69%, and organic (cellular) 22%, which is mostly in collagen (90%), but also in proteoglycans, sialoproteins, gia-containing proteins, alpha-2HS-glycoproteins, growth factors, cytokines.
Rate of bone formation versus bone resorption?: Formation rate is faster up until adulthood, but actual point when itâ€™s equal is debated, and depends on diseases and drugs. After that, bone resorption is always faster than formation. However, the two processes are linked so that if one increases, so does the other.
How fast is bone turnover?: About 250mg Ca per day, or about 10% of skeleton per year. This is why bone treatments take a long time. Trabecular bone turns over faster than compact bone
What is bone modeling?: Mechanical forces affecting bone shape. Example is jaw bone, whose shape is helped by mechanical forces. In long bones, the mechanical stress lines exist where most force is exerted
How do osteoblasts work?: Exert canaliculi when attached to communicate with other OBLs in the area. They have many receptors (PTH is most important, but also growth hormones, PGE2, TGF-beta, vit D, estrogen, and others). They are inhibited by corticosteroids. Their most importnant product is collagen, a triple helix laid down in a staggered ray, so ends never adjacent to other ends (just end-to-end). When they become buried in bone, they are osteocytes.
Characteristics of osteoclasts?: Multi-nucleated, and receptor-poor, so respond to few stimuli
What is cortical versus trabecular bone?: Cortical is solid, dense, and remodelind is slow. Trabecular is net-like, so more surface area for remodeling to occur, and provides mechanical strength.
Characteristics of bone mineralization?: Hardens collagen and other proteins, and occurs in holes between collagen fibers with hydroxyapatite. The Gla domain of collagen get carboxylated, so it can adhere to Ca on hydroxyapatite crystals. If not calcified, can get osteomalacia, so bones bend and break.
35 should be A
What is OBL OCL coupling?: OBLs and OCLs secreting signals that activate each other. So, normally OCLs secrete signals to OBLs to activate bone formation. In osteoporosis, the coupling is not transduced correctly.
What is effect of calitonin on OCLs?: Strong signal to stop bone resorption and shrivel up
Life cycle of OCLs?: Start out as bone marrow progenitors, then fuse to become multinucleate cells under the influence of PTH, IL-1, vit D. These cells attach to hydroxyapatite, polarize, and resorb bone. OCLs then go into apoptosis, which is promoted by TGF and estrogen. Estrogen treatment to inhibit bone resorption works, but has many side effects. PTH and IL-1 inhibit OCLs
How do OCLs perform resorption?: Polarization creates extensions that make spaces between OCL and bone. HCl is secreted into the spaces to degrade mineral component. Proteases are secreted (that are optimally active in acid environment) to dissolve the collagen. The only way cancer cells can degrade bone is by activating OCLs because OCLs are only cells with the proper machinery
What is difference between remodeling in cortical versus trabecular bone?: Trabecular remodeling occurs on the bone surface, but in a tunneling fashion through the cortical bone (resorption in front, formation in back)
How do OCLs and OBLs mature?: OBL precursors express RANK ligand. OCL precursors express RANK. When RANK ligand binds to RANK, OCLs fuse. A protein called osteoprogenin (OPG) binds RANK to prevent OCL maturation. Antibodies that do the same thing are in clinical trials to prevent OCL activity.
What does measuring TRAP-Tartate resistant acid phosphate tell you?: It is secreted by OCLs, so high levels show high OCL activity
What does measurement of urine collagen peptides tell you?: Collagen peptides increase due to high OCL activity
What is alk phos measured for?: Itâ€™s a product of OBLs, so can measure how well treatment is working.
Imaging and histology to measure bone growth and degradation?: Imaging not sensitive enough, and hitology is invasive to get section
Calcium absorption?: About 0.4 â€“ 1.5 g ingested per day, but 15-20% absorbed (mostly in duodenum). Low serum Ca increases PTH and vit D. But growth, pregnancy, and lactation can change absorption through hormone-independent mechanisms
Dietary sources of Ca?: Ca citrate supplements are best. Calcium in juice not very bioavailable. Phosphrous (such as in soda) binds Ca, and is not absorbed.
How is calcium absorbed in gut?: Active and passive transport
What hormones affect ca absorption?: Vit D is most important, but PTH and calcitonin affect vit D. Estrogens and GH and glucocorticoids too. Glucocorticouds inhibit absorption, promote OCL and inhibit OBL, and increase mineral excretion
How does calcium excretion work? How controlled?: 99% reabsorbed in kidney, both transcellular and paracellular, in LOH and proximal tubule. Inhibited by furosemide (Ca-wasting). Distal tubule absorbs 10% of filtered load. Stimulatesd by PTH, inhibited by calcitonin. Vit D has trivial effect. Reabsorption stimulated by thiazides (inhibit Na and Ca excretion)
Amount of Ca excretion per day?: 50-250mg/day (0.5-1% of filtered load). If hyperPTH, then decreased Ca clearance, and so high serum Ca
Characteristics of PTH molecule?: Secreted from parathyroid glands (4-8 of them), 84 AAs. First 25-30 are the active part. The remaining part may have other activity besides PTH receptors. PTH is cleaved from prepro and pro versions.
Effects of PTH on bone?: Increases OCL activity. Constant high PTH causes resorption, but intermittent causes bone formation (this is theory behind Forteo)
Effect of PTH on kidney?: Decrease Ca excretion, increase Phosphorous excretion, so hyperparathyroid causes high serum Ca, low serum P
Effect of PTH on GI?: Increase Ca and P absorption (indirectly through vit D)
Effect of PTH on blood?: Increases Ca, decreases P (due to effect on kidney
What is the PTH receptor?: A GPCR
What is CaSR?: Calcium-sensing receptor, works like PTH receptor, only with Ca as ligand. This is the main way that PTH is regulated. PTH gland has CaSR, and changes in PTH are large in comparison to small changes in Ca. CaSR is also in kidney. Vit D and Phosphorous also affect PTH
2 Roles of calcitonin? where secreted from?: Secreted from C cells in thyroid and other neurons. It has two roles. One is Ca homeostasis, the other is as an NT that has local vasodilatory effects. CT sequence is complex, and not conserved well across animal kingdom. Salmon CT is more potent than human CT.
What is effect of CT on bone?: Inhibit OCL activity
Effect of CT on kidney?: Increase Ca excretion and P excretion. The enhancing P excretion is the one way CT does the same thing as PTH. Otherwise, they are direct opposites of each other. Still, the effects of CT on the kidney are much less drastic than PTH effects
Effects of CT on the GI tract?: Mildly inhibits Ca absorption
Effects of CT on blood Ca and P?: Decrease Ca (helps bone formation and decreases P slightly
How is CT regulated?: High Ca causes high CT (which is opposite of PTH). It is also affected by age, gender, and GI state
Types of vit D?: 1,25(OH)2D. it is cholecalciferol (D3) in animals, and ergocalciferol (D2) in plants (used in most supplements because cheaper, but probably less absorbed)
How is vit D made in the skin?: Cholesterol is turned into 7-dehydrocholesterol, which is then converted by UV light into pre-vit D-3, and then vit D3. It is released into the blood, attaches to vit D binding proteins, and goes to liver (gets released from binding protein, and 25-hydoxylase makes D3 into 25-OH vit D). It is then rereleased into the blood and attaches to vit D binding proteins. Vit D then goes to kidney, gets released from binding protein and enters proximal tubule. There, 1-alpha-hydroxylase makes Vit D3 into 1,25 OH vit D (which is the biologically active form). The inactivation pathway (24-hydroxylase) is also in the kidney. The active form then leaves the kidney, binds to binding protein, and goes to target cells (enters nucleus and heterodimerizes with RXR to transcribe genes).
Causes of vit D deficiency?: No sun, liver disease, kidney disease. The last one is most important because supplements donâ€™t help (canâ€™t convert), so must treat with active form to prevent bone disease.
How to measure vit D levels?: Measure 25-OH vit D because it is the most stable
What are the membrane effects of vit D?: Cause Ca flux, and other effects through a peptide preceptor-like molecule on surface (this is in addition to nuclear effects)
What stimulates 1-alpha-hydroxylase production?: Low Ca is MAIN stimulus. Also, PTH, low P, estrogen/androgens, prolactin, placental lactogen, GH, CT. A multiplier effect occurs because Ca directly stimulates production, but also PTH, which enhances it tooNote: 1-alpha hydoxylase is the enzyme that makes 1,25 OH2 vit D
What inhibits 1-alpha-hydroxylase production?: High Ca, high P, and 1,25 (OH) vit D (direct negative feedback)
Effect of Vit D on bone?: Promotes mineralization of osteoid, but only by increasing Ca levels, and increases resorption at toxic doses.
Effect of vit D on kidneys?: Minimal effect to decrease Ca excretion and P excretion
Effect of vit D on GI?: The MAIN effect of vit D. increase Ca absorption by many mechanisms, but mostly by increasing synthesis of Ca binding proteins. It also increases P absorption by similar mechanism.
Effect of Vit D on blood Ca and P?: Increase both (by effects on Gi absorption mainly
Effect of vit D on 24-hydroxylase production?: Increase catabolism of 24-hydroxylase.
Effect of vit D on OBLs?: Increases function and increases collagen
Effect of vit D in macrophages and OCLs?: Inhibits differentiation of them
Effect of vit D on PTH?: Decreases PTH
Effect of vit D on immune function?: Increase innate immunity of the skin
Effects of vit D on cancer?: Anti-cancer

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