Endocrinology
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Endocrinology - First Day 04, 1996 Wednesday, September Polyuria is a symptom that the patient may not be aware of, anemia is another example - the above situations are of symptomatic patients that are unaware of it - actual dx may be very difficult - What is the function of the thyroid - it is to make thyroid hormone - 90% of patients with hyperthyroidism have Grave’s Disease - The most common causes of endocrine disorders - bla bla bla - very few diseases do we know the cause of - very few - EXAMS - last class did very poorly - Unit exams are over the reading assignments - first exam is 2 weeks from today Wednesday, September 11, 1996 - talked most of the first hour about comp board gripes - look up the purpose of thyroid hormones - the effector of the endocrine system are the hormones - effector = hormone - diabetes - is due to improper utilization, most or many of the diabetics have normal to elevated insulin levels - the classic model of the primary signal of a hormone don’t fit or explain a # of endocrine diseases - signs and symptoms - there is a problem with ulitilizing symptoms - example not all people have a butterfly rash with Lupis Cushings - syndrome and disease - these are very different disorders Cushings Disease - is a pituitary tumor, theses people have hyperpigmentation - is caused by cortisol both individuals have elevated cortisol - which is responsible for most of the symptoms except hyperpigmentation, the ACTH drives the adrenal gland to produce cortisol, they may have an ectopic tumor or they may have a hyperplastic overadrenal production Cushings Syndrome - is elevated cortisol, can be caused by an atopic ACTH tumor, most common is the exogenous use of corticosteroids - a symptom is nothing more than the result of something - pituitary hormone produces ACTH ----> drives the adrenal gland to produce cortisol - POMC - this large precursor molecule contains a # of large peptides - one being beta-endorphin, after this molecule is produced it undergoes post translational cleavage, this causes hyperpigmentation by increasing melanocyte # - increasing pigment - for every sign or symptom there is a reason or mechanism, a person with hyperpigmentation - you could explain why this persons elbows are so brown General Concepts of endocrine effectors: - In general there are two aspects to a hormone: 1 hormone ------> # of activities 1 activity --------> # of hormones - males in general have a higher hemoglobin level - testosterone has an action to stimulate production of erthropoietin - testosterone does what it does the same way every time, but it has a number of acitivities - carbon tetrachloride - kills the liver, brain, depends on the effector tissue, it did the same thing to both but the impact is different - testosterone acts on the same cell everyway - it is the cell it acts on - one biologic activity is under the control of many hormones - example - the control of glucose - a # of things are reponsible for this - thyroxine stimulates the appetite - we have more mechanisms to protect against hypoglycemia, than hyperglycemia - peptide hormones - are those hormones just made up of peptides or proteins - steroid hormones - steroid nucleus - can you compare and contrast a peptide hormone, mechanistically, chemically and functionally - how are they the same: all hormones are present in small amounts, all hormones are controlled by targeting, they are very premisquous - small is a relative term - weight 100 pounds Hgb 15 g/100m; 100 mg/dl; T4 ug/100 liters; HCG - turns the dipstick blue ng/100 ml, how much endorphins do you have 10 to the - 15 femto per gram - Monday, September 16, 1996 - afternoon hour - Determination of baseline values - BASELINES - lets use bilurubin as an example 0.2 - 1.2, the first time you see the patient there bilirubin level is 1.2 mg/dl which is with in the normal range - RBC degradation of hemoglobin produces bilirubin - if production exceeds elimination then the value goes up, we measure the net effect - huge excess capacity overwhelms the capacity of the normal liver - babies destroy blood cells quickly because they have too many when they begin to breath on there on, this exceeds the capability of their small livers and they become jaundiced, the light UV - bilirubin absorbs it and causes in to degrade - interpret a value of 1.2 now and a bilirubin value of .2 a year ago - this represents a 6 fold increase most peoples bilirubin is very stable - maybe they started to exercise a great deal, what ever it is the cause needs to be established - baseline value can help you fine tune normal - another reason to order a lab test is the staging or grading a disease - you may order a blood test to determine how anemic - some diseases have histologic criteria for acute and chronic distinctions - sometimes we use different antibody types to stage a disease - prodromal - acute - continuing on to convalesence (on the mend) or chronic 9. The last reason to order a lab test is Defense - Defensive Chiropractic - to protect your rear end -- malpractice, negligence, and patient responsibility Wednesday, September 18, 1996 Endo Exam Reading for first exam Chapter 199 page 1176-1185 Hormone Activity Hormone Concentration - the more hormone that you have the more biological activity we may expect from this hormone Innate Mechanism of endocrine activity - there is a homeostatic relationship btw the body and the hormone levels - Receptors in relation to hormone concentration, w/o receptor there is no hormone activity - We call a substance that interacts with a receptor a ligand - the specificity is high - The receptor is within the cell membrane Thyroid Gland produces T4 - the T4 levels elevate slightly but the heart rate doesn’t go up - when the thyroid begins to produce too much T4 we need to shut down the concentration - it does this by inhibiting TSH - which doesn’t stimulate the thyroid - the thyroid hormone levels drop - it shuts off the normal production but not the tumorous production hyperthyroidism - hypothetical senario - when the receptors on a particular organ all become bound with hormone - a process called down regulation occcurs in which the number of receptor sites on the organ is diminished, this is a rapid process - the change in receptor number occurs in nanoseconds, there is both a quanitative - when excess hormone there is diminished numbers, qualitiative- the affinity changes to the hormone - how can a person have elevated levels of thyroid hormone and not suffer any of the symptoms - the explanation is the above - periods when there are diminished hormone levels there also appears to be no effect - the number of receptors is up regulated - so that the amount of hormone present is more effectively used - for most hormones only 10% bonds to the receptor, we can fully saturate the system with 10% - A lot of people with diabetes don’t have anything wrong with the pancreas, but may have a problem with the receptor - typically as the hormnone concentration goes up the receptor number goes down - type II diabetes is usually a receptor disease - This is a perfect example of why signs and symptoms of disease are a poor indicator of disease - Peptide Hormone 1. Cell Surface Receptor 2. “Second Messanger” 3. Biological Amplification - the first event that this receptor does is to stimulate or activate the second messenger - a casscade of events - one being the generation of many molecules of Cyclic -AMP - Response proteins from production can turn the system off - a form of negative feedback system - Coffee is a stimulant with the active ingredient being caffeine - which inhibits phosphodiesterase (inhibitor) so stimulation - caffeine inhibits phosphodiesterase, so increase in cAMP, then body produces more phos., everything is fine until you stop drinking caffeine - no energy, constipated - because now none of the phosphodiesterase is inhibited and it is degrading all of your cAMP, in 3 or 4 days phospho levels return to normal - when you inhibit the net effect is stimulation - What are some other second messengers - calcium Agonist vs Antagonist - Agonist - materal, subs., molecule that activates, stimulates (mimincs real ligand) receptor - Antoonist - blocks receptor from binding normal ligand eg. graves disease due to something binding to the TSH receptor - an auto-antibody - these act like TSH and are more potent - one molecule can cause more than TSH - Febrile - changes the structure of a lot of proteins - which alterate function and hence you are toast - Steroid hormone receptors tend to be intracellular, these hormones tend to modulate sythesis by turning on and off genes - steroid hormone activates receptor and brings about a conformational change for that hormone, this dictates where it is and what gene is going to turn on - very specific - one protein gene - message into mRNA and then translate into protein - the steroid hormone goes to a particular gene - difficult to mimic steroid hormone Wednesday, September 25, 1996 - The next quix will cover “The Anterior Pituitary” -Biorhythms - rthythms in the release of hormones are common in almost all endocrine systems and can occur over minutes to hours (testosterone), daily (cortisol), weeks (estrogen), or months (seasonal variations in thyroid hormones) - Biorthyms 1. Hormonal Rthymicity Do To: 1. Neurogenic factors-sleep associated (cortisol) 2. environmental factors 3. time delay factors - feedback delay Hormonal Transport 1. Water soluble (peptide) hormones require no transport proteins 2. Water insoluble (steroid) hormones do require transport proteins 1. Transport proteins are either general or specific 1. General - albumin or prealbumin 2. Specific - thyroixine binding globulin or cortisol binding globulin 1. The specific transport proteins are not exclusive 2. A specific hormone can be transported by a general transport protein - What is prealbumin ? Prealbumin has all the functions of albumin but it is a molecularly distinct species. - Electrophoresis - is similar to chromotography - separation based on sixe, electro - separates on the basis of size and charge - In reference to Multiple Myeloma - the reversal of the A/G ratio is in reference to the #s and not the migration on cellular acetate - Bence Jones protein - is heat stable - MM - most definitive is to do an electo analysis of the serum of the urine - you will see a huge concentration of gamma globulin protein on the strip - can be done with the densitometer, the densitometer spike in the gamma region is called the M-spike - which stands for myeloma - In myelom - the tissue that has gone wrong is the plasma cell - called a plasma cell dyscrasia, also called Light Chain Disease - Free or unbound, and bound - free is the only one that has any activity - this is the only one that can interact with a receptor - T4 + TBG ----> T4TBG - Endocrine Pathology 1. Abstract or subhromonal secretion due to: 1. Abnormal or absent endocrine gland 2. Abnormal development of the gland 3. normal gland is destroyed by secondary process 4. idiopathic 2. Hormone excess due to: 1. Tumors - adrenal cortex (Cushing’s Disease) 2. hyperplasia - parathyroid (hyperparathyroidism) 3. autoimmune - thyroid (Grave’s Disease) 4. viral - thyroid (thyroiditis) 3. Production of abnormal hormones 1. Gene mutations of hormone structure/ function 2. incomplere processing of hormone precursors EG ----> H precursor - post-translational modification - Vitamin D - 1,25 (OH)2 vitamin D - requires liver and the kidney enzymes - Kidney - contains - alpha - hydroxylase, if the person has kidney disease - we find drop offs in this enzyme and falling vit D levels, the person goes up with renal osteodystrophy - bone disease secondary to kidney disease 4. Resistance to hormone action: 1. Target tissue response defect 2. qualitative receptor defect 3. Quanitative receptor defect 5. Abnormal hormone transport 1. Deficient transport protein 2. Very rare (if ever) cause of hypo or hyperfunction 3. “artifical” circumstances = cortisol and cirrhosis Wednesday, October 02, 1996 - The pituitary and dysfunctions of it. - Hypothalamus is the master gland of the body. The products of the pit. control alot of other glands. We were not initially able to measure the products of the hypothalamus, so people use to think it was the pituitary. - Target glands of the pit. hormones: TSH - the clinical result is hypothyroidism, pat. presents clinically as hypo - this is a secondary form, the primary defect is seconday to a pit dysfunction - Review of the pit hormones: 1. ACTH (corticotropin) 2. Growth hormone 3. Prolactin 4. Thyrotropin (TSH) 5 Follicle Stimulating hormone (FSH) 6. Lutenizing Hormone - ACTH - produced by the pit., cheif target for is the adrenal glands, binds to cell surfaces and uses cAMP - so we know it is a classic peptide hormone, stimulates lipolysis in fat cells, amino acid and glucose uptake in muscle, stimulates secretion of growth hormone, stimulates insulin secretion, these actions are not significant at normal levles - Levels of ACTH are highest in the morning and lowest in the PM - understand the role of ACTH in hyperthyroidism and hypothyroidism - nocturnal hypogylcemia - wake up with head aches, the insulin action isn’t the mechanism, excess ACTH increase uptake of glucose and is compounded by increase glucose utilization - example of extra endocrine activity - Circadian rthythms - common in daily cycles of ACTH production, ACTH levels seem to be highest in the morning and lowest in the evening - abnormal means different from everyone else, but this does not mean that it is clinically significant - ACTH is stimulated by CRF and inhibited by cortisol Hypothalamus -----> Pit (causes release of ACTH) ------> Adrenal gland to release cortisol -----> which turns off the pit and the pit turns off the hypothalamus - increased cortisol - the ACTH level will be low - we will call this an appropriate depression - Growth hormone - short kid with normal growth hormone - why is the kid short - GH Effect - activity is determined by two things - 1. concentration and 2. activity - GH expression of activity is controlled by a variety of extraendocrine activities - GH secretion is augmented by: Stress (traumatic, surgical, infection), alpha adrenergic agonists, beta adrenergic antagonists, hyperglycemia (fasting), falling fatty acid levels, uremia, hepatic cirrhosis, estrogens, glucagon, vasopressin GH - is inhibited by: emotional deprivation, alpha adrengeric antagonist, beta adrenergic agonist, hyperglycemia, increasing fatty acid levels, obesity, somatotropin, high doses of cortisol - We don’t see larger than normal children with hyperglycemia because - increased glucose --- produces decreased GH effect - decreased glucose --- increased GH effect - best way to test for coronary heart disease - is a stress test, another way is through glycolytic stresses - in the normal individual if we induce hyperglycemia there growth levels should drop - thyrotropin - synthesis in the thryrotophic celss, found in the central wedge of the gland and make-up about 5-15% of the cells - TSH regulation - TSH synthesis is stimulated by thyrotropin-releasing dkkdkdkdk - T4 definitely turns off TSH, prob T3 and T4 does also ????? - Prolactin - involved in milk production, stimulation of the ductal epithelium of the mammary tissue - at the time of delivery estrogen levels drop off and we thereby remove the inhibition of prolactin by estrogen - High levels of estrogen during pregnancy inhibits prolactin - Clinical significance of GH def. in an adult - not clear what the clinical consequences are in an adult - There is a normal age related decline in growth hormone. - Lutenizing Hormone - acts on Lidig cells to produce testosterone, this hormone is controlled by GRH kdkdkdk - Look up FSH - chart in the action notes and book - Clinial conditions and abnormalities with these hormones: hypopituitarism - broad category that encompasses a lot of clinical pictures Hypopituitarism unrecognized -------------------------------------------> Death asymptomatic - hyperpituitarism can’t ignore this condition - causes death - Pan Hypopitiotarism - all 5 - 1. The hormones involved 1, or 2 or 3 or 4 A - decreased TSH B - decreased TSH and decreased ACTH C - decreased TSH and decreased LH and decreased ACTH - the clinical symptoms are related the particular hormone that is deficient 2. The extent of hormone deficiency - A, B, C - Thyroid disease - the best way to evaluate is the Thyroid function panel 3. Duration and the rapidity of the onset 4. Age - a 50% reduction in growth hormone is more recognizable in a 12 year old than a 50 year old 5. Gender Endocrinology reading for the quiz on next Wednesday - 1206-1221 Wednesday, October 09, 1996 He will be giving the overheads to Forrest for us to copy. - 3 Patients with clinically apparent hypothyroidism - which patient has primary, secondary and tertiary - The question would be: TRH, TSH, T4 - elevated, normal or depressed - With primary - TRH - would be increased or decreased, this is due to competing signals; TSH - up; T4 down - Seondary - T4 down; TSH - down - because this is primary secondary hypothyroidism, TRH - up, up - Tertiary - TRH - down, TSH - down, or up or down; T4 down - The most common cause of primary - is autoimmune destruction of the thyroid gland, pituitary - the most common is a tumor, Hypothalamic - either a tumor or a neuroendocrine problem - A Goiter is a hyperplastic condition due to iodine deficiency. - We almost always do simulataneous check several different hormones when checking the thyroid gland. -The booster action of the pituitary may be able to bolster a failing thyroid by increasing FSH Wednesday, October 23, 1996 - remembering that hypopituitarism - there isn’t such a distinct identifiable clinical picture, extend of hormone defic, what they are and how long they have been deficient - Hyperpituitarism - is more distinct because, most often hyper involves the over production of a sinlge hormone, the clinical result is more confined and characteristic - can be primary or secondary - can reactive or conpensatory - the far most common cause of hyper is a tumor - functional - there are lots of ways to classify tumors - one way is functional and nonfunctional - functional tumore tend to be malignant but not always - malignant - referrs to its ability to metastasize - a tumor can be histologically benign, but are malignant due to there location - like a glioma - physiologically malignant or functional tumors in the endocrine system are common - the problem with this - endocrine system is under the control of a number of other features - turn on and turn off feedback inhibition - if the source of the TSH is from a functional tumor - but there is no feedback inhibition because there are no feedback physiological controls - nondifferentiated - means it becomes more primitive - they look like a very undifferentiated cell - doesn’t have contact inhibition - many of these cells are immortal - they do not respond to normal physiological control mechanism - refractory to feedback inhibition - hyperpit - brand name diseases - Amennorrhea-Glactorrhea Syndrome - Hyperprolactinemia - is the most common form of pituitary hyperfunction and is most often due to a functional ademona of the pituitary. These functional tumors are present in as many as 25% of infertile women - Cininal features - in females - oligomenoorrhea or amenorrhea, lactation, mild hirtutism, infertility - In males - impotence, decreased ligibdo, lactation - Diagnosis of Hyperprolactinemia 1. Clinical features 2. Elecated Prolactin levels 15 to 20 ng/ml to 10,000 ng/ml 3. Prolactin levels less than 200 ng/ml are almost never of tumor origin - normal levels of prolactin is 5-10 in females males may almost be zero - the magnitude of the elevation is quite definative Primary ACTH Hypersecretion (Cushing’s Disease) - in about 90% of cases the cause of ACTH hypersecretion is the result of a functional basophilic adenoma or bilateral hyperplasia (cortical) of the pituitary - The vlincial features are essentially the same as those produced by adrenocortical ademoans and affect females in the 30-60 yeat old age group most often Cushing’s Disease and Cushing’s Syndrome - Cushing’s disease id a primary pituitary disorder (functional adenoma) wiht an oberproduction of ACTH by causing secondary hypercorisolism - 2, Syn - hyeprcortisolism due to exogenous cortisol administration or overproduction by adrenal , pgs 8-9 sn and sx Cushing’s - central obesity, hypertension, amenorrhea, hirtuism, muscular atrophy, weight gain?. osteoporosis and compression fractures, increased capillary fragility, impaired wound healin, hyperglycemia, increased skin pigmentation - elbows, knees, knuckles Diagnosis of Cushing’s Disease - typical clinical findings, elevated plasma cortisol (50%), elevated urinary free-cortisol (85-90%), plasma ACTH elevated or inappropraite for cortisol level, differential adrenal tumor, ectopic ACTH production - Free cortisol - means that it is unbound - major cortisol binding globulin - is cortisol binding globulin, it is bound to albumin or prealbumin - these act as the transport for the hormones that are not soluble - receptors only recognize the unbound form - the definitive or sensitve - would be the free urinary cortisol levels - loss of the normal diurnal variation and somewhat diffinitive for both ACTH and Cortisol - ACTH - disease - have elevated ACTH levles, Syndrome - decreased levels - Cortisol - disease increased, syndrome - increased - Cushing’s syndorme - most common cause of the Cushinoid features are exogenous administration of cortiosteriods, or bilateral adrenal hyperplasia, these symptoms are reversible once they get off steroids - prime example of ACTH from an ectopic source - is an oat cell carcinoma of the lung, have symptoms of Cushing’s - Dethamexasone suppression - if ectopic it will have no effect, then we know that this is from an exogenous source - Acromegally versus Giantism - If prior to epiphyseal joint closure - they are normal but just big - Acromegally - they grow larger but not bigger, do not have linear bone growth - Acromegally typical clincal finding - typically change in shoe with - they get too narrow, change in ring size, there is a variety of visceral disorders - Cushing’s - cortisol excess - symptoms appear in 10-15 days - Growth hormone excess may take 5-10-15 years - Acromegaly - soft tissue swelling, hypertrophy of the extremitites and face, skin becomes thickened, skin folds increase in prominence, increased hair growth and increase pigmentation, visercomegalyliver, spleen, kidney, tongue, salivary glands, thyroid enlargement with nodules, tufting of the terminal phalanges, osteophyte proliferation, hypertorphic athropathy - crippling arthritis, peripheral nerve damage due to entrapment by tissue overgrowth - Diagnosis of GH Hypersecretion - clincial signs and symptoms, elevated GH levels, GH levels that are not suppressed by Glucose - we find more people with hypopituitarism - than we use to prob, because we are better at screening for it Quiz next Wednesday - is over ADH, Vassopressin ADH purpose: to prevent diuresis clincal consequences is polyuria - an increased 24 hour urine output most of the time there is also increased frequency Clincal condition from an ADH defic - Diabetes Insipidus lack of ADH AKA diabetes insipidus Frank ADH def - Pituitary Diabetes Insipidus failure of ADH to affect water conservation there are people with DI - have elevated ADH they have a failure of ADH to affect water conservation, these people are said to have Nephrogenic Diabetes Insipidus Nephrogenic Diabetes Insipidus They have a kidney problem - an ADH receptor defic - either aquired or congenital hyperosmolality one of the cosequences of polyuria is that the increased h2o loss and elevation of NA this is a condition we call hyperosmolality When we study osmosis - we are really considered with the intracelluar concentration of Na, K ADH acts and responds to the solute concentraion of the extracelluar fluid compartment which is controlled by the intracellar concentraion What comes out of this cell it shrinks Hypertonic encephalopathy children and puppies are susectible to massive diureses they dehydrate infants can diurese and be dead in 24 hours due to dehydration if they live they will have perm dain bramage (just kidding) they can get very sick how can you tell if someone is dehydrated one way to do this is urine specific gravity - urine specific gravity - 1.005 and water 1.000 no units because specific gravity is a relative measure with water as the standard - this is not a good measure - a mole of sodium chloride - we use serum osmolality and it is a commonly performed test - look up the differnce btw osmolality and normality - check serum urine plasma - as the osmolality decreases we develop hypertonic encephalopathy - Differntial diagnosis - primary polydysia - they drink alot and develop polyuria - must determine what cause what Wednesday, October 30, 1996 - Thyroid Reading Hypo and Hyper - Rheumatoid Arthrititis, Lupis, and Rheumatic Heart Disease - are all more frequent in women - The most common cause have an autoimmune pathogenesis - There are prob more ways to exam the thyroid gland than any other single tissue Thryroid Gland Elevation - Anatomical - Metabolic Indices of Thyroid Status - Tests of Thryoid Regulation - Tests of thyroid function - The thyroid gland is prob the only endocrine gland palpateabe - susectible to chemical and toxic injury - subject to intracit control mechanism - most common anatomical evaluation of the thyroid gland is - they all fail to give a clear indication of thyroid function - What is the function of the thyroid gland - produce hormones - T3 and T4 - How do you access the thryoid gland - levels of thryoid hormone - prior to the 60’s they were unable to detect these levels - we used metabolic indices of these - these thyroid hormones control cellular metabolism - metabolism has nothing to do with nutrition - one of the common lab assessment in the 60’s was the basal metabolic rate - If hypothryoid - they had a bad metabolism or too thin an under active metabolism - is this a valid test - this is not a good test for hormonal level - it does not measure hormonal level, - body temperature is an index of body metabolism - cellular energy utlilization of cellular efficiency - how we measure basal metabolic rates and we put a rubber hose into mouth and this tube was connected to a set of bellows - bags, the patient would lie there and breath - the bellow was connected to a pin recorder with paper, as paper was moving a graph would form - this graph was labels and after 5 minutes a line was formed representing the basal metabolic rate - what did we actually measure - respiration rate, complex and expensive, better way to measure respiration rate is just to count - a better measure of hypo and hyper thryoidism is the heart rate - either elevated or depressed - The metabolic indices - are a first or second generation test - they do not evaluate what you are interested in - Test of thryoid regulation - it is regulated by a number of other physiological functions - when identify a defic of thryoid hormone - this doens’t mean there is a thryoid disease - There are lots of tests done to evaluate the thyroid gland - How about using free serum T4 to evaluate thyroid function - [T4] = [T4] + [T4 TBC] - this form is inert because the T4 receptors which are internal to the cell only recognize the free form - for T4 to be expressed it requires the acitvity of a receptor - Suppose 1000 molecules of thyroid hormone roughly 999 are biologically inert and only 1 hormone has any biological activity - When we talking about nanograms of hormone activity - the single most important thing is the concentration of the unbound or the free - There is a test called the T7 test - T4 = 10 T3 5 T7 0.2 - lots of doctors think that this is a mistake, there is no such thing as T7, the T7 value is calculated estimation of free T4, these were used that the free and the unbound is the real measure, today we don’t have to guess or estimate we simply measure - T7 is a calcualted estimate of the free T4, now we just measure it directly - T7 is a good measure - Sinlge best test of thyroid function is the free T4 - T4 and or T3 - do you have to measure both or just one - when do you need to measure both - Why would we measure both - to be more specific - interested in knowing when clinical suspicion might indicate a thryoid problem - What are the clinical signs and symptoms - how do we predict - What would this cause or bring about in the patient - What is the basic difference Thyroid gland = 90% T4 and or T3 10% - Concentration - [100] [20] - of the concentration floating around these 20 molecules 16 or 80% of the T3 concentration comes from the T4 molecule - the rate controling determinate of the T3 concentration - rather the conversion of T4 to T3, that is why the T4 concentratio is the single most important for being informative - most of the T3 concentration in normal individuals is the result of T3 concentration - normally there is 4 times as much T4 as T3 - the acitivity of T3 is about 4 times greater than T4 - that refers to the potency - the 1/2 life of T4 is 4-6 times that of T3 - For any substance we are using hormones - the ultimate effect of a hormone on tissue is determined by these 3 features - the only thing we ever think about is how much, what is the effective minimal dose - Do they have too much or too little - We understand the mechanism that controls the dose - we can maintain an effect - if we decrease the concentration of the hormone a 50% reduction - we can maintain this effect by a 50% increase in the half life - this is the times available inviv to do what ever it does - this is also emcompasses is it in the right form - Calcium has to be in an ionic state - 50% of the calcium is bound - one component is the half life there are a variety - some other conditions alter the half life - The other activity is the potency - there a variety of condition with physiologic alterations - concentration and activity - when we start to change these we begin to get different responses at the targer organs - for next Wednesday - hypo and hyper and be ready to havve an exam the first period the second week Wednesday, November 06, 1996 - Actions of the thyroid hormones - The thyroid hormones affect many physiological processes and are necessary for the optimal acticiity of numerous other hormones. Thus, abnormalities of thyroid function can lead to gross alteration of nomrla physiology. - The thyroid hormones have been shown to: - block feedvack ingibition of pit TSH secretion - inhance the lopolytic respocse of adipose tussue - increase the number of mitochondria within target vells - increase the rate of intestinal glucose absorption - Hypothalamic Piturtary Tyroid Axis - TRH - secreted kkkkkk - Thyroid binding Globulins - is the major binding carrier of the thyroid hormones, mechanisms that control it are distinct from those that control thyroid gland production - looking at pregn or the pill elevate TBG - Albumin and prealbumin - Huge percentage of thyroid hormone that is biologically inert - greater than 99 % of the thryroid hormone is bound and has no activity - Remembering then that when we cli Wednesday, November 13, 1996 - Grave’s Disease - tachycardia or prob better to say an elevated pulse is classic of Grave’s disease, widened pulse pressure in this disease - almost all the symptoms are due to increased metabolic rate - Grave’s Opthalmopathy - this finding in more than 50% of patients with Grave’s disease and its almost never present with other forms of hypothyroidism - Pretibial Myxedema - Dx - elevated T4 normal T3 - The most definitive would decreased TSH - T4 production - shuts down the production of TSH - Thyroid storm - 20-40% mortality rate, usually caused from superimposed stress - could be pregnancy Hypothyroidism - Has many more causes or types - 90% of the time failure of the thyroid to produce hormone due to Hashimoto’s Disease - Clinical Manifestations are due to both - 1. Decreased Horomone levels 2. Myxedema - accumulation, these occur in the prolonged cases of hypothyroidism - 3-6 years, this material begins to accumulate - it appears to be reversal if a euthyroid state can be obtained - occult hypothyroidism - symptoms are so nonspecific it may be considered accidently by normal symptoms of aging - Weight gain, bradycardia, intolerance to cold, hearing loss, memory loss, vocal changes - the voice gets huskier or deeper - Dx - decreased T4, increased TSH, increased cholesterol, mild anemia - other classical findings include - an increased cardiac shadow - due to myxedemous infiltration, EKG in addition to bradycardia, a low voltage QRS complex - The vocal cords are very sensitive due to the accumulation of this material in the vocal cords - other aspects - myxedema colon - or megacolon - can go from mild to frank obstruction - can lead to loss of peristalsis - In both hypo and hyper - pulse pressure is the difference btw the systolic and the diastolic - hyper - increased systolic and decreased diastolic - hypo - increased diastolic, and decreased diastolic - Hyperthyroidism is straight forward - Hypothyroidism - is not so straight forward, lots of people have this and don’t know it - Onset of symptoms - Grave’s Disease - in 6 weeks symptoms, in Hypo - 6 years and symptoms Wednesday, November 20, 1996 No class next week - independent reading assignment on the adrenal cortex - this is the Wednesday after Thanksgiving - Quiz for Diabetes is from the lecture only - this will be the final Showed an overhead of Thyroid condition often hidden - This article was a good example of the nondescript nature of the disorder - JAMA - found that it is cost effective to do thyroid screenings on women over 40 - People don’t feel well and gets very tired - With respect to incidences of endocrine diseases - another is diseases of the thyroid - diabetes - research into diabetes - falls under many different areas - Diabetes Mellitus is a truely heterogenious disorder primary disoreder of carbohydrate metabolism with multiple etiologic factors that generally involve absolute or relative insulin defic. or insulin resistance - In general diabetics have an insulin problem - absolute or relative insulin defic - relative - not enough insulin activity - The cause of diabetes Mellitus in individuals is unknown - Epidemiology - the incidence is 600,000 cases a year - The prevalence is 2.5-3.5 million people he was guessing - The incidence is the number of cases that occur in a population in a year - the prevalence is the number of people with in a years time that have this disorder - With a cold the incidence can be higher than the prevalence - With diabetes it is difficult to determine how many people have diabetes - Part of the confusion of diabetes is who has it and who does not - What clinical findings must be present before you tell the patient they have Diabetes - In the past there have been a number of criteria in which people were diagnosed - Typically use a glucose tolerance test to make this determination - there are problems with the test there are 2 different systems - OGTT - is a fasting test - the rational for this is that it is a challenge - to determine how it metabolizes a concentration of glucose - prior tho that the glucose level is measured - 30 minutes, 1 hr, 2 hr, 3 hr - they are then plotted against the time versus glucose - this is the glucose tolerance curve - Method A - might get - Method B - might get negative - using the same numbers - difficult for everyone to agree who has diabetes - Method A or B and a third method - the good news is we don’t use any of these anymore - we now use very straight forward valid criteria - to establish who does and does not have diabetes - almost no one who has diabetes - almost no false positives or negatives now - Dx criteria - there are three criteria - only takes one to make the diagnosis: 1. Gross and equivocal glucose elevation - if we use a normal value among people who don’t normally have diabetes - we find almost all diabetics having a fasting glucose less than 115, and nonfasting less than 200 - If have a value of 600 - 2 ways this can occur - Diabetes for one, and the other way is an intravenous infusion - glucose is 600 - the first thing we are going to do is to retest or confirm this - have the patient come back fasting and perform a fasting glucose - if that fasting glucose is greater than 140 that person is a diabetic - How can we be certain with only one number - 95% of people 80-115, 98% 70-125, and 99.9 60-120; there is almost no overlap in these numbers and this is how we can be certain 2. Fasting > 140 mg/dl, on more than one occasion - make sure this is not a mistake Fasting glucose of 130 and a random sampling 275 3. OGTT - 30 min, 1 0r 2 hour > 200 - this is the patient I would perform the glucose tolerance test on - With a value of 350 no need to do a glucose tolerance test because the disorder is clear - Patient comes in complaining of fallen off bike and they have a compound open fracture - would you take an X-ray to make this clincal descision - why take the X-ray if you can see that it is broken - In our career we will prob never need to take an a glucose tolerance test - When you do this 20% of the people throw up - like take a 12 oz can of pepsi - and pour 1/2 cup of sugar in it and drink it - Second Hour - 80-115 Normal - 75 ---> hypo < 50 ---> hypo (clinical consequences) - Patient - Trembly, Anxious, Shakey, Sweaty, Nervous, Heart Palpitations - Many times food ingestion - the doctors in the 80’s said just eating something - when in fact eating caused these problems - hypertension - have to know blood pressure to correctly identify having anemia - anemia - Hct or RBC or Hgb - moron - IQ - all of the above conditions have a criteria - Hypoglycemia - need to know blood glucose - In the last 4 or 5 years we have been taught that an oral glucose tolerance test is worse than worthless - in hypoglycemia - in that it gives you bad information - What is required to appropriately tell someone that they are suffering from hypoglycemia - must demonstrate Whipples Triad - 1.S/S of decreased glucose 2. decreased glucose 3. Loss of s/s, and normalization of the glucose then this person has hypoglycemia - Do the test and you find that it is 45 milligrams give them a banana and the blood glucose goes up to 85 - this was the easy part - the tough part is to find out why it is occuring - Next week we will discuss a variety of symptoms - The physiological threshold for glucose is 15-25 - the person can go into a coma and die due to CNS depression - due to lack of glucose - physical fitness - is the ability to run a 26 miles marothon a good way to define physical fitness - Could you in 3 months get in good enough shape to be able to do this - the same phenomenon for glucose tolerance test - you have to prepare the patient particularly for diabetics - 3 days before - Random 215 and Fasting 130 - This is when you need to use a glucose tolerance test - 2000 calories, 200 grams of carbohydrate, patient should have a normal activity - they should not be chair bound but mobile, the forth one is that they should not be sick, they should be under 60 - You may not have typical ambulatory patients - meaning a seditary life style may not have a noraml glucose tolerance test - Next time we meet after our exam Wednesday, December 04, 1996 Oral glucose tolerance test - When an oral glucoese tolerance test is employed, it must be rigoursly controlled - Standard oral glucose dose (75 to 100 gm) - appropriate antecedent dkdkdk - Type I Insulin dependent, Juvenile onset, ketosis prone, brittle diabetes - These pateints have little or no endogenous insulin secretory capacity and develop extreme hyperglycemia, ketosis, and associated symptomatology, unless treated with exogenous insulin. This type, usually, but not always develops prior to early childhood. - These people are very prone to ketoacidosis - if we look at all diabetics - about 10% of diabetes is type I, about 90% is type II - Islet Cell transplants - have been going on for about 5 years, not talked about yet because not univeral and the successful ones have only been off insulin for around a year. - What is the etiology of type I - with human genome project - they find particlualar genes for diseases, one of the first genes they found was for the disease diabetes - Problem with calling it a genetic disease - despite the fact that diabetes aggregates in families and has a strong familial component, a precise genetic contribution to Diabetes has been difficult to find. - 1. NO specific genetic marker has been identified in all cases 2. There is a great amount of etiologic heterogenity btw Type I and II 3. “Diabetogenic” gene interaction with external factors 4. The actual transmission rate from generation to generation are low. - Twin studies < 40 Type I - 50% >40 Type II - 100% Transmission rates: 1 Type I parent ----> 2-5% 1 Type II parent ---> 10-15% HLA studies HLA BB 2-4X; HLA DR3 4-10 X; HLA DR4 4-10X However, 35-40% of the population get from Amy - Look up Penitance - and in some but not all patients there is altered cellular immunity in type I Pathogenesis of Type I Diabetes Autoimmune Disease Get these overheads from Saunders - Talked about viruses and its role with diabetes - The cause and etiology of diabetes is unknown - Genetic - virus - immunity - some people have a gentic predisposition that may tolerate a viurs infection - might set up an autoimmune response - these antibodies - may cross react with there own Beta cells - problem with this is we can’t always find the perfect genetics and the environment in some individuals with diabetes - Clincial presentation of Type I - these people have little to no endogenous and usually present with abrupt clincial symptoms of polyuria, polydopsia, and poluphagia - weight loss, fatique and infections are common - ketosis or ketoacidosis Type II diabetes - Known as adult onset - Non - insulin depenedent, Adult onset, Non-ketotic, Stable diabetes - These patients retain significant endogenous insulin secretory capacity. Athough treatment with insulin - Diabetics can develop gangrene - Diabetes is a disease of blood vessels and nerves - Complications - why do they come about - acute and chronic - if can’t cure it - supportive care, acute ketoacidosis - can die in as little as 24 hours - the acute complications of diabetes can occur in 24-48 hours - the chronic complications - 3-20 years for these to develop - if we are treating acute symptomatology - Chronic complications - neurological - the most common chronic disabling complication is neurologic people don’t die from diabetic neuropathies - but they prob have the greatest impact on activities of daily living - People die of the vascular complications of diabetes - renal failure, and cardiovascular - these are all vascular related disorders - arteriosclerosis in the eye - we can it retinopahty, kidney nephropathy - the bottom line is that diabetes is a disease of blood vessels and nerves - Why do diabetics have renal failure - the efferent and afferent arterioles - the cardiovascular, the lumenal narrowing the hyperlipidemia - What can we do for these diabetics - within the last 25 years - the chronic complications that occur can be minimized by controling the glucose levels - The role of elevated lipds and atherosclerosis - We can help them with maintainance of a healthy life style - When adjusting these patients you need to monitor there glucose
