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151 Cards in this Set
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Metformin frequency?
Hypoglycemia risk? Side effect? |
2-3x/day
Does not cause Hypoglycemia Lactic Acidosis if *lactate is over-produced (CHF, Surgery, ischemia, binge drinking) or *under-cleared (renal failure) |
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Sulfonylurea
Hypoglycemia? |
yes
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Sitagliptin
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inhibits DPP-IV, which breaks down incretins. Increases insulin secretion, slows gastric emptying, inhibits glucagon. Does not cause weight loss. Oral.
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Repaglinide
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Non-Sulfonylurea Insulin Secretagogue
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Weight gain, fluid retention, $$$ - third line
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Thiazolidinediones
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Glyburide
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Sulfonylurea
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Injected
"Ideal signals to the body that a meal has been ingested". Weight loss. Nausea. |
Incretin mimetics - Glucagon Like Peptide 1 (GLP1) analogue - Byetta. Pramlintide
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activation of nuclear receptors in PPAR-gamma family of genes.
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Thiazolidinediones
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Glimipride
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Sulfonylurea
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Acarbose
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Alpha-Glucosidase Inhibitors
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Pramlintide
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Incretin mimetics
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Chlorpropamide
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Sulfonylurea
longest acting |
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Nateglinide
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Non-Sulfonylurea Insulin Secretagogue
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Miglatol
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Alpha-Glucosidase Inhibitors
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Glipizide
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Sulfonylurea
shortest acting |
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Pegvisomant
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Tx acromegaly:
block GH receptor dimerization |
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Tx DI:
injection? oral (2)? avoid what in tx? |
Vasopressin - injection - vascular effects
DDAVP - oral Thiazides - Natriuresis, volume contraction, decrease GFR [avoid Hyponatremia, brain edema] - need some polyuria |
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Propylthiouracil
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PTU -for hyperthyroidism
Block organification of thyroid peroxidase-catalyzed iodination of tyrosine residues in thyroglobulin. They are also immunosuppressive (used for Grave's Disease) PTU - Blockade of T4-T3 conversion (preferred in severe thyrotoxicosis) PTU is preferred in pregnancy (less placental crossing) Need once a day dose of MMI not PTU (both po) Need 3-12 weeks to exhaust pre-formed hormone Therapy is continued for 6-12 months after euthyroidism is restored Treatment failure = NON-COMPLIANCE!!! PTU also inhibits peripheral T4-T3 conversion (little clinical sig.) |
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Methimazole
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PTU - Propylthiouracil
MMI - Methimazole -for hyperthyroidism Block organification of thyroid peroxidase-catalyzed iodination of tyrosine residues in thyroglobulin. They are also immunosuppressive (used for Grave's Disease) MMI - mild or moderately hyperthyroid use (preferred because of longer half life) PTU - Blockade of T4-T3 conversion (preferred in severe thyrotoxicosis) PTU is preferred in pregnancy (less placental crossing) Need once a day dose of MMI not PTU (both po) Need 3-12 weeks to exhaust pre-formed hormone Therapy is continued for 6-12 months after euthyroidism is restored Treatment failure = NON-COMPLIANCE!!! PTU also inhibits peripheral T4-T3 conversion (little clinical sig.) |
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Conivaptan
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ADH receptor antagonists (administered IV and specific for V2)
Tx SIADH |
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Pioglitazone
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Thiazolidinediones
Rosiglitazone - associated with MI! Pioglitazone - BETTER! Promote insulin signalling via activation of nuclear receptors in PPAR-gamma family of genes. Reduce peripheral insulin resistance - exciting! (only modestly effective) Do not cause hypoglycemia Weight gain, fluid retention, $$$ - third line |
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Demeclocycline
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Tx SIADH:
(second line after water restrict) antibiotic that causes resistance to ADH in kidneys - it is a tetracycline |
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Rosiglitazone
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Thiazolidinediones
associated with MI! |
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Bromocriptine
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D1/D2 agonist
(3x/day) Tx acromegaly, hyperprolactinemia |
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Octreotide
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Somatostatin receptor agonists=> prevent GH release (2, 5).
Tx acromegaly |
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Insulin Detemir
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Long Acting
(complexed to a fatty acid that binds albumin in the SC tissue) |
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DM II drugs with Action in GI tract (and excreted in feces - diarrhea)
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Alpha-Glucosidase Inhibtors: Acarbose, Miglatol.
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Glulisine Insulin
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Fast Acting - More monomers
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Glucagon Like Peptide 1 (GLP1) analogue - Byetta
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Incretin mimetics
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Insulin Aspart
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Fast Acting - More monomers
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Insulin Glargine
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Long Acting
Insulin Glargine (Acid pK so it precipitates at physiologic pH - timing unpredictable) |
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Regular Human Insulin
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Short Acting
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Insulin Lispro
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Fast Acting - More monomers
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NPH (Neutral Protamine Hagedorn)
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Intermediate Acting
NPH (Neutral Protamine Hagedorn) - Protamine crystallization |
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Cabergoline
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D2
(1x/wk) heart valve abnormalities). Treat hyperprolactinemia, acromegaly |
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Kimmelstiel-Wilson lesions
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Diabetes Glomerulus
nodular glomerulosclerosis (the Kimmelstiel-Wilson lesion) of diabetes mellitus. Nodules of pink hyaline material |
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Pituitary adenoma vs. Pituitary Carcinoma?
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******** metastatic dissemination IS a distinguishing feature ***********
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Pituitary adenomas
____________ are the most common type of adenoma. |
Prolactin Cell Adenomas (prolactinomas)
Given the exquisite sensitivity of young women to elevated prolactin levels, prolactinomas are usually discovered while they are very small (microadenoma stage = tumors less than 1 cm). In men and post reproductive women, prolactinomas are more apt to be silent and not come to clinical attention until they are large enough to cause mass effect. |
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Thyroid follicular adenoma vs. follicular carcinoma
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Nearly identical morphology.
**The distinction can only be made by identifying tumor invasion. |
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papillary thyroid carcinoma histology (3)
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Psammoma bodies
Papillary formations Optic nuclear clearing |
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Activating mutations of the RET proto-oncogene
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sensitive, specific, and highly predictive means of identifying patients who have or will develop familial medullary thyroid carcinoma
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adrenal cortical adenoma vs. adrenal cortical carcinoma?
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gross features: Tumor weight in excess of 100 grams is highly suggestive of malignancy. Tumor weight below 50 grams is highly suggestive of benignancy.
Microscopic features: Several histologic features are useful in predicting malignant behavior. These include vascular invasion, tumor necrosis, mitotic activity, and cellular anaplasia. |
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rule of “10s”
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pheochromocytomas - chromaffin cells of adrenal medulla
* 10% are located outside of the adrenal gland (i.e. paragangliomas); * 10% are bilateral; * 10% are malignant; * 10% occur as part of a familial syndrome (MEN IIA and MEN IIB) |
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Thyroid carcinoma:
(1) Most prevalent - psammoma, optic nuclear clearing, _____ formations (2) Vascular or capsular invasion (3) Young people - MEN2A/2B (4) Fast killer |
(1) Papillary
(2) Follicular (3) Medullary (4) Anaplastic |
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HbA1c targets?
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< 7% is considered very good.
> 9% is poor control |
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Diabetic Nephropathy - How bad?
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Peak incidence of albuminuria ~12 yr
May progress to uremia: ~6-8 yr later ESRD in ~6-8 years after uremia |
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“Diabetic Foot” - a two-etiology problem:
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Combination of Peripheral Neuropathy and Peripheral Vascular Disease.
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Neuropathies: 3 kinds.
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Peripheral Symmetrical Polyneuropathy - (Distal, stocking-glove, symmetrical, numbness, tingling, dysaesthesias =>> muscle wasting):
• Metabolic schwann cell defect, e.g. excess sorbitol accumulation and/or depleted myoinositol • Primary axonal degeneration of unclear etiology Autonomic Neuropathies: (Erectile dysfunction, enteropathy, gastroparesis, orthostatic hypotension) • Considered to be similar pathologic process as that causing peripheral neuropathy, but affecting autonomic nerves Mononeuropathies (peripheral or cranial) - Single nerve pain or palsy, rapid onset: • Considered to be ischemic (microinfarcts of the nerve) |
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Diabetic Nephropathy - Prevention?
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ACE inhibitors to control blood pressure (~50% risk reduction in Type I trial)
[prevent HTN-related effect on kidney... Increased renal blood flow causes hyperfiltration, increases intraglomerular pressure] |
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Theories of Pathogenesis of Retinopathy:
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•Ischemic or intraocular pressure changes
•Vasoproliferative factors, IFG, VEGF •Basement membrane or mural cell leak |
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Diabetic Retinopathy
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•Background, non-proliferative changes (sub-retinal microaneurysms, microhemhorrages, hard exudates)
•Proliferative changes (New Vessel Disease, with fine vessels extending into vitreous) • Vitreous bleeds with vision-threatening sequellae (Also, categorized as nonproliferative, preproliferative, proliferative) |
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Pathophysiology of DM Macrovascular Atherosclerosis:
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2-4 fold increased risk
• Atherogenic shift in LDL particles to small-dense LDL; • Other dyslipidemias associated with diabetes—especially hypertriglyceridemia and low HDL-C • Hypercoagulable state, reduced fibrinolytic activity • Atherogenic effect of hyperinsulinism |
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A Unifying Hypothesis of the Pathophysiology of Diabetic Complications?
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Oxidative Stress:
Hyperglycemia-induced overproduction of Superoxide by mitochondrial electron-transport chain 1. Activation of protein kinase C (PKC), initiating a cascade of stress responses; 2. Nonenzymatic glycation of proteins yielding “advanced glycation end-products” (AGEs); 3. Increased polyol pathway activity leading to sorbitol and fructose accumulation; 4. Increased hexosamine pathway flux. |
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Pathophysiology of Hyperosmolar Nonketotic States?
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DM II
Tons of glucose. • Massive osmotic diuresis, dehydration, possibly “pre-renal azotemia” (decreased renal blood flow), • Ultimately, vascular collapse Hyperosmolar nonketotic state, like DKA, is fatal if not treated |
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Pathophysiology of Diabetic Ketoacidosis?
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DM I - 0 insulin
• Unrestrained lipolysis • Enhanced ketone body synthesis; • Acidosis, ketonemia, dehydration, arrhythmias, vascular collapse. “Kussmaul respiration” |
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It is widely thought that diminution of ___-phase insulin release is the earliest detectable defect of ß-cell function in individuals destined to develop type 2 diabetes.
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First.
ß-cell exhaustion after years of compensation for antecedent insulin resistance. --- There may be reduction in both phases - not certain. |
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Natural History of Type 2 Diabetes
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10 years before Dx
Insulin resistance increases until it stabilizes at higher level Relative beta cell function slowly declines to 0 (from 10 years before Dx until 30 years after Dx) At time of Dx Postmeal glucose (first) and Fasting glucose (second) both rise steadily |
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What does Insulin resistance + normal Beta cell function look like?
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Compensatory hyperinsulinemia
=> Normoglycemia |
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"Secondary Diabetes" (read)
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• Loss of pancreatic tissue (e.g. pancreatectomy, chronic pancreatitis);
• Excess counterregulatory hormones (e.g. acromegaly, hyperadrenocorticism); • Drug induced (e.g. thiazides) • Rare insulin receptor abnormalities |
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Gestational Diabetes (read)
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counter insulin hormones of pregnancy which cause insulin resistance
-hyperglycemia transmits transplacentally, causing fetal pancreatic hypertrophy. -large, fat baby, with high incidence of neonatal complications. -Maternal higher risk of type II later in life! |
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How many calories does a gram of fat hold?
A gram of carbohydrate? |
9 cal/gm
4 cal/gm |
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Definition of diabetes
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1. Fasting Plasma Glucose > 126 mg/dl
or 2. Symptoms of diabetes with casual plasma glucose > 200 mg/dl or 3. 2 hours post 75 gm oral glucose (OGTT) - plasma glucose > 200 mg/dl |
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“Pre-Diabetes”:
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The level of glucose tolerance between normal and diabetes.
1) “Impaired fasting glucose”: FPG 100 – 125 mg/dl 2) “Impaired glucose tolerance”: 2 hours after 75 gm glucose, PG 140-199 mg/dl (even if fasting glucose is in normal range) |
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DM:
4 main Symptoms + "others"? |
1. Polydypsia (excess thirst)
2. Polyuria (excess urine volume) 3. Weight loss 4. Polyphagia (excessive appetite) 5. Other Acute Effects of Hyperglycemia: Poor Wound Healing Vaginitis Gingivitis, dental caries Fatigue Blurred Vision |
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What’s wrong with continuing gluconeogenesis for the prolonged fasting state?
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requires glucogenic aminoacids, N is lost as urea or ammonia, both excreted, which depletes the muscle mass
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Prolonged Fast (> 24 hours):
• _______ insulin - Glycogen? - Lipo____? |
Very low insulin
• Heptic glycogen is largely used up after 24 hr, so: • Lipolysis takes over, with lipid as the main fuel source |
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"Counter-Regulatory" Hormones:
Raise Blood Glucose, Acting in Opposition to Insulin: |
Fight or flight:
1. Glucagon 2. Epinephrine 3. Corticosteroids 4. Growth Hormone 5. Norepinephrine keep blood glucose from falling too low |
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A Working Definition of Hypoglycemia ("Whipple's Triad"):
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• Documented low plasma glucose
• and symptoms of hypoglycemia • and response to administered carbohydrate Lower Limits of Normal Plasma Glucose: • 12 16 hour fast: approx. 60 mg/dl • Prolonged fast as low as 30 - 50 mg/dl Symptoms of Hypoglycemia: 1. Adrenergic (“flight or fight”): not as dangerous 2. Neuroglucopenic - dangerous, =severe Cabohydrate, given orally or intravenously, specifically ameliorates the symptoms |
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2 types of hypoglycemia
Fasting vs. Post Prandial ("Reactive")? |
1. Fasting Hypoglycemia occurs post-absorptively, i.e. > 10 hours or so after a meal.
• It is distinctly unusual and definitely abnormal. • It must be documented not only by plasma glucose but by objective symptomatology. 1. Excess Exogenous Insulin 2. Excess Endogenous Insulin (insulinoma, Sulfonylurea Ingestion, Neisidioblastosis (Islet Cell Hyperplasia in Newborns)) 3. Defective Gluconeogenesis (hepatic or lacking substrate (cachexia)) 4. Counterregulatory Hormone Deficiency (low adrenal/pituitary) 5. Odd tumors: insulin-like secretion or glucose-consuming 2. Post Prandial ("Reactive") Hypoglycemia occurs 2-5 hours after a meal. • It may be common though hard to document, and is not often due to defined disease. |
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POSTPRANDIAL ("Reactive") Hypoglycemia:
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Commonly diagnosed, rarely proven… a controversial diagnosis (vast majority of patients with postprandial autonomic symptoms do not have hypoglycemia.)
Post-Oral Glucose: • Alimentary hypoglycemia (Rapid Gastric Emptying) Post Gastric Bypass Surgery for Obesity |
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LDL-cholesterol targets:
BP? |
<100 mg/dL
Possibly <70 mg/dL (<130/80) |
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ADA Glycemic Targets:
Pre-prandial ? Post-prandial ? Bedtime ? HbA1c ? |
Pre-prandial 80-120 mg/dL
Post-prandial < 180 mg/dL Bedtime 100-140 mg/dL HbA1c < 7% |
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Sugars:
mono di polyols polysacc |
Monosaccharides: glucose, galactose, fructose
Disaccharides: sucrose, lactose Polyols (sugar alcohols): sorbitol, mannitol, xylitol, ismalt, malitol, lactitol, hydrogenated starch, hydrolysates Polysaccharides (>9 molecules) Starch: amylose, amylpectin Fiber: cellulose, hemicellulose, pectins, hydrocolloids Oligosac: (3-9 molecules) Malto-oligosaccharides: maltodextrins Others: raffinose, stachyose, fructo-oligosaccharides |
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% of energy intake
Carbohydrate and monounsaturated fat? Protein? Saturated fat? Polyunsaturated fat? Cholesterol intake? |
Carbohydrate and monounsaturated fat - 60-70%
Protein - 15-20% Saturated fat - <7% Polyunsaturated fat - ~10% Cholesterol intake <200mg/day |
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Fats
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Polyunsaturated fatty acids (n-3) 'veg' / fish
Monounsaturated fatty acids *cis:'nuts' / trans:'margarine/dressing' Saturated fatty acids - meats/dairy/processed |
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Myristic acid
Eicosapentanoic acid Oleic acid Lauric acid Docosahexanoic acid Palmitic acid Linoleic acid Elaidic acid Stearic acid |
Myristic acid - Saturated
Eicosapentanoic acid (EPA) - Polyunsaturated, fish Oleic acid - Monounsaturated, cis form (nuts/plants) Lauric acid - Saturated Docosahexanoic acid (DHA) - Polyunsaturated, fish Palmitic acid - Saturated Linoleic acid - Polyunsaturated Vegetable/plant Elaidic acid - Monounsaturated, trans form (hydrogeated oils, margarine) Stearic acid - Saturated |
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Best fats to lower LDL?
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Monounsaturated > Polyunsaturated (>>Saturated/Transunsaturated)
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Big long list of diet rec's for DM
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Total amount of carbohydrate more important than source or type (A)
Sucrose-containing foods can be substituted for other carbohydrate sources (i.e. need not be avoided, just substituted) (A) Non-nutritive sweeteners are safe if consumed w/in FDA limits (A) Insulin (pre-meal level+) 1 unit humalog/15 grams carbohydrate Low-glycemic index foods don't have a clear long-term benefit. (B) Dietary fiber is encouraged. (B) Protein does not increase plasma glucose in persons with controlled type 2 diabetes but can increase serum insulin response (B) Protein requirements may be greater than recommended daily allowance in patients with uncontrolled diabetes Due to increased protein turnover (although most patients protected from protein malnutrition) (B) <7% of energy intake from saturated fat to lower LDL-cholesterol (A) (replace with carbs or monounsaturated if weight loss is not a goal) Dietary cholesterol intake <200 mg/day to lower LDL-cholesterol (A) Minimize intake of transunsaturated fatty acids (B) Polyunsaturated fat: 2 or more servings of fish per week recommended (~10% of energy) (C) -500 to 1000 fewer calories than for weight maintenance (A) -Weight loss goal: 5 to 7% of starting weight (A) HTN: Goals: <130/<80 Use behavior therapy: 130-139 / 80-89 Behavior + Rx: >140 / >90 Carbs: 1 serving=80 calories=15 grams |
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Free (unbound) T4 is converted to ___ by _________. ________ is the active form of thyroid hormone that binds to ________ receptors to exert different regulatory effects.
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T3, deiodinase enzymes
Free T3 is the active form. nuclear receptors |
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(1) Hyperthyroidism caused by growth of multiple autonomously functioning hyperplastic thyroid nodules, May develop in the setting of a previously euthyroid multinodular goiter, Nodules may vary in size, Hyperthyroidism may be precipitated by exposure to iodine (Jod-Basedow phenomenon), More common among older individuals
(2) Also known as Plummer’s disease, hyperthyroidism caused by growth of a single autonomously functioning hyperplastic thyroid nodule |
(1) Toxic mulitnodular goiter
(2) Toxic adenoma |
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hyroiditis
(1) Inflammation leads to the formation of granulomas consisting of giant cells clustered about foci of degenerating thyroid follicles, Onset is often preceded by a nonspecific viral illness, thyroid function tests typically reveal a hyperthyroid phase lasting 1-4 weeks caused by release of thyroid hormone, followed by a resolving hypothyroid phase lasting 1-3 months caused by impaired production of thyroid hormone (2) May develop in 5-8% of all women following pregnancy, Thyroid function tests typically reveal a hyperthyroid phase caused by release of thyroid hormone (90% of cases), followed by a resolving hypothyroid phase caused by impaired production of thyroid hormone (50% of cases) |
(1) Subacute thyroiditis
(2) Autoimmune thyroiditis |
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Hypothyroidism
Most common? Second most common? |
(1) Autoimmune - Hashimoto (only spontaneous cause of hypothyroidism in an adult)
Autoimmune T and B cell pathogenesis -Lymphocytic infiltrate -Circulating antibodies Anti-thyroid peroxidase (Anti-TPO) Anti-thyroglobulin (Anti-TG) (2) Ablation or surgery (?iodine deficiecy?) Drugs (lithium, others) or peripheral resistance (rare!) |
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Hyperthyroidism
Most common? Next most common? |
– Antibody-mediated stimulation of orthotopic thyroid tissue (88%)
• Graves’ disease – Autonomously functioning orthotopic thyroid tissue (10%) • Toxic multinodular goiter • Toxic adenoma • Iodine exposure |
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Hyperthyroidism is a subset of Thyrotoxicosis:
non-hyperthyroid thyrotoxicosis? |
– Ingestion of exogenous thyroid hormone
– THYROIDITIS causing release of endogenous thyroid hormone (hyperthyroid phase lasting 1-4 weeks caused by release of thyroid hormone, followed by a resolving hypothyroid phase lasting 1-3 months) -- Infectious (inflammation) OR autoimmune (often postpartum!) T3 levels relatively elevated compared to the T4 levels |
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Hyperthyroidism
• Radionuclide testing |
Uptake study
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Why TSH as test of choice?
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Less variance with binding proteins
For best results, Wait until acute non-thyroidal illness has resolved before evaluating thyroid function |
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Four parameters of normal growth?
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Height between the 3rd and 97th percentiles
Track along a percentile line on the growth curves Between 2 and 8-10 years of age [1/3 of infants cross percentile up (small infant of tall parents) 1/3 of infants do not cross percentiles 1/3 of infants cross percentiles down (large infant of small parents)] Growth velocity > 2 inches/yr (5 cm/yr) After 4 years of age (Growth velocity decreases until the adolescent growth spurt begins .. many boys drop below the 5cm velocity before puberty) Height appropriate for genetic potential [Average the parents heights after correcting for sex difference in mean adult height (5 in. = 13 cm)] |
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Puberty Start?
Menarche? |
Boys start puberty age 9-14 years
Girls start puberty age 8-13 years Average age of menarche 12.5 years |
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Hormones that affect growth
Stimulate growth? Inhibit growth? |
Stimulate growth:
Thyroid hormone Growth hormone Sex hormones (androgens, estrogens) Impair growth: Glucocorticoids (growth is very sensitive) - can be iatrogenic! -Impair linear growth -Stimulate appetite, causing increased weight gain |
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A leading cause of mental retardation prior to uniform newborn screening
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Hypothyroidism in the neonate causes mental retardation
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1. Central Precocious Puberty
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-Activation of the hypothalamic-pituitary-gonadal axis at a pathologically early age
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2. Non-gonadotropin dependent sex-hormone production (peripheral precocious puberty)
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Adrenal (will present with androgen effect in both boys and girls)
Congenital adrenal hyperplasia Tumor Gonad (will generally present with androgen effect in boys and estrogen>>androgen effect in girls) Tumor McCune-Albright Syndrome Testotoxicosis in boys (activating mutation of LH receptor) Exogenous/Environmental source Causes growth acceleration in childhood, but results in short final height |
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First sign of central puberty:
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Boys: enlargement of testes (< 2.5 cm = pubertal)
Girls: thelarche (breast development) |
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Malignant pituitary tumor?
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Doesn't exist
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Microprolactinoma
Symptoms? Tx? |
Depresses GnRH (think breastfeeding as contraception!) =>
Premenopausal women: hypogonadism, oligomenorrhea, or amenorrhea. Less often galactorrhea. Postmenopausal women: By definition, already hypogonadal. Men: decreased libido, impotence, infertility, gynecomastia, or rarely galactorrhea. Dopamine agonists: Shrink the lesion, Restore gonadal function, Resolve galactorrhea Bromocriptine - dose 1-2x/day Cabergoline - dose 1-2x/week - fewer side effects, but may cause heart valve problems Extra: Idiopathic hyperprolactinemia is the most common pathological cause of hyperprolactinemia. other than in the setting of a prolactin-secreting macroadenoma, the serum prolactin level is less than 250 ng/ml.] |
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Acromegaly:
Test what? Tx to reduce what? |
IGF-1
IGF-1 Transsphenoidal surgery (Best cure rate in micro (not macro) adenoma.) Rx - somatostatin analoges (Octreotide, high aff for somatostatin receptors 2 and 5 - often expressed on tumors (SQ monthly) 50% success rate) OR GH RECEPTOR ANTAGONIST (Pegvisomant, Prevention of GH-R dimerization - good results) Radiation |
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growth hormone (or IGF) following oral glucose challenge
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should drop
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A 25 year-old man presents with polyuria and polydipsia. He is taking lithium.
Woman with metastatic breast cancer. Polyuria, polydipsia and new-onset headaches and visual field cuts. Her serum sodium is 150 mEq/L schizophrenic woman with polyuria and polydipsia. Her serum sodium is 130 mEq/L man presents with widely metastatic small cell carcinoma of the lung. His serum sodium is 119 mEq/L |
Nephrogenic DI
Central DI Psychogenic DI SIADH |
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Apoplexy
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Spontaneous hemorrhage
Severe HA, N/V, fever and stiff neck Hypopituitarism - acute cortisol deficiency is life-threatening. Neurologic symptoms -visual loss -diplopia -ptosis |
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Which pituitary hormone can you most not afford to lose?
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CRH
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Tx hypopituitarism:
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Replace the hormones
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Kallman syndrome:
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loss of LH and FSH
anosmia |
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Something that inhibits prolactin?
Stimulates? |
- dopamine
+ TRH |
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Craniopharyngioma
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Squamous epithelial tumor - compresses things
Arises from stalk, hypothalamus or third ventricle. Solid and cystic components Peak incidence in childhood Surgery (+rad) |
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Empty Sella Syndrome
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Normal function in 95% of cases
No intervention Must be distinguished from cyst, which can progress. |
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polyuria
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> 3L urine per day
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Chronic glucocorticoid excess results in...
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hypertension
catabolic protein wasting and skeletal myopathy insulin-resistant diabetes mellitus body fat redistribution to trunk, mesentery, and mediastinum immune suppression with increased susceptibility to bacterial, viral and fungal infections |
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Local variation in _______ isoenzymes or ______ proteins allows tissue-specific glucocorticoid actions
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11HSD
nuclear receptor |
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Loss of negative feedback by glucocorticoids is a characteristic feature of _____________. Withdrawal of exogenous glucocorticoids may
lead to prolonged ___________ of the HPA axis. |
Cushing
Depression |
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What do CRH and Vasopressin have in common?
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Stimulating ACTH release
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ACTH deficiency OR excess =>
mineralocorticoid deficiency? |
ACTH deficiency doesn’t usually produce mineralocorticoid deficiency, but ACTH excess can lead to mineralocorticoid excess
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Cortisol and the immune system can be thought of as:
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negative feedback loop (immune stim's CRH release)
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What hormone is *maintained* in secondary Adrenocortical Insufficiency?
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aldosterone secretion is sustained by the Renin/Angiotensin pathway
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Sx of adrenocortical insufficiency?
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Symptoms: Signs:
Weakness Weight loss Sleepiness/fatigue Hyperpigmentation (ACTH, MSH excess)* Anorexia Hypotension* Nausea/vomiting Dehydration Abdominal pain Loss of pubic and axillary hair (females) Postural light headedness* Salt craving* *= relatively specific for primary vs. secondary |
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Acute Adrenal Crisis
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Muscle, joint, and abdominal pain, intractable vomiting, severe dehydration, hypotension (poorly responsive to pressors), electrolyte disorders, clouded sensorium.
Empiric glucocorticoid treatment is lifesaving in this setting. |
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Adrenal Insufficiency
*** Initial study of choice? |
Plasma Cortisol at baseline and 30’ and 60’ after ACTH 250 mcg IV bolus
follow-up studies: a) ACTH, renin, aldosterone levels b) CRH and Metyrapone tests |
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Cushing’s Syndrome?
Cushing’s Disease? Workup? Tx? |
Cushing’s Syndrome
Generic hypercortisolism regardless of cause: ACTH-dependent Pituitary ACTH-secreting tumor (Cushing’s Disease) (ACTH partially resistant to suppression) Ectopic (ACTH highly resistant to suppression) Small cell lung cancer Carcinoid, medullary thyroid, pheochromocytoma ACTH-independent Exogenous glucocorticoid treatment Adrenal adenoma Adrenal carcinoma Pseudo-Cushing’s: Alcoholism or major depression Cushing’s Disease Hypercortisolism from an ACTH-secreting pituitary tumor Confirm Hypercortisolism -24 h urinary free cortisol (3x normal. NOT plasma cortisol.), MN salivary cortisol -Low dose dexamethasone suppression test Biochemical localization -Plasma ACTH [Sky high - Ectopic ACTH Medium high - Pituitary ACTH (Cushing Dz) Low - Adrenal tumor] -High dose dexamethasone suppression test Radiographic localization -MRI of pituitary, or chest/abdomen -Inferior petrosal sinus sampling Tx: surgery for almost all. |
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Dexamethasone Suppression Tests
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High Dose
Pituitary Cushing’s Disease: preserved feedback by high dose glucocorticoids Adrenal tumors or ectopic ACTH: lack of feedback by high dose glucocorticoids |
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Congenital Adrenal Hyperplasia (CAH)
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family of inherited disorders caused by mutations in genes encoding steroid biosynthetic enzymes
decrease in cortisol production leads to increased levels of ACTH ACTH excess leads to: 1) accumulation of cortisol precursors upstream of the enzymatic block and 2) adrenal cortical hyperplasia |
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21-hydroxylase deficiency
Dx confirmation? |
Form of CAH
very mild attenuated form and a severe salt wasting form. Diagnosis is confirmed by high 17-hydroxyprogesterone level. (Two steps upstream of Cortisol) |
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Attenuated CAH:
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○ Partial enzymatic block; no cortisol or aldosterone deficiency symptoms
○ Only apparent in females; mild androgen excess after puberty leading to menstrual irregularities and hirsuitism |
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Salt-losing CAH:
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○ Most severe variant with cortisol and aldosterone deficiency and androgen excess at birth
○ Subjects respond to glucocorticoid and mineralocorticoid replacement The steroid pathway is blocked from making aldosterone and cortisol BUT sex steroids are still made --- so loss of cortisol feedback increases ACTH leading to sex steroid excess. |
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In most pheochromocytomas, _ is the major catecholamine. _ are catecholamine metabolites useful in diagnosis.
Sx pattern? |
norepinephrine
i. Metanephrines - stable catecholamine metabolite (interference: antihypertensives, and drug or alcohol withdrawal) (+Clonidine possible. Metanephrines are suppressed by clonidine in normal individuals) - paroxysmal sx - emotional distress does not typically induce pheochromocytoma paroxysms |
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pheochromocytoma
Hereditary Disease Associations list |
Café au lait spots,cutaneous neurofibromas, pheo = Neurofibromatosis (NF-1)
Medullary thyroid cancer, pheo, hyperparathyroidism = Multiple Endocrine Neoplasia Type 2 Paraganglioma and pheo = Succinate Dehydrogenase B and D Von-Hippel Lindau Disease (VHL) = CNS and retinal hemangiomas, renal carcinoma, pheo, paraganglioma Suspect hereditary disease when tumors are early-onset, bilateral, or extra-adrenal. |
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Most specific features for hypercortisolism:
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truncal obesity with peripheral wasting
abdominal striae proximal myopathy |
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Clinical features of chronic adrenal insufficiency:
Features of Addisonian crisis include: |
hyperpigmentation (high ACTH!), increased requirement for sleep, lassitude, salt craving, weight loss, nausea and abdominal discomfort.
hypotensive shock, clouded sensorium, hyponatremia, hyperkalemia, and sometimes hypoglycemia. |
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pheochromocytoma tx
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Beta-blockers may be unsafe, due to disinihibition of alpha adrenergic activity associated with beta-2 receptor inhibition. Alpha or combined alpha 1-beta blockers are especially indicated.
=> surgery |
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hypothyroidism in aging?
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Overt or subclinical hypothyroidism affects 7 to 15% of people over age 60 especially common among women
Overt hypothyroidism hyperlipidemia and increase risk of CHD Check TSH levels and treat subclinical hypothyroidism in elderly people |
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fat and muscle in aging?
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Fat increase rate seems constant (age 20-80)
Muscle loss seems to accelerate after age 55. Not surprisingly, the loss of muscle mass is associated with a loss of muscle strength. |
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Estrogen and Progesterone:
Benefits of replacement? Risks of replacement? |
Benefits:
Lower menopausal symptoms. Slow bone loss. Decreased risk for: Colorectal cancer 37%. Risks of replacement Increase risk of breast cancer with long-term risk Increase uterine cancer with unopposed estrogen Increase venous thrombosis Increased risk for Coronary heart disease 25% Breast cancer 26% Stroke 41% |
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GH in aging?
Somatostain in aging? GH replacement? |
Both decline.
GH replacement: Increase Lean body mass Decrease total body and abdominal fat Functional status - no change Total and HDL cholesterol - inconsistent BUT risk of bone pain, fluid retention, HTN, etc. (Studies not great) |
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Is DHEA the fountain of youth?
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“At present, adrenal insufficiency is the only evidence-based indication for the administration of DHEA”
There is “no justification for administering DHEA to healthy older people”. Decreased Body fat + Improved skin status + |
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What is Addison's Disease?
What causes it? |
primary adrenal insufficiency
Was TB. Now autoimmune disease. |
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Money’s Gender Theory?
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Hopkins guy.
Believed that GI is learned, GR is in part hormonally programmed Lecture seems to agree with him. |
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Optimal Gender Theory?
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GI is learned, then newborns affected by DSDs should be reared according to the sex that their genital phenotype most resembles.
Easier to surgically construct female genitalia than male genitalia in DSDs. |
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“Biology is Destiny” Theory of Gender
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Both early androgen exposure and possession of a Y chromosome masculinize the brain and behavior in humans in an additive or synergistic manner
***Studies*** - Gender role is the only area where this may be true and early androgen exposure is more important than genotype. Closer to Money's theory. |
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other predictors might be useful for sex assignment?
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-Otoacoustic emissions and auditory evoked potentials
=Stronger in females than males (even newborns) |
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Pulsatile Release of Hypothal. GnRH →
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Pulsatile Release of Pituitary LH
→ T production in ♂, E2 production in ♀ Fetus: male: -testes develop in presence of testes-determining factors -testosterone secretion begins during mid-1st trimester and increases to mid-pubertal levels at birth female: ovary develops and E2 secreted in 2nd trimester infant ♂ - peak LH at 3 mos ♀ - peak FSH at 6 mo |
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At 6-7 yrs,
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adrenal androgens (DHEA/DHEA-S) begin to be secreted.
Adrenals produce Androgens →pubic hair=Adrenarche |
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Menarche occurs
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after maximal growth velocity
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Precocious or Delayed
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Precocious = 2 years early
Girls Precocious puberty (traditional): All races Breast Dev. < 8 yrs PP (revised): Breast Dev. White <7, Af. Amer. <6 unless rapid progression Delayed: Secondary Characteristics ≥13, Menarche ≥16 Boys Precocious Puberty: All races Testicular enlargement <9 Delayed: Testicular Enlargement ≥ 14 |
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Height:
The earlier the onset of puberty, |
the shorter the final height
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Precocious:
How Do GnRH agonists work? Induce pituitary desensitization |
Induce pituitary desensitization -- higher doses than in adults!
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Mutations in the LH Signaling Pathway:
(1) LH-R mutations? |
LH-R mutations - FMPP
Familial male precocious puberty |
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McCune-Albright
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Activating G mutations-
McCune-Albright (polyostotic fibrous dysplasia of bone, café au lait spots with irregular borders.) - male or female, isosexual. |
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Delayed Puberty
Primary hypogonadism- What will LH, FSH, T, and/or E2 levels be? Caused by: Secondary hypogonadism- What will LH, FSH, T, and/or E2 levels be? Caused by: |
High LH and FSH, Low T and or E2
Insult/injury to gonads (chemo, tumor, radiation, infection, autoimmune destruction) Gonadal Dysgenesis (XXY[Klinefelter’s syndrome], XO[Turner Syndrome] Low LH/FSH, T and/or E2 CNS disorders (Disorders of pituitary, hypothalamus) Chronic systemic disease Isolated gonadotropin deficiency Constitutional Delay of Puberty (Late Bloomers) |
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Central precocious puberty:
LH, FSH, T and or E2 levels? |
All high
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Suggested % body fat in males? Females?
Obesity %s? Age? |
Male - 15-20%
Female 20-25% Obesity in males 25%, females 33% Body fat increases with age. |
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Appetite Stim?
Inhibit? |
Pro-appetite factors (2):
'G, Y don't we eat?' -Ghrelin (stomach) -Neuropeptide Y (hypothalamus) Anti-appetite factors (3): 'Let me tell You Y... alpha melanocyte stim hormone' -Leptin (adipose tissue, resistance in obese individuals) -Peptide YY (small bowel/colon) -alpha melanocyte stimulating hormone |
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Adipose
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Free fatty acids
**diabetogenic. More readily released from visceral fat (adrenergic stim) TNF-α is a peptide released by adipose tissue that stimulates lipolysis and, consequently, is diabetogenic. Adiponectin, another peptide released by adipose tissue, is an insulin sensitizer. Paradoxically, adiponectin levels are reduced in obesity despite the increase in adipose tissue mass, thereby increasing insulin resistance. |
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Weight loss
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The best results were obtained when diet, behavior intervention, and an appetite suppressant were combined, but the study lasted only one year. Long term maintenance of substantial weight loss is still rare.
(The most widely used procedure = Roux-en-Y gastric bypass) |
