Exam 1 Week 2 Endocrine Flashcards

Question

Identfiy the condition based on the following severe symptom ACUTE ADRENAL CRISIS (1) intractable vomiting, abdominal pain, hypotension, coma, vascular collapse - Death if corticosteroids NOT replaced immediately **causes (3)

Answer 1

Chronic adrenocortical Insufficiency (Addison’s disease) 1. AUTOIMMUNE (60-70%) - 1/2 restricted to adrenals - rest; POLYGLANDULAR SYNDROMES - HLAB8 and DR3 2. Infections - TB - fungi; a) histoplasm capsulatum b) coccidiodes immitis 3. Metastatic disease - LUNG AND BREAST most common - other; GI, melanoma, hematopoietic

Answer 2

Chronic adrenocortical Insufficiency (Addison’s disease) 1. Onset insidious 2. Progressive weakness and easy fatigability 3. GI- anorexia, nausea, vomiting, weight loss, diarrhea 4. Primary adrenal - hyperpigmentation due to increased pre ACTH precursor - NOTE; pituitary and hypothalamic causes DO NOT have increased ACTH - NO pigmentation 5. Decreased mineralocorticoids - HYPERKALEMIA (increase K), HYPONATREMIA (decreased Na), volume depletion, hypotension 6. Hypoglycemia 7. Heart often smaller (hypovolemia?) 8. ACUTE ADRENAL CRISIS - intractable vomiting, abdominal pain, hypotension, coma, vascular collapse - Death if corticosteroids NOT replaced immediately

Answer 3

Acute adrenocortical insufficiency 1. pts. with chronic adrenocortical insufficiency may develop an acute crisis following any stress 2. pts. on exogenous steroids may develop acute crisis due to rapid withdrawal of steroids or failure to increase steroids in stress a. atrophic adrenals can’t respond normally to ACTH 3. Massive adrenal hemorrhage A. Newborns secondary to birth trauma, anticoagulant therapy, disseminated intravascular coagulation, pregnancy B. Overwhelming sepsis (WATERHOUSE FREIDERICHSEN SYNDROME) - classically due to Neisseria meningitis - other; pseudomonas species, pneumococci and H.flu

Answer 4

A. Functional (secrete hormone) or non-functional adrenocortical neoplasm is based on clinical findings NOT morphology (either adenoma or carcinoma can be functional) B. Morphology 1. Adenomas - most nonfunctional a. generally small (1-2 cm) 2. Carcinomas - rare a. any age b. more likely to be functional c. large, invasive, met by lymphatic and/or bloodstream d. median survival - 2 years

Answer 5

Hypothalamus ; GRH, somatostatin, CRH, TRH, GnRH (LHRH), PIH, PRH Anterior pituitary 1. GH - liver - somatomedins 2. ACTH - adrenal cortex - glucocorticoids, mineralocorticoid and androgen 3. TSH - thyroid - thyroxine 4. FSH - estrogen 5. LH female - estrogen, ovary, progesterone 6. LH male - testis - testosterone 7. Prolactin - breast

Answer 6

ADENOHYPOPHYSIS (anterior pituitary) a. growth hormone releasing hormone (GHRH) ─ growth hormone (GH) b. corticotrophin-releasing hormone (CRH) ─ adrenocorticotropic hormone (ACTH) c. thyrotropin-releasing hormone (TRH) ─ thyrotropin (TSH; thyroid-stimulating hormone) d. gonadotropin-releasing hormone (GnRH) ─ follicle stimulating hormone (FSH) e. GnRH ─ luteinizing hormone (LH) f. TRH; other releasing factors (?) ─ Prolactin (PRL) Hormones from the neurohypophysis (POSTERIOR PITUITARY) a. antidiuretic hormone (ADH, vasopressin) b. oxytocin Feedback loops a. For anterior pituitary hormones, feedback (usually negative) to the hypothalamus or pituitary can occur by either the target tissue hormone (e.g. estrogen, thyroid hormones) or by the pituitary hormone (e.g. GH). b. For posterior pituitary hormones, release may be regulated in response to changes in plasma osmolality or extracellular volume or sensory nerve input.

Answer 7

a) HYPOTHALAMIC DWARFISM – TREAT WITH GH REPLACEMENT. Will not work in patients with closed or closing epiphyses, bone age > 15 years, and in individuals who cannot make IGF1. Also contraindicated in instances of active malignancy. Sex steroids may be given at puberty for sexual development. b) GH Preparations include: a. SOMATROPIN, which is an exact match with human growth hormone. Produced by recombinant DNA technology. Administered subcutaneously 1x/day in the evening. b. SERMORELIN – synthetic GHRH. No longer used in US. c) Additional uses of GH include: a. Turner’s syndrome, Prader-Willi syndrome (in the absence of morbid obesity or sleep apnea- if not cause sudden death), chronic renal insufficiency, children with idiopathic short stature, treatment of AIDS wasting. d) Side effects of GH therapy. a. Early in treatment increased intracranial pressure may occur. May be diabetogenic, due to anti-insulin actions that result in decreased glucose utilization. e) *Human recombinant IGF-1 (Mecasermin) - used to treat growth deficiency due to low levels of IGF-1. This is particularly important for LARON DWARFISM, which is a genetic disorder with mutations in the GH receptor

Answer 8

Excessive GH could be attributed to GH secreting adenoma. a) SOMATOSTATIN ANALOGS. OCTREOTIDE and LANREOTIDE are somatostatin analogs with longer half-lives than somatostatin. They are used to inhibit GH secretion and reduce levels of IGF-1. They are administered SUBQ. Octreotide was three times per day, but long acting form is available. Lanreotide is long acting * *Adverse effects; GI adverse effects - including diarrhea, nausea, and abdominal pain―occur in up to 50% of patients. Approximately 25% of patients develop gallstones, due to ↓ in gall bladder contraction and gastrointestinal time. Somatostatin analogs will also reduce the levels of thyrotropin secretion (may be used for thyrotrope adenomas). B) Pegvisomant – is a competitive GH receptor antagonist that reduces levels of IGF-1. Pegvisomant is FDA-indicated for acromegaly (second line therapy) and is administered SUBQ. Liver function needs to be monitored with Pegvisomant use. Adverse effects: Lipohypertrophy occurs at injection site.

Answer 9

HYPERPROLACTINEMIA - Most often hyperprolactinemia is caused by a prolactin-secreting pituitary adenoma. Other causes include: hypothalamic, pituitary disease that results in a ↓ in dopamine, renal failure, hypothyroidism (↑ TRH), and treatment with dopamine-receptor antagonists. Treatment 1. DOPAMINE RECEPTOR AGONISTS: *CABERGOLINE (PREFERRED drug), and Bromocriptine stimulate dopamine D2 receptors to inhibit spontaneous and TRH-induced release of prolactin, they also interact to a lesser extent with D1 receptors. Cabergoline has a longer half-life and greater selectivity for D2 receptors than bromocriptine, thus cabergoline is more potent than bromocriptine. Cabergoline and bromocriptine are FDA- indicated for hyperprolactinemia. Bromocriptine is also FDA- indicated for acromegaly. * *ADVERSE EFFECTS - Relative to bromocriptine, cabergoline has a lower tendency to induce nausea, however may induce hypotension and dizziness. Cabergoline has also been linked to valvular disease an effect that could be attributed to its ergot activity (mediated through 5HT2B receptor).

Answer 10

a. PROTIRELIN - synthetic TRH that stimulates the release of TSH. Used for diagnostic purposes in hypothyroidism*** b. If after a protirelin administration, TSH and T3, T4 levels are normal, then a hypothalamic defect is present. If TSH and T3/T4 are not increased by protirelin, then pituitary failure has occurred. If TSH levels are increased, but T3/T4 levels are not increased, then thyroid gland problems exist.

Answer 11

COSYNTROPIN

Answer 12

Endogenous GnRH has to be released in pulses in order to stimulate FSH and LH release. *Long-acting GnRH analogs downregulate GnRH receptors and are used to block release of FSH and LH.

Answer 13

Human chorionic gonadotropin (hCG) - placenta hormone extracted from the urine of pregnant women

Answer 14

1. MENOTROPINS - human menopausal gonadotropins (hMG) - An extract from the urine of postmenopausal women. 2. UROFOLLITROPIN 3. A. Follitropin beta and alpha (recombinant human FSH) B. Choriogonadotropin alpha (recombinant human LH)

Answer 15

1. Human chorionic gonadotropin (hCG) 2. MENOTROPINS 3. UROFOLLITROPIN 4. A. Follitropin beta and alpha (recombinant human FSH) B. Choriogonadotropin alpha (recombinant human LH) Side effects - gonadotropin mimics in women include risk of multiple births (common), and ovarian hyperstimulation syndrome. The most common side effect in men is gynecomastia, which occurs in up to one- third of patients.

Answer 16

1. CLOMIPHENE – Is an estrogen receptor antagonist. *Clomiphene increases gonadotropin secretion and ovulation. It is FDA- indicated for female infertility due to ovulatory disorder and *female infertility due to Polycystic ovary syndrome (common endocrine disorder that manifest with irregular menstrual periods, infertility, hirsutism, excess levels of androgens). - Clomiphene increases the levels of LH and FSH by inhibiting estrogen negative feedback at the level of hypothalamus. **** *Clomiphene side effects can include multiple births, antiestrogenic effects on the developing follicle, ovarian cysts endometrium and cervical mucosa. 2. GONADORELIN is synthetic human GnRH. Administered via a pump to mimic endogenous GnRH release.

Answer 17

Leuprolide, goserelin, nafarelin and histrelin a) *Synthetic GnRH agonists (or analogs) have longer half-lives than endogenous GnRH due to substitutions at position 6 (confers resistance to proteolysis), and substitutions at C terminus (improves receptor binding affinity) b) *After transient stimulation of gonadotropin secretion, they down-regulate the GnRH receptor and inhibit gonadotropin secretion; this is useful in several instances in which disorders are responsive to reductions in the gonadal steroids. c) Given continuously (2-4 weeks) to be effective. d) *Used in endometriosis, uterine fibroids, advanced prostate cancer, breast cancer, and central precocious puberty. e) *Adverse effects include hot flashes, decreases in bone density, vaginal dryness and atrophy, erectile dysfunction, (effects are related to decreases in estrogen levels in women and testosterone levels in men).

Answer 18

a) Tamoxifen, Raloxifen, Toremifene b) Bind to estrogen receptors (ER) and modulates estrogen receptor activity (ER). c) Tissue selective activity: anti-estrogenic in breast cancer, BUT estrogenic in bone, brain, and uterus. d) *THERAPEUTIC USES: breast cancer (all SERMs) and osteoporosis (raloxifen) e) *ADVERSE EFFECTS: Hot flashes (all SERMs), endometrial and uterine cancer (tamoxifen), deep vein thrombosis and pulmonary embolism (tamoxifen, and raloxifen)

Answer 19

Selective estrogen receptor downregulator (SERDs) | a) Fulvestrant

Answer 20

Aromatase inhibitors a) Anastrozole, Exemestane, Letrozole b) Aromatase inhibitors that reduce estrogen levels

Answer 21

Androgen receptor antagonists 1. flutamide, bicalutamide **combine with long acting GnRH agonist to prevent loss of feedback**

Answer 22

5α-reductase inhibitor 2. Finasteride

Answer 23

1. Long-acting synthetic GnRH agonists - leuprolide, goserelin, nafarelin and histrelin 2. Selective estrogen receptor modulators (SERMs) - Tamoxifen, Raloxifen, Toremifene 3. Selective estrogen receptor downregulator (SERDs) - Fulvestrant 4. Aromatase inhibitors - Anastrozole, Exemestane, Letrozole 5. Androgen receptor antagonists - flutamide bicalutamide 6. 5α-reductase inhibitor - Finasteride

Answer 24

``` DIABETES INSIPIDUS (DI) a. May result from a central defect (inadequate ADH release) or be nephrogenic (inability to respond to ADH). ``` b. Central DI can be induced by surgical or traumatic head injury near the hypothalamus of pituitary, hypothalamic or pituitary tumors, cerebral aneurysms, CNS ischemia, brain infections c. Nephrogenic DI may be congenital or acquired. Hypercalcemia, hypokalemia, postobstructive renal failure. d. Symptoms include polyuria, polydipsia (if thirst mechanism is working appropriately), and dilute urine. e. Diagnosis is determined through administration of synthetic vasopressin. If vasopressin induces increases in urine osmolality, then central DI. If no effect on urine osmolality, then nephrogenic ID.

Answer 25

1. Could administer synthetic vasopressin, but more likely will use Desmopressin 2.Administer desmopressin and adjust fluid intake. 3.*Desmopressin (DDAVP) is a synthetic analog of vasopressin. *It has reduced vasopressor activity, but enhanced anti-diuretic activity compared with vasopressin. 4. Will also stimulate increases in factor VIII and von Willebrand factor. Also FDA-indicated for von Willebrand disease type 1 (Mild to Moderate) and Primary nocturnal enuresis. Adverse effects - Vasopressor activity (due to activation of V1 receptor) can induce facial pallor, increases in GI activity leading to nausea and cramps, and may induce vasoconstriction of coronary arteries. *These effects are more prominent with vasopressin compared with desmopressin, because of higher activity toward the V1 receptor. Overstimulation of V2 in the tubules can result in water intoxication. Drug interactions - CHLORPROPAMIDE and CARBAMAZEPINE will increase the sensitivity of the collecting duct to vasopressin. - Lithium and demeclocycline will inhibit the action of vasopressin on the collecting duct within kidney. *As many as one in three patients taking Lithium will develop nephrogenic DI.

Answer 26

1. Adequate water intact. Thiazide diuretics reduce polyuria in patients with NDI and are often used in patients with NDI. (they can reduce urine volume by 50% in NDI. Restriction of sodium intake helps. **promotes water reabsorption at the proximal tubule 2. Amiloride blocks Li+ uptake by the Na+ channel in the collecting duct system and maybe effective in patients with mild & moderate concentrating defects. Is used to reverse Li+ induced NDI

Answer 27

Syndrome of inappropriate secretion of ADH (SIADH) a. Impaired H2O excretion, leading to hyponatremia, hypo-osmolality induced by inappropriate secretion of ADH. b. SIADH induced by malignancies, pulmonary diseases, CNS injuries/diseases and generally surgery. Many drugs can induce SIADH including selective serotonin reuptake inhibitors, tricyclic antidepressants, sulfonylureas and vinca alkaloids. Treatment 1. Fluid restriction is a mainstay of therapy in most patients with SIADH 2.Demeclocycline, a tetracycline, inhibits the action of vasopressin on the collecting duct has been used. 3. Conivaptan (V1 and V2 receptor antagonist) and tolvaptan (selective V2 receptor antagonist) are FDA approved for euvolemic or hypervolemic hyponatremia associated with SIADH 4. Other treatments can IV hypertonic saline, and loop diuretics (which inhibit the concentrating effects of the kidney

Answer 28

OXYTOCIN ** Preparations (synthetic oxytocin) may be administered by different routes for different purposes. IV to induce labor; IM to control post-abortion hemorrhage; intranasal to induce lactation.

Answer 29

HYPOGONADISM

Answer 30

Testosterone must be administered by injection (IM) or transdermal. - Testosterone is not administered by the oral route. WHY? Because an oral dose of testosterone is metabolized by the small intestine and undergoes extensive first pass effect (low bioavailability). 1. Testosterone Injectable - IM 2-3 times/week 2. Transdermal gel, patch or buccal preparations A. Topical GELS active ingredients is TESTOSTERONE. The gel (Androgel, Axiron, Fortesta and Testim) is applied to the shoulders or upper arm has a 10% absorption of testosterone through the skin. Acts as a 24 h depot for slow release of hormone into the blood. NOTE: FYI FOR THE TRADE NAMES B. Topical PATCH; One Patch available (Androderm) and active ingredient is testosterone in a patch that must be applied daily. Numerous problems with compliance occur with the patches due to local irritation. - Androderm patch are applied to the back, arm or abdomen BUT NOT to the scrotum (potential to absorb too much testosterone if applied to scrotum) - Androderm patch contains aluminum foil. Remove patch if patient is undgeroing MRI (magnetic resonance imaging test) as burns have occurred due to aluminum activation by Magnetic resonance. - Androderm patch may cause acne or abnormal hair growth in female Partner (female partner must avoid contact with patch) C. BUCCAL (strains) is also available. The lozenge is placed on the gum and it forms a gel that slowly releases testosterone. The tablet must be applied twice daily. Testosterone is absorbed through the buccal area. **FDA BLACK BOX WARNING..FOR ALL GELS and TOPICAL SOLUTIONS..VIRILIZATION can occur in children exposed to topical testosterone. Children SHOULD NOT come in contact with product.

Answer 31

TESTOSTERONE ESTERS - ESTER converted in the body to testosterone Use - Hypogonadism - Metastatic breast cancer in women (testosterone enanthate)

Answer 32

17 alpha-alkylate testosterone ** Methyltestosterone, fluoxymesterone Contraindications - MALE breast cancer - Prostate cancer - Pregnancy Adverse reactions - Cholestatic hepatitis and jaundice with low doses. Greatest risk of HEPATOTOXICITY for testosterone analogues associated with methyltestosterone and fluoxymesterone - edema (induce salt and water retention) - liver cancer - bleeding due to decline in levels of clotting factors II, V, VII and X

Answer 33

Contraindications for all testosterone analogs (3) 1. Prostate cancer 2. Male breast cancer 3. Pregnancy Adverse effects for all testosterone analogs (3) 1. Induce salt and water retention (hypertension) 2. High doses or prolonged use associated with jaundice. - Greatest Risk t with 17α-alkylated testosterones Methyltestosterone & fluoxymesterone 3. High doses or prolonged use associated with hepatic carcinomas

Answer 34

DANAZOL Uses 1. Endometriosis 2. Hereditary Angioedema 3. Fibrocystic breast disease Adverse Effects 1. Weight gain 2. Acne 3. BLACK BOX WARNING: Thromboembolism, Benign Intracranial hypertension 4. Mood swings 5. Hepatic dysfunction Contraindications 1. Pregnancy 2. Breast feeding

Answer 35

STANAZOLOL Mechanism 1. 17α-alkylated derivative of testosterone 2. Strong anabolic and weak androgenic action 3. Increases mRNA levels and protein levels of C1 INH and C4, Adverse effects 1. Increased bleeding times due to lower levels of clotting factors II, VII, IX and X 2. Edema 3. Acne 4. Virilization in women, baldness (may not reverse) 5. HEPATIC TOXICITY Contraindications 1. Pregnancy 2. Male Breast or prostate cancer 3. Female breast cancer with hypercalcemia

Answer 36

OXANDROLONE Side effects - edema, water retention - hypertension - irritability, aggression, excitation Contraindications - breast cancer (men or women) - prostatic cancer - Pregnancy

Answer 37

ANTI-ANDROGENS ; Finasteride and Dutasteride MoA - Finasteride and Dutasteride reduce the levels of dihyrotestosterone. 5α-Reductase is the enzyme that converts testosterone to dihydrotestosterone. - In the body there are 2 isoforms, called Type 1 and 2. Type 1 and 2 are present in the prostate, liver, skin and androgen sensitive tissues. - Finasteride is a competitive inhibitors of the type 2 form of 5α- reductase. - Dutasteride is a competitive inhibitors of type 1 and 2 forms of 5α-reductase. - The result is a block in the conversion of testosterone to dihydrotestosterone. Serum dihydrotestosterone levels fall by as much as 50% following treatment with finasteride. Adverse effects - gynecomastia - decreased PSA values, -will lower PSA levels in males by 50% - decreased dihydrotestosterone but elevated testosterone - Finasteride must be used with caution in hepatic dysfunction (metabolized by liver) Contraindications - contraindicated in women and children - Pregnancy Category X - Pregnant women should not handle tablets due to risk to fetus - Women should not handle tablets if breastfeeding or if they believe they may be pregnant

Answer 38

LEUPROLIDE Adverse effects - Hot flashes/night sweats (50% incidence in men treated for prostatic cancer) - Edema (incidence is 8-20% depending on dose) - gynecomastia - Bone pain, higher risk of osteoporosis - Greater risk of thrombosis

Answer 39

FLTUAMIDE Side effects - Gynecomastia - Elevated liver function tests**. Over 20% of men taking flutamide must stop medication due to elevated liver function tests. Liver abnormalities are reversible.

Answer 40

A. Primary hypergonadism treat with dutasteride - Incorrect, Finasteride and Dutasteride are antiandrogens B. Primary hypogonadism treat with testosterone topical - CORRECT ANSWER, treat with testosterone replacement C. Primary hypogonadism treat with leuprolide - Incorrect, Leuprolide would worsen low testosterone levels D. Secondary hypogonadism treat with testosterone intramuscular injections - Incorrect, secondary hypogonadism would display low FSH and LH levels

Answer 41

A. Anemia ; Incorrect because anabolic steroids can cause polycythemia B. Gynecomastia ;Incorrect, occurs with anti-androgens C. Hearing loss D. Hyperthermia E. Liver damage Correct answer anabolic steroids increase the risk of LIVER DAMAGE and PROSTATE CANCER

Answer 42

C. Testoserone absorption via secondary exposure. Correct answer- Patients should avoid direct skin contact between Testosterone gel and women or children. - Keeping a piece of clothing such as a shirt may prevent secondary absorption.

Answer 43

A. Alfuzosin; Afluzosin and Tamsulosin (α1-adrenergic receptor antagonists) decrease the symptoms of difficulty with urination but do not shrink the prostate. B. Finasteride Correct answer, finasteride is a 5α-reductase inhibitor which decreases conversion of testosterone to dihydrotestosterone. C. Fluoxymesterone 17α-alkylated orally administered testosterone, if used would worsen symptoms D. Oxandrolone synthetic testosterone derivative would also worsen symptoms E. Stanazol

Answer 44

A. Dutasteride associated with gynecomastia but not liver dysfunction B. Fluoxymesterone does not cause gynecomastia C. Flutamide correct answer D. Leuprolide associated with gynecomastia but not liver dysfunction E. Methyltestosterone does not cause gynecomastia

Answer 45

Adrenal medulla A. Derived from neural crest - Chromaffin cells; synthesis and secrete catecholamines B. Preganglionic nerve fibers from sympathetic nervous system stimulate secretion

Answer 46

PHEOCHROMOCYTOMA (chromaffin cells) 1. HTN A. 2/3 chronic sustained; may have element of labeled B. Paroxysmal - abrupt, precipitous elevation in blood pressure C. Increased risk myocardial ischemia, HF, renal injury and CVA 2. Tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension. Pain in abdomen or chest, nausea, and vomiting a. may be ppt. by emotional stress, exercise, changes in posture, and palpation in the region of the tumor 3. Sudden death - may be due to increased catecholamines; myocardial instability - ventricular arrhythmia TREATMENT Rx - if single, surgery; if bilateral or multiple, medical Rx for hypertension

Answer 47

Pheochromocytoma Morphology 1. small to large; 10% multicentric and/or bilateral 2. hemorrhage, necrotic, and cystic 3. stain with silver stains 4. benign may have capsular and vascular invasion 5. malignancy based exclusively on metastases **CD99 negative

Answer 48

NEUROBLASTOMA 1. less than 2 yrs - protuberant abdomen with abdomenal mass, fever, and weight loss 2. older - metastases - hepatomegally, ascites and bone pain 3. 90% produce catecholamines a. hypertension less than pheochromocytoma **Similar presentation of WILMS TUMOR

Answer 49

NEUROBLASTOMA Labs 1. Increased serum catecholamines and increased of their metabolites VMA and HVA in urine Prognosis 1. stage and age most important 2. genetics a. deletion of short arm of chromosome 1 - aggressive behavior b. amplification of N-myc oncogene - poor prognosis Stains; CD99 positive

Answer 50

MEN1 - Multiple Endocrine Neoplasia Syndromes (WERMER’s SYNDROME) Parathyroidism most common - an adenoma or hyperplasia Pancreatic islet cell next most common 1. insulin, glucagon, gastrin, somatostain, VIP 2. may be benign or malignant 3. often multiple Pituitary - less prominent; any one

Answer 51

MEN IIa (Sipple’s syndrome) Thyroid medullary carcinoma seen in 100% 1. associated with foci of C-cell hyperplasia 2. usually aggressive Pheochromocytoma (40 to 50%) often bilateral or extral adrenal 1. may be benign or malignant Parathyroid hyperplasia also seen with hypercalcemia or renal stones (10-20%)

Answer 52

A. Genetically distinct - mutation of RET protooncogene different than MEN IIa B. Thyroid medullary carcinoma, pheochromocytomas (same as IIa) 1. with neuromas and/or ganglioneuromas 2. NO parathyroid disorder

Answer 53

Islets of Langerhans 1. beta cells - insulin 2. Alpha cells - glucagon 3. Delta cells - somatostatin (suppress release of insulin and glucagon) 4. PP (pancreatic polypeptide) - in islets and all through pancreas

Answer 54

Diabetes Mellitus 1.hyperglycemia common feature 2.may be secondary to diseases causing extensive destruction to islets 3.Primary A. Type I (insulin-dependent diabetes; juvenile-onset; kenos is prone) ; 10-20% of primary diabetes B. Type II (non-insulin dependent diabetes; adult onset diabetes); 80-90% of primary diabetes C. BOTH have same long term complications

Answer 55

Type I ; begins by age 20 1. Polyuria, polydipsia, polyphasic and ketoacidosis 2. Decrease insulin - increase glucose - POLYURIA (glucose, Na, K, Mg, PO4 - osmotic diuresis) - decrease intracellular water - triggers osmoreceptors of the thirst center in brain - POLYDIPSIA 3. Decrease insulin - catabolism of protein and fat - negative energy balance - polyphasic (increased eating) A. Catabolic effects prevail - weight loss and muscle weakness - weight loss and polyphagia are paradox; therefore, if you see, think diabetes (or possibly thyrotoxicosis) 4. KETOACIDOSIS is almost exclusive to Type I A. Due to severe insulin deficiency and absolute or relative increase in glucagon. - Decreased insulin - expressive breakdown of fat - increase free fatty acids. Go to liver and are oxidized by acetyl co-enzyme A to ketone bodies (acetoacetic acid and beta hydroxybuteric acid) B. glucagon accelerates oxidation of free fatty acids C. rate of formation of KETONE BODIES EXCEEDS utilization by muscles and other tissues - ketonemia and ketonuria - nausea, vomiting, respiratory difficulties

Answer 56

Type II Diabetes Mellitus ** often older (>40) and frequently obese (80%) 1. May present with polyuria and polydipsia, but usually asymptomatic; easier to control than Type 1 2. CAN HAVE HYPER-OSMOLARITY NONKETOTIC COMA - due to severe dehydration from sustained hyperglycemia in patients who do NOT drink enough water - absence of ketoacidosis and symptoms so don’t seem medical advice until coma

Answer 57

1. Synthesized and stored in granules in beta cell 2. Release BIPHASIC (2 pools) A. Increase glucose - release from granules B. If persists - delayed and protracted response due to active synthesis C. Increase glucose trigger insulin release and initiates insulin synthesis 3. insulin major anabolic hormone 4. principal metabolic function is to increase rate of glucose uptake by striated muscle, including cardiac, fibroblasts, and fat cells 5. INSULIN RECEPTOR is a tyrosine kinase

Answer 58

1. General (1) Due to severe, absolute lack of insulin secondary to reduction in the beta-cell mass (2) usually develops in childhood Genetic susceptibility (1) Class II MHC most important (2) see HLA-DR3 or HLA-DR4 in 95% of patients (3) associated with linked DQ allele HLA-DQ*0302; HLA- DQ*0602 is protective against diabetes.; studies have shown that asparagine at position 57 in the DQbeta chain protects against Type 1; its absence increases susceptibility (4) however most individuals who inherit DR3 or DR4 do not get diabetes, so environmental factors are important

Answer 59

Autoimmunity 1. insulinitis-CD8 Lymphocytes with variable CD4+T lymphocytes and macrophages (T cell mediated autoimmunity) 2. Beta cells selectively destroyed 3. expression of class II HLA antigens on beta cells (normal -NO expression) 4. 70% - 80% of Type I have islet cell antibodies that react to glutamic acid decarboxylase (GAD) and several other cytoplasmic proteins - antibodies to GAD can be detected long before clinical symptoms 5. 10% have other organ - specific autoimmune disorders Environmental factors (1) molecular mimicry - a viral protein shares common amino acid with beta cell -theory * *GAD shares sequence with Coxsackie virus (2) environmental injury could lead to damage of beta cell by viruses, followed by autoimmune reaction.

Answer 60

1. General; much less is known, not autoimmune disease A. GENETIC FACTORS more important; twin concordance is 60-80%, but not linked to HLA, appears to result from a collection of multiple genetic defects B. DERANGED BETA-CELL SECRETION OF INSULIN - in early stage, see disorder of pattern of insulin release, with blunted rapid first stage -later-mild to moderate deficiency of insulin (less severe than Type I) -no evidence of viral or immune-mediated injury 2. INSULIN RESISTANCE; lack responsiveness to insulin signal - a major factor in development of Type II diabetes - in both non-diabetic obese individuals and pregnant women, see reduced insulin sensitivity to target tissues - related to both decreased number of insulin receptors and problems in receptor signaling - RESULTS IN; inability of insulin to direct deposition of glucose and other metabolic fuels, more persistent hyperglycemia & more prolonged stimulation of beta-cells 3. ROLE OF OBESITY - 80% of Type 2 diabetics are obese; early on with weight loss and exercise lead to a reversal in impaired glucose tolerance - insulin resistance occurs in non-obese type II diabetics

Answer 61

``` Prevalence TYPE 1 - Onset <20 yrs - Normal weight - decreased blood insulin - Anti islet Cell ab - ketoacidosis common ``` TYPE 2 - onset >30 yrs - obese - NI/ increase blood insulin - No antibodies - ketoacidosis rare Genetics Type I - so-70% concordance in twins - HLA-DR3 and/or DR4 Type 2 - 60-80% concordance in twins - No HLA association; multiple genes involved ``` Pathogenesis Type 1 - Autoimmunity - severe insulin deficiency - ISLET CELLS; early insulitis, marked atrophy, beta cells depleted ``` Type 2 - insulin resistance - relative insulin deficiency - ISLET CELLS; focal atrophy and amyloid, Mild beta cell depletion

Answer 62

General 1. microangiopathy, retinopathy, nephropathy, neuropathy 2. complication due mainly to hyperglycemia * *strict control can delay complications NONENZYMATIC GLYCOLSYLATION ; glucose attached to free amino acid groups of protein without aid of enzymes (eg. hemoglobin-HbAic) 1) when attached to long-lived proteins - (eg. collagen) leads to irreversible advanced glycosylated end products (AGEs 2) traps low-density lipoprotein (LDL) in blood vessel wall which lead to deposition of cholesterol which lead to ATHEROGENESIS 3) AGEs bind to receptors on many cells and leads to intracellular hyperglycemia with disturbances in polyol pathways. * Nerves, lens of eye, kidney, blood vessels do NOT require insulin for glucose to enter cell. However, hyperglycemia lead to increased glucose in these tissues that is converted to SORBITOL which eventually lead to fructose. * *Increased sorbitol and increased fructose - influx of water - osmotic cell injury. * These changes are believed to injure the Schwann and cause neuropathy and damage the retinal capillaries and cause the retinopathy.

Answer 63

1. Pancreas - Type 1: see reduction in number and size of islets & insulitis - Type II-may be subtle reduction in beta cell mass & amyloid deposits in islets, however generally would not see any significant findings in the pancreas 2. Vascular system - *** ACCELERATED ATHEROSCLEROSIS: SEE INCREASED RISK of MI(#1 cause of death in diabetics), gangrene of the lower extremities (100 x more common in diabetics) & renal artery stenosis - HYALINE ARTERIOLOSCLEROSIS: more prevalent & severe in diabetics, but not specific; related to disease duration & degree of hypertension( but can develop without HTN) * * DIABETIC MICROANGIOPATHY- see diffuse thickening of basement membrane, esp. capillaries of skin , skeletal muscle, retinas, renal glomeruli, and renal medullae> Composed of concentric hyalin material composed primarily of collagen type IV, makes the membranes LEAKY

Answer 64

Diabetic Nephropathy; - this is second to MI as cause of death in diabetics. In the glomeruli, the capillary BM thickened throughout entire length.GET: - DIFFUSE GLOMERULOSCLEROSIS; diffuse increase mesangial matrix mesangial cell proliferation; thickened capillary BM, when marked may - nephrotic syndrome, but may also be seen in old age and HTN * *NODULAR GLOMERULOSCLEROSIS (KIMMELSTIEL-WILSON DISEASE) - occurs in 10-35% of diabetics, nodules form at periphery of glomerulus composed of mucopolysaccharides; these impede flow of blood of efferent arterioles lead to tubular ischemia. * *If you see this finding, think diabetes

Answer 65

Renal vascular lesions: - see arteriosclerosis frequently & is severe. Hyaline arteriolosclerosis seen and affects both the afferent & efferent arterioles, rarely encountered in non-diabetics. Pyelonephritis - acute or chronic inflammation of kidneys beginning in interstitium and affecting tubules (extreme cases also glomeruli) - more common in diabetic - may lead to acute necrosis of papilla (NECROTIZING PAPILLITIS)

Answer 66

Diabetic ocular complication Retinopathy 1. Non proliferative (background) - intraretinal or preretinal hemorrhages, retinal exudates, microaneurysms, venous dilations; edema, and thickening of retinal capillaries (MICROANGIOPATHY) 2. Proliferative - neovascularization and fibrosis - may lead to blindness - vitreous hemorrhages can form; if organize may pull retina - retinal detachment - can see glaucoma and cataracts from sorbitol deposition

Answer 67

Diabetic neuropathy 1. peripheral and symmetric neuropathy of lower extremities affecting motor and eyes sensory 2. autonomic neuropathy 3. brain - widespread microangiopathy - generalized neuronal degeneration - predisposed to CVA and brain hemorrhages - NONE specific to diabetes Complications - MI, CVA, gangrene of leg, and renal insufficiency are the most threatening and most common complications - ENHANCE SUSCEPTIBILITY TO INFECTIONS - Type I more likely to die from diabetes than type II Lab diagnosis 1. 1.fasting blood glucose (FBS) greater than or equal to 126 mg/dl on more than one occasion a. FBS- 99 mg/dl and below= normal b. FBS- 100-126 mg/dl= pre-diabetes 2. 2.Glucose Tolerance Test (GTT)- give 75 gm of glucose & measure blood glucose at 0, 30 min, 1 hr & 2 hrs. If at 2 hr, glucose is > 200 mg/dl, dx is made.

Answer 68

Islet Cell tumors INSULINOMAS ; obviously secrete insulin - lead to HYPOGLYCEMIA Differential Dx I. insulin sensitivity II. diffuse liver disease - decrease glycogenolysis and decrease gluconeogenesis III. inherited glucogenoses IV. certain retroperitoneal fibromas or fibrosarcoma which ectopically produce insulin V. factious; inject themselves with insulin, can detect by measuring the C-peptide in blood.

Answer 69

Islet cell tumor ZOLLINGER-ELLISON SYNDROME (GASTRINOMAS) -secrete gastrin lead to extreme gastric acid secretion - severe peptic ulceration which is intractable to usual therapy & occurs in an unusual location, such as jejunum; think of ZE syndrome in patient with intractable jejunal ulcer. Laboratory- see raised basal level of gastric acid - limited rise in gastric acid secretion by gastrin injection Rx - histamine (H2) blockers and excision of neoplasm

Answer 70

Biosynthesis of insulin - Preproinsulin converted to proinsulin (rough endoplasmic reticulum) - Secretory granules (Golgi apparatus), proinsulin & Ca-dependent endopeptidases - Insulin, C-peptide and Amylin are released from β-cell - Insulin exists as monomer, dimer and/or hexamer; * BIOLOGICALLY ACTIVE FORM IS THE MONOMER * Hexamer, form stored in secretory granules

Answer 71

INSULIN SECRETION - Glucose metabolism alters the cellular ratio of ATP/ADP, inhibition of ATP-sensitive K+ channels results in depolarization of the β-cell - Activation of voltage-dependent Ca+2 channel - Influx of Ca yields increased intracellular Ca+2 and stimulates PI turnover - PI turnover to form inositol triphosphate further increases intracellular calcium levels - Insulin secretion ultimately requires a rise in intracellular calcium

Answer 72

GLUCOSE is the principal stimulus for insulin secretion Agents that STIMULATE INSULIN RELEASE - glucose, glucagon, gastrin, secretin, ketones - amino acids, isoproterenon (beta 2 agonist), vagal stimulation, fatty acids, suldonylureas Agents that INHIBIT INSULIN RELEASE - beta 2 antagonist - alpha 2 agonist - somatostatin - diazoxide

Answer 73

1. Insulin receptor has an α and β subunit; insulin binds to external α-subunit 2. β-subunit of receptor is located transmembrane 3. β-subunit autophosphorylation of tyrosine residues↑tyrosine kinase activity which is critical for insulin response Diabetic - fasting glucose >126 - 2 hours after meal >=200

Answer 74

Type I - 10% of all diabetics - Low circulating insulin levels; antibodies to islet cells - Prone to KETOACIDOSIS TYPE II - 90% of diabetics; ASSOCIATED WITH OBESITY - Normal/elevated basal insulin levels - Insulin resistance/decreased number of insulin receptors

Answer 75

SOURCES Historically Porcine…. Today, insulin sequence is human or modified -why porcine? Readily available. Low immunogenicity -Human derived initially by chemical modification of porcine insulin B-30 to Threonine -Recombinant methods A CHAIN - human; threonine, serine - porcine; threonine, serine B chain - human; isoleucine, threonine - porcine; isoleucine, ALANINE INSULIN PREPARATIONS ; background - Insulin preparations vary in their onset, duration of action and species source - Variability in response most magnified with long acting preparations - Variation in zinc:insulin ratio and crystal size influences duration (hexamer, monomer)

Answer 76

RAPID ACTING (3); onset 5-15 min, peak 30-90min, lispro peak is 30-120 min, duration <5hrs 1. Insulin aspart 2. Insulin glulisine 3. Insulin Lispro ``` SHORT ACTING (1) - Regular Insulin; onset 30-60 min, lead 2-3 hr, duration 5-8hr ``` Intermediate (3) ; PROTEIN IS PROTAMINE 1. NPH/isophane insulin; onset 1-4hr, peak 4-10hr, duration 10-18hr 2. Mix insulin aspart + aspart protamine ; onset 10-20min, peak 1-4hr, duration 18hr 3. Mix insulin lispro + lispro protamine Long acting (3) ; onset 0.5-4hr 1. Insulin Detemir; duration 18-23 hr 2. Insulin Glargine; duration 24hr 3. Insulin degludec; duration >42hr

Answer 77

RAPID ACTING INSULIN Insulin ASPART 1) Replace proline at Beta chain 28 with aspartic acid 2) Rapidly changes to monomer when injected - Absorbed 3 times faster from subcutaneous site than regular insulin 3) Inject just prior to meal (5 min) 4) Injected sub-cutaneous, insulin infusion pumps and IV 5) Compatible only with NPH insulin Insulin LISPRO 1) Insulin analogue of human insulin; Inversion of amino acids Proline-Lysine at positions 28 & 29 of Beta chain Lispro (Lys-Pro Beta chain 28&29) 2) Exists primarily in monomer form 3) Inject sc, infusion pump and IV 4) Inject 15 min prior to meal or just after a meal 5) Compatible only with NPH insulin in the syringe Insulin GLULISINE 1) Insulin analogue: glutamate replaces lys at B29 &Lys replace Asparagine at B3 2) Inject sub-cutaneous, insulin infusion pumps and IV 3) Inject 15 min before a meal or within 20 min of starting a meal 4) Compatible only with NPH insulin in the syringe***

Answer 78

1. Short acting insulin - REGULAR | 2. Intermediate acting insulin; ISOPHANE INSULIN SUSPENSION (NPH)

Answer 79

1. Insulin DETEMIR 2. Insulin GLARGINE (LANTUS) 3. Insulin DEGLUDEC

Answer 80

1. Site of injection abdomen > arm > thigh > buttocks 2. Blood flow 3. Insulin preparation 4. Physical activity 5. Increased insulin requirements - fever, hyperthyroidism, surgery, trauma, infection 6. Decreased insulin requirement - nausea/ vomiting; hypothyroidism, renal impairment, liver impairment

Answer 81

1. Hypoglycemia, most common adverse effect a) SYMPTOMS: sweating, dizziness, nervousness, tremor, hunger progress to confusion, disorientation, unconsciousness b) CAUSE: incorrect dosage, timing, missed meal 2. Hyperglycemia a) Symptoms thirst, loss of appetite, drowsiness, ketones or acetone on breath b) Cause - inappropriate dosage of insulin - eating more than meal plan 3. Insulin allergy - local redness, itching and swelling at injection site reaction to additives or insulin; usually stops after a week - systemic rare 4. Lipodystrophies a) Lipohypertrophy - Accumulation of fat at injection site; avoid by rotating injection sites b) Lipoatrophy - Atrophy of subcutaneous fat at site of injection SPECIAL CASES OF INSULIN USE 1. Gestational diabetes 2. Type II diabetics requiring intermittent insulin therapy

Answer 82

SYNTHETIC AMYLIN ANALOG (PRAMLINTIDE) MECHANISM; Synthetic amylin analog. Amylin released with insulin by βeta cells. Amylin actions include: - slows gastric emptying - amylin suppresses glucagon secretion following a meal - leads to suppression of endogenous glucose output from the liver - satiety lower decreased caloric intake and potential weight loss USE - approved for Type I and 2 diabetics - Injected sc

Answer 83

1. Stimulate insulin release - drug class; Sulphonylureas, Meglitinides - agents; Chlorpropamide, glyburide repaglinide, nateglinide 2. Decrease hepatic glucose - drug class; Biguanides - agents; METFORMINE (most common drug for type2) 3. Decrease carbohydrate absorption - drug class; Αlpha-glucosidase - agents; Acarbose, Miglitol 4. Peripheral cell insulin sensitizers - drug class; Thiazolinediones - agents; Pioglitazone 5. Amylin analogs - drug class; Amylin analogs - agents; Pramlinitide 6. Glucagon-like analog - drug class; Glucagon Like Peptide 1 agonist - agents; Exanatide & Liraglutide 7. Dipeptidyl peptidase IV (DPP-4) inhibitor - drug class; Dipeptidyl Peptidase IV Enzyme Inhibitor - agents; Sitagliptin, Saxagliptin 8. Increase glucose excretion - drug class; Sodium-glucose co- transporter 2 (SGLT2) inhibitor - agents; Canagliflozin

Answer 84

SULPHONYLUREAS 2 main MoA 1. Stimulate insulin release -Binds to cell surface receptor decreases conductance of ATP-sensitive K+ channels, causes membrane depolarization -Cellular response of Ca+2 influx through voltage sensitive Ca+2 channel -Increased intracellular influx of calcium ions and insulin secretion 2. Extrapancreatic effect - Increase number of insulin receptors - Stimulates synthesis of glucose transporters - Decrease hepatic gluconeogenesis 2 generations - First Generation: Chlorpropamide, Tolbutamide & Tolazamide - Second Generation: Glimepiride, Glyburide, Glipizide First and Second Generation Oral Hypolycemics a. All undergo hepatic metabolism and renal excretion b. Second generation advantages over 1st generation - 100 times more potent (2nd vs 1st) - Less less binding displacement drug interactions - Second generation have less water retention

Answer 85

SULPHONYLUREAS Adverse reactions a. Hypoglycemia b. Contraindication ketoacidosis must use insulin c. Chlorpropamide - water retention enhanced action of ADH - alcohol induced flushing - cholestatic jaundice Contraindications - sulfonamide allergy - DIABETIC KETOACIDOSIS Drug interactions a) Miconazole, erythromycin and ketoconazole inhibit P450 isozyme - higher incidence of hypoglycemia b) β-blockers, salicylates, NSAIDs (binding displacement)

Answer 86

MEGLITINIDES (REPAGLINIDE, NATEGLINIDE) Adverse reactions - Hypoglycemia CONTRAINDICATIONS - KETOACIDOSIS must treat with insulin DRUG INTERACTIONS a) Miconazole, erythromycin and ketoconazole inhibit P450 isozyme - higher incidence of hypoglycemia b) Metabolism increased by inducers of Cyp 3A4 (rifampicin & carbamazepine)

Answer 87

BIGUANIDES (METFORMIN) 1. Phenformin 2. Metformin Contraindications - Presence of renal or hepatic disease - Congestive heart failure - Ketoacidosis - History of lactic acidosis Adverse reactions - Diarrhea, nausea, vomiting, flatulence incidence is 30% - Decreased absorption of vitamin B12 - Lactic acidosis worsened by alcohol METFORMIN has USE not related to diabetes - Polycystic ovary disease (PCOD) and infertility related to obesity -PCOD associated with high LH, androgen excess, insulin resistance - Used prior to conception - Insulin inhibits sex hormone binding globulin synthesis –higher free androgens - Metformin reduces insulin resistance (decrease in hepatic glucose output)

Answer 88

α -GLUCOSIDASE INHIBITORS, ACARBOSE, MIGLITOL Adverse effects 1. High incidence of flatulence, abdominal pain & diarrhea 2. Acarbose-Elevated transaminase levels 3. Acarbose > Miglitol Incidence of Flatulence & GI pain Contraindications 1. Diabetic ketoacidosis 2. Acarbose liver cirrhosis

Answer 89

THIAZOLINEDIONES (PIOGLITAZONE and ROSIGLITAZONE) Adverse effects and contraindications 1. Hepatic dysfunction, Elevated transaminase levels - must monitor liver enzymes!! - DO NOT USE IN LIVER DISEASE 2. Edema 3. FDA BLACK BOX WARNING: May cause or worsen heart failure 4. Contraindicated in moderate to severe Heart Failure (Class III & IV)

Answer 90

GLUCAGON LIKE PEPTIDE-1 (GLP-1) Agonists (EXENATIDE, LIRAGLUTIDE & DULAGLUTIDE) Adverse effects - hypoglycemia - acute pancreatitis - FDA BLACK BOX WARNING Thyroid cancer Precautions/contraindications - Liraglutide family history of thyroid cancer

Answer 91

DIPEPTIDYL PEPTIDASE IV (DPP-4) INHIBITORS (ALOGLIPTIN, SAXAGLIPTIN & SITAGLIPTIN) Adverse effect - hypoglycemia, - hypoglycemia risk increased when combined with sulphonylureas or metaglinides - pancreatitis, must discontinue IMMEDIATELY** - elevated liver enzymes, discontinue - worsen renal impairment Precaution and contraindication - no contraindications at this time - must reduce dose when used with a CYP3A4 inhibitors (ketoconazole, atazanvir, erythromycin)

Answer 92

SODIUM-GLUCOSE CO-TRANSPORTER (SGLT2) INHIBITORS (CANAGLIFLOZIN, DAPAGLIFLOZIN and EMPAGLIFLOZIN) Adverse effects 1. Increased genitourinary infections (bacteria and mycotic); due to increased glucose now present in urine 2. Hyperkalemia; worse with K sparing diuretics 3. Hypotension Precautions and contraindications - Severe renal dysfunction - FDA Warning for increased ketoacidosis

Answer 93

1. GLUCAGON 2. DIAZOXIDE - ADMINISTERED ORALLY TO INDUCE HYPERGLYCEMIA - Interacts with ATP-sensitive K+channel on the pancreatic Beta-cell - Used in patients with insulin secreting tumors - Side effects include sodium and water retention

Answer 94

1. Induce hypoglycemia (3) A. Sulphonylureas, metaglinides B. Insulin C. DPP-4 inhibitors, GLP-1 agonists 2. Must monitor hepatic enzymes (3) A. Acarbose B. Thiazolinediones C. DPP-4 inhibitors 3. Weight gain and water retention (2) A. Thiazolinediones B. Chlorpropamide

Answer 95

Type I - body habitus ; Non obese - age of onset; Earlier - insulin resistance; No - family history; 10% Type II - body habitus; Obese (BMI >95) - age of onset; later - insulin resistance; yes (acanthosis, lipids, HTN, PCOS) - family history; 75-90%

Answer 96

Type 1 Definition - Chronic disorder of metabolism; carbs and fat - Absolute/relative deficiency of insulin secretion - Ineffective response to insulin - Hyperglycemia Epidemiology - incidence increase as you go farther from the equator - more common in males/adolescence (10-14yrs) Gene - HLA DR3/4 - pat has a trigger; e.g cold, virus * *Both induce autoimmunity - beta cell destruction (80% loss) - type 1 diabetes Risk factors • Viruses • Diet • Higher SES • Obesity • Vitamin D deficiency • Season (winter/spring) Presentation - 3 Ps; polyuria, polydipsia, polyphagia - Weight loss - DKA; in 25% of cases - Silent Criteria - A1C >= 6.5% - Fasting BG >=126mg/dL - 2 hr BG >=200mg/dL - random BG >=200mg/dL Differential diagnosis • Critical illness • Medications (steroids) • Neonatal • Gestational Associations 1. Thyroiditis; anti GAD 2. Celiac; tTG 3. Addison’s 4. Autoimmune polyglandular syndrome 2 5. IPEX; immune dysregulations, polyendocrinopathy, enteropathy, X-linked. Complications • Hypoglycemia (BG <70) • Hyperglycemia • DKA • Growth • Autoimmune diseases • Psychiatric (depression, eating disorders) • Vascular • Nephropathy • Hypertension • Retinopathy • Neuropathy • Cardiovascular • Gastroparesis

Answer 97

Type 2 Prevalence • 1/3 new cases of DM <18 y/o • Most common 10-19 y/o ``` Pathogenesis • Hyperglycemia • Insulin resistance • Not immune mediated • Risk factors - OBESITY - Family history - Specific racial/ethnic groups - Female ``` Presentation • Asymptomatic • Symptomatic • DKA • Hyperglycemic hyperosmolar (non ketotic) state Screening 1. BMI >=85th AND >=2 of the following • T2DM in first or second degree relative • High risk racial/ethnic group • Signs of insulin resistance ((HTN, PCOS, acanthosis, dyslipidemia) • Maternal hx diabetes or gestational diabetes ``` Management goals • Glycemic control • Improve insulin sensitivity • Treat comorbidities • Prevent vascular complications ***METFORMIN • Mechanism of action - Decreases hepatic glucose production - Improves insulin sensitivity • Side effects - Cardiac - GI - Renal - Lactic acidosis • Start low, work up ```

Answer 98

Pathophys Type I - HLA DR3/4 - pat has a trigger; e.g cold, virus * *Both induce autoimmunity - beta cell destruction (80% loss) - type 1 diabetes ``` Type II • Hyperglycemia • Insulin resistance • Not immune mediated • Risk factors - OBESITY - Family history - Specific racial/ethnic groups - Female ```

Answer 99

Diagnosis - A1C >= 6.5% - Fasting BG >=126mg/dL - 2 hr BG >=200mg/dL - random BG >=200mg/dL Differential - Type I; Critical illness • Medications (steroids) • Neonatal • Gestational Complications • Hypoglycemia (BG <70) • Hyperglycemia • DKA • Growth • Autoimmune diseases • Psychiatric (depression, eating disorders) • Vascular • Nephropathy • Hypertension • Retinopathy • Neuropathy • Cardiovascular • Gastroparesis **HYPOGLYCEMIA • Definition-BG <70 • Symptoms (tachycardia, diaphoretic, cranky) • Classification • Risk factors • Insulinoma • Ketotic hypoglycemia

Answer 100

``` Management Type I 1. Depends on age 2. Education - Testing - Administration - Signs/symptoms 3. Glycemic control - Daily monitoring - HbA1C 4. Insulin - Rapid acting; Lispro (Humalog), Aspart (novolog) - Short acting; regular insulin - Intermediate acting; NPH (Humulin) - Long acting; glargine (Lantus), determinants (levemir) 5. Diet 6. Activity ``` ``` **Indications for pump • Recurrent severe hypoglycemia • Wide fluctuations • Suboptimal control • Microvascular complications • Lifestyle • Other; young children/infants, adolescents with eating disorders, Kenosha prone, athletes ```

Answer 101

Pathophys; ``` Clinical presentation • 3 Ps - polyphagia, polydipsia, polyuria • Weight loss • Symptoms usually < 1 month • Dehydration • Kussmaul • Acetone • Abdominal pain • Vomiting • Obtundedcoma ``` Diagnosis • Hyperglycemia (>200) AND • Acidosis (pH<7.30 or bicarb <15) AND • Ketosis-ketonemia, ketonuria; beta OH butyrate (>= 3) • Glucosuria • Leukocytosis • Elevated amylase • Electrolyte abnormalities Differential - gastroenteritis - ingestion - infections - pancreatitis - appendicitis

Answer 102

Management **MAINSTAY is FLUIDS and INSULIN 1. Correct dehydration • Treat shock first*** • NORMAL SALINE initial fluid of choice **** • Can change to 0.45% NS later • 1.5-2 X maintenance is sufficient • Add glucose when BS<300; D5W for BS <250-300, D7.5W for BS <250, D10W for BS <200 2. Correct acidosis • Bicarb rarely needed • Correcting dehydration, providing insulin corrects acidosis 3. Correct electrolytes • Sodium; False hyponatremia (1.6 mEq/100 BS). (As blood sugar goes down, sodium should come up). • Potassium; Add when K <5.5 • Phosphorous; KPhos with first liter of fluids • Chloride; Too much worsens acidosis ``` 4. Provide insulin • Stop pump/exogenous insulin • Bolus not needed • Give only regular insulin IV; 0.05-1 unit/kg/hr • Never stop insulin infusion*** ``` ``` **Monitor • ABG • Glucose STAT and q1h • Electrolytes STAT and q2h • EKG • Flowsheet-meds, I/O, BS • Frequent neuro exams (cerebral edema can occur) • Mannitol (Incase you develop cerebral edema) ```

Answer 103

Complications Osmol Serum = 2Na + glucose/18 + BUN/2.8 OR Osmol serum = 2Na + glucose/20 + BUN/3 1. Cerebral edema • Clinically apparent in ~1% DKA • 60-90% of all DKA deaths • Prevent • Treat with MANNITOL, hypertonic saline, ventilation ** Also; • Dehydration, hypoperfusion • Intrinsic factors **Degree of edema may correlate with dehydration, hyperventilation at presentation **Risk for cerebral edema in DKA; • Younger • New onset • Longer duration of symptoms 2. Hypoglycemia; we want blood sugar to go down about 100 per hr 3. Electrolyte abnormalities 4. Thrombosis, PE Summary • Diabetic ketoacidosis presents commonly in children • Diagnosis is easy with few tests and good H and P • Insulin and rehydration are key to management • Treat acidosis, no just hyperglycemia • Attention to details prevents complications

Answer 104

Normal saline (0.9%) or lactated ringer’s bolus of 10-20ml/kg over 1-2 hrs ** WE DO NOT GIVE INSULIN BOLUS IN A CHILD. WE DO INSULIN INFUSION BUT MOST START FLUID FIRST

Answer 105

**Begin infusion of dextrose containing isotonic fluids at 1.5-2 times maintenance and begin insulin infusion of 0.1 units/kg/hour **Remember start giving dextrose if blood sugar is <300 D5W; 250-300 D7.5W; 200-250 D10W; <200 This is given to correct the acidosis because insulin doesn’t correct the acidosis just the hyperglycemia

Answer 106

THYROID ; colloid, follicular epithelial cells, C cells 1. COLLOID serves as a reservoir of materials for thyroid hormone production and, to a lesser extent, acts as a reservoir for the hormones themselves. Colloid is rich in a protein called thyroglobulin. 2. FOLLICULAR EPITHELIAL CELLS convert thyroglobulin into T4 and T3 3. T4 and T3 INCREASE the basal metabolic rate 4. PARAFOLLICULAR CELLS (C cells) - secrete CALCITONIN; • Causes absorption of Ca by the skeletal system • Inhibits resorption of bone by osteoclasts

Answer 107

Hyperthyroidism • INCREASE in Free T4 and/or Free T3 • Hyperthyroidism - HYPERFUNCTION of Thyroid - e.g., Graves Disease • Thyrotoxicosis - Excessive LEAKAGE of thyroid hormone • Certain thyroiditises • RESULT: Hypermetabolic State CAUSES (Most Common): • Graves’ Disease • Ingestion of excess thyroid hormone; for Rx of hypothyroidism • Hyperfunctional Multinodular Goiter • Hyperfunctional Adenoma of the Thyroid • Certain Thyroiditises Other less common causes • TSH Producing Pituitary Adenoma (RARE) • Struma Ovarii; Thyroid tissue in the ovary Signs and symptoms • Due to increased thyroid hormones - INCREASED Basal Metabolic Rate - GI: hypermotility, malabsorption, diarrhea • Due to overactive SYMPATHETIC NERVOUS SYSTEM - Nervousness, Tremor, Tachycardia, Palpatations, Hyperreflexia and Irritability - Possible CHF (esp. in the elderly) - Wide Gazing Stare and Lid Lag; Stimulation of levator palpebrae superioris (eyelids do not come down as they should) • Heat Intolerance

Answer 108

THYROID STORM • Abrupt onset of severe and life threatening thyrotoxicosis with exaggeration of usual symptoms of hyperthyroidism Clinical presentation • CV- marked tachycardia seen, as high as 140 beats/min • Thermoregulatory dysfunction- temperature can go quite high- up to 104-1060F • GI- can see nausea, vomiting, diarrhea • Most common in GRAVES’ DISE!SE • Can be seen following surgery on thyroid- due to release of excessive hormone • May cause DEATH ``` • SCREEN: Measure fT4 and TSH - Increased fT4 - Markedly Decreased TSH (Primary -- Thyroid) • Sometimes due to T3 - Then measure T3 ```

Answer 109

1. Beta-Blockers for adrenergic tone 2. Thionamides to BLOCK New Hormone Synthesis 3. Agents to PREVENT CONVERSION of T4 to T3 4. Radioiodine to ABLATE the Thyroid Function

Answer 110

ENDEMIC CRETINISM • Was common in areas of the world where dietary iodine deficiency is endemic • With widespread supplementation of food with iodine it is rarely seen **Hypothyroidism - most cases are PRIMARY (THYROID) • Surgery • Hashimoto’s thyroiditis • Primary Idiopathic

Answer 111

MYXEDEMA **Amorphous material in extracellular area most cases of hypothyroidism are PRIMARY (THYROID) • Surgery • Hashimoto thyroiditis • Primary Idiopathic Labs 1. TSH is MOST SENSITIVE - increased in primary (Thyroid) - decreased in secondary (pituitary) 2. T4 DECREASED in BOTH

Answer 112

GRAVE’S DISEASE - overproduction of thyroid hormone, which causes enlargement of the thyroid and other symptoms such as exophthalmos, heat intolerance and anxiety. S&S 1. TRIAD** • Thyrotoxicosis (100%) [Hyperthyroidism] • Exopthalmus (40%) • PRETIBIAL Myxedema (LOCALIZED, Infiltrative dermopathy) [Minority] 2. Thyroid enlargement, diffuse 3. May be bruit over thyroid

Answer 113

Exopthalmus Graves’ disease TRIAD; ** • Thyrotoxicosis (100%) [Hyperthyroidism] • Exopthalmus (40%) • PRETIBIAL Myxedema (LOCALIZED, Infiltrative dermopathy) [Minority]

Answer 114

GRAVE’s disease; triad of thyrotoxicosis, exopthalmus, pretibial myxedema (localized, infiltrative dermopathy) Multiple autoantibodies • TSI (Binds TSH Receptor) Stimulates Thyroid Hormone Production • TGI (Binds TSH Receptor) Stimulates Growth • TBII -- TSH Binding Inhibitor Immunoglobulin - prevents binding of TSH - may stimulate or inhibit Morphology (Thyroid) • Diffuse Hypertrophy and Hyperplasia • Follicular Cells: tall, columnar, and crowded • May have papillae WITHOUT FIBROVASCULAR CORE***; This contrasts with papillary cancer which has papillary structures with fibrovascular cores • Colloid- shows scalloping Think of Graves’ as systemic autoimmune disease with manifestations in several organs A. HEART; hypertrophied and ischemia B. OPHTHALMOPATHY; mucopolysaccharides and lymphocytes. *Many think autoimmune reaction, not direct effect of thyroid hormone C. DERMOPATHY (Pretibial myxedema) - Mucopolysaccharides and lymphocytes - orange peel texture LABS - Radioiodine scan; diffuse uptake - Increased fT4 and T3 - Decreased TSH Treatment 1. Beta blocker 2. Thinonamides (Propylthiouracil) 3. Radioiodine ablation 4. Surgery

Answer 115

GOITERS (diffuse and nontoxic goiter and multinodular goiter) 1. Iodine deficiency ; iodine content of plants and animals • Determined by soil content • Areas with excess rainfall and mountains- low iodine content • Iodized salt helps, but Iodine deficiency on rise -recent study show 11% deficient- -WHO says world health problem 2. Endemic goiter • Most common in mountainous areas • Endemic=>10% of population 3. Sporadic • Many causes • Environmental and genetic • Often exact cause not known

Answer 116

PLUMMER’S SYNDROME Goiter S&S 1. Enlargement of thyroid can cause A. Cosmetic problems or B. Airway obstruction, dysphagia, compression of large vessels in the neck and thorax (Mass Effect) 2. PLUMMER’s SYNDROME 3. Overall most goiters are EUTHYROID (thyroid is normal) 4. Hypothyroid Less Common 5. May MASK or MIMIC Neoplasms; this is why we do fine needle aspirations to rule out cancer

Answer 117

GOITERS Morphology • Due to Hypertrophy and Hyperplasia; Caused by INCREASED TSH • Usually T3, T4 levels wnl; TSH slightly elevated or wnl • If have episodes of STIMULATION & INVOLUTION - RESULT; nodular or multinodular goiter - asymmetric nodules

Answer 118

``` THYROIDITIS 1. Nonspecific Lymphocytic Thyroiditis 2. Hashimotos Thyroiditis; if you see germinal centers 3. Subacute (Granulomatous) Thyroiditis • de Quervain’s 4. Other - acute bacterial - Mycobacterium TB or fungi - RIEDEL’s thyroiditis ```

Answer 119

NONSPECIFIC Lymphocytic Thyroiditis Morphology • Mild Symmetric Enlargement • Multifocal Small Lymphocytes - If Germinal Centers Present, Think Hashimotos Labs • May Get THYROTOXICOSIS due to Injury to Thyroid Follicles - Increased T4 and T3 - Decreased TSH - Radioiodine Scan: DECREASED UPTAKE (graves’ has increased uptake)

Answer 120

HASHIMOTO’S THYROIDITIS Pathogenesis A. Similar Abs as Graves - but anti-TSH receptor Ab blocks action of TSH - Result; HYPOTHYROIDISM B. Believed to be a primary T-cell defect Morphology - usually diffuse, symmetric enlargement - mononuclear infiltrate with **GERMINAL CENTERS - small thyroid follicles ``` Labs 1. HASITOXICOSIS - increased T4 and T3; decreased TSH - Radioiodine scan; decreased uptake (Graves’ see increased uptake diffusely) 2. HYPOTHYROID - most often - decreased T4 and T3 - Increased TSH ``` * *INCREASED risk of developing B-CELL LYMPHOMAS * *Molecular studies suggest a predisposition to papillary carcinoma

Answer 121

De QUERVAINS THYROIDITIS Morphology (GIANT CELL mixed with neutrophils and lymphocytes) • PMN infiltrate • Scattered lymphocytes and plasma cells • Macrophages • Disrupted follicles with extruded colloid; RESULT - GRANULOMATOUS rxn Labs • INCREASED leukocyte count • INCREASED sedimentation rate • INCREASED T4 & T3; disrupted follicles • DECREASED TSH • Radioactive iodine uptake DECREASED; Low TSH ** Typically SELF-LIMITED (patients will be fine later)

Answer 122

RIEDEL’s THYROIDITIS **Whole thyroid gland is fibrotic**

Answer 123

``` Clinical clues • Solitary nodules may be more often neoplastic than multiple; Debated in literature • “HOT” nodules more likely BENIGN - Younger pts > Neoplasms - males> Neoplasm - Radiation>incidence of malignancy ```

Answer 124

THYROID ADENOMA Pathogenesis • SOMATIC MUTATIONS (50 - 75%); Chronic stimulation of cAMP pathway • RESULT: autonomously functioning MONOCLONAL Thyroid Adenoma • Mutations of Gs-alpha mimic exaggerated TSH stimulation ``` Morphology • Solitary, Spherical, Encapsulated • Various Histologic Types • Usually NO Papillary Changes; Think of Encapsulated Papillary CA • Well-Defined, Intact CAPSULE ``` Diagnosis • Careful Histologic Examination • MALIGNANT TRANSFORMATION does NOT occur EXCEPT in exceptional circumstances

Answer 125

CARCINOMA OF THE THYROID 1. Papillary CA - MOST COMMON 2. Follicular CA 3. Medullary CA 4. Anaplastic CA

Answer 126

PAPILLARY CA **MOST COMMON thyroid carcinoma S&S ; MASS IN NECK - thyroid OR - cervical LN; isolated involved cervical LN ; NO CHANGE In prognosis * *remember features - psammoma body - ORPHAN ANNIE NUCLEI - GROUND GLASS NUCLEI

Answer 127

FOLLICULAR CA ``` • SECOND Most Common • PEAK: Middle Age • May be predisposed - In iodine deficient areas - Nodular Goiter • SIGNS & SYMPTOMS: - Solitary “COLD “ nodule (may be hyperfunctional) ``` Rx: • Surgery • Better Differentiated Ones May Respond to SUPPRESSION by Thyroid Hormones (NOTE: Suppresses TSH)

Answer 128

MEDULLARY CA Neuroendocrine Tumor • Derived from parafollicular cells (C cells) - secrete CALCITONIN - May secrete Other polypeptide hormones e,g VIP 2 forms 1. Sporadic (80%); 5th to 6th decade 2. MEN IIa and IIb - germ line mutations of RET PROTOONCOGENE - younger pts PROGNOSIS - sporadic and MEN IIb; AGGRESSIVE - MET via blood - familial that are NOT MEN; USUALLY LESS AGGRESSIVE

Answer 129

ANAPLASTIC CARCINOMA * Bulky * Grows Rapidly beyond thyroid; Into NECK Structures * Giant cells or squamoid cells or sarcomatous cells * Sometimes small cell; Distinguish from lymphoma

Answer 130

PARATHYROIDS 1. ACTIVATES OSTEOCLASTS • Ca Released from BONE (Resorption) ``` 2. KIDNEY • Reabsorption of Ca • INCREASED cAMP in Urine • Conversion of 25OH-Vit D to 1,25 diOH-VitD • INCREASED Urinary PO4 ``` 3. GI- get increased Ca Absorption with 1,25diOH Vit D 4. NET: INCREASED Ionized Ca

Answer 131

1. Primary - PTH adenoma or hyperplasia or carcinoma (very rare) 2. Secondary 3. Tertiary

Answer 132

PRIMARY HYPER -PTH; caused by - • Autonomous ADENOMA (#1)- 75-80% cases • HYPERPLASIA- 10-15% • Carcinoma- less than 5% - adults; females - sporadic or MEN - Cause BONE RESORPTION and RENAL DISEASE (Stones and nephrocalcinosis) * *INCREASED Ionized Ca ``` Pathogenesis • SPORADIC (95%) • Small % are Inherited (MEN I) • Some adenomas have genetic alterations called- Parathyroid Adenoma 1 (PRAD 1) - Encodes Cyclin D1 - Inversion of Chromosome 11; PRAD 1 JuXtaposed to 5’ PTH gene regulator, caused overexpression of cyclin D1, results in proliferation of cells - 10-20% of sporadic adenomas ``` MEN I - homozygous loss of; PUTATIVE SUPPRESSOR GENE ON - chromosome 11q13 - 20% of sporadic adenomas * *Many without these defects Morphology 1. Adenomas - see circumscribed lesion with loss of fat - RIM of COMPRESSED NORMAL PARATHYROID 2. Hyperplasia - see diffuse enlargement of 2 or more glands; usually all enlarged - etiology; sporadic or MEN I or MEN IIa

Answer 133

SECONDARY HYPER-PTH • Due to excessive secretion of PTH caused by hypocalcemia, results in parathyroid hyperplasia • Seen in patients with CHRONIC DEPRESSION of Serum Calcium- leading to overactivity of parathyroid gland - Associated With Increased PO4- directly depresses serum Ca Causes • RENAL FAILURE #1 Cause • Other Causes; Inadequate Diet of Ca, Steatorrhea (Fat BINDS Ca), Vit. D Deficiency Parathyroid glands are hyperplastic • SIGNS & SYMPTOMS: - Bone Abnormalities & Other Changes Less Severe than primary ``` CALCIPHALAXIS • Seen in CHRONIC RENAL FAILURE • Due to INCREASED PHOSPHATES - PPT. Ca in Blood Vessels - May Cause ISCHEMIA to Skin and Other Organs ```

Answer 134

TERTIARY HYPERPARATHYROIDISM • Occurs when treatment for secondary HYPER-PTH either quits working, does not respond or patient not treated • SECONDARY HYPER-PTH becomes AUTONOMOUS & excessive; Can no longer reverse this condition

Answer 135

HYPOPARATHYROIDISM • Far LESS COMMON than HYPER-PTH ``` Causes ; FAMILIAL HYPOPARATHYROIDISM • PRESENTS in Childhood with the ONSET of CANDIDIASIS - Then Hypoparathyroidism - In Adolescence Adrenal Insufficiency develops ``` Signs and symptoms 1. TETANY due to HYPOCALCEMIA • Neuromuscular Irritability • Tingling to Spasm to Laryngospasm to Seizures • Chvostek sign-; Tap along facial nerve, induce contactions of muscle of eye, mouth or nose • Trousseau sign- inflate BP cuff, induce carpal spasm, goes away when deflate the cuff

Answer 136

PSEUDOHYPO-PTH Defects PSEUDOHYPOPARATHYROIDISM TYPE 1 1. Diminished cAMP response to PTH Due to • A Deficiency of Gs-Alpha protein -OR- • Abnormalities of the Hormone Receptor Complex 2. CLINICAL • Round Facies, Short Stature, Short Metacarpal and Metatarsal Bones (Albright Hereditary Osteodystrophy) ``` PSEUDOHYPOPARATHYROIDISM TYPE 2 1. Normal PTH-Induced cAMP • With a Blunted response to the Second Messenger 2. Do not have developmental defects ``` * HYPOCALCEMIA RESULTS * Causes Secondary Parathyroid Hyperfunction; INCREASED PTH

Answer 137

1. Active transport of iodide into thyroid follicular epithelial cells occurs via the Na/I symporter - Active Transport process requires ATP - Inhibited by uncouplers of oxidative phosphorylation (lose ATP production) - Inhibited by thiocyanate and perchlorate 2. Iodide can be concentrated in thyroid to a level over 100 times higher than plasma. Most individuals have a thyroid:plasma ratio of between 20-50:1 3. Iodide trapping stimulated by TSH

Answer 138

IODINATION OF TYROSINE RESIDUES 1. Iodide oxidized by Thyroid peroxidase in the presence of hydrogen peroxide 2. Thyroid peroxidase located on the APICAL MEMBRANE. The oxidation of iodide provides a more reactive iodide that allows for iodination of tyrosyl residues of thyroglobulin and this is called ORGANIFICATION. The iodination will form monoiodotyrosine (MIT) and diiodotyrosine (DIT) Formation of TRIIODOTHYRONINE AND THYROXINE 1. Thyroid peroxidase and hydrogen peroxide once again catalyze coupling of MIT and DIT together to form T3 or 3,5,3’-triodothyronine or the combination of 2 DIT to form (T4) or 3,5,3’5’-tetraiodothyronine (T4) 2. The thyroglobulin still contains the T4 and T3 residues covalently bound and is stored as COLLOID in the lumen of the follicle

Answer 139

RELEASE OF THYROID HORMONE 1. TSH stimulates the thyroid and stimulates thyroglobulin endocytosis into vesicles or colloid droplets containing lysosomes 2. The Lysosomes fuse with vesicles or droplets and are necessary for proteolysis. Endocytosis is stimulated by TSH 3. Products of lysosome proteolysis are T4, T3, MIT and DIT. The MIT and DIT are deiodinated and the Iodide recycled 4. Free T3 and T4 are transported into the bloodstream 5. Iodide concentration inversely modulates thyroid hormone secretion 6. Lithium inhibits thyroid hormone release CIRCULATION AND DISPOSITION OF THYROID HORMONES 1. T4 and T3 both released into circulation 2. T4 and T3 transported bound to thyroxine binding globulin (TBG). T4 is also carried bound to transthyretin 3. T4 is the predominant hormone in blood (IMPORTANT, REMEMBER THIS FACT) 4. However, T3 is 3-5 times more active than T4 (IMPORTANT TO REMEMBER) 5. T4 deiodinated to T3 by iodothyronine 5′-deiodinase. - there are 3 isozymes of 5’ deiodinase - isozyme 1 (D1) is expressed in the liver, kidney and thyroid. D1 is responsible for conversion of T4 to T3. D1 is responsible for the majority of circulating T3. D1 is inhibited by propylthiouracil. - Isozyme D2 is expressed in the brain, pituitary, skeletal and cardiac muscle. D2 influences intracellular T3 levels in these tissues. D2 is not responsive to propylthiouracil. 6. 5’-deiodinase highest activity in liver 7. 5’-deiodinase is a mechanism for conversion of T4 to T3 8. Thyroid hormones metabolized by P450. THUS, ENZYME INDUCERS WILL INCREASE CONVERSION OF T4 TO T3.***

Answer 140

PRIMARY HYPOTHYROIDISM: diminished thyroid hormone production and high TSH levels 1. Hypothyroidism 2. Chronic autoimmune thyroiditis or Hashimoto’s thyroiditis. This autoimmune disorder is the most common cause of hypothyroidism in U.S. 3. Thyroid damage due to treatment with Iodine131 4. Surgical removal of the thyroid SECONDARY, pituitary hypothyroidism due to TSH deficiency

Answer 141

1. LEVOTHYROXINE (T4) is the drug of choice 2. Levothyroxine is more consistent than T3 in its therapeutic action. T4 has a prolonged duration of action. T4 can be taken once a day. 3. Levothyroxine has a long half-life of 6-7 days, takes 4 weeks to achieve steady state 4. Liothyronine (T3) has a shorter half-life (2 days), greater variability in response. Can be used for individuals with a 5′-deiodinase deficiency

Answer 142

LEVOTHYROXINE T4 **Adverse effects; CARDIOVASCULAR: Increased incidence of cardiovascular side effects of palpitations, tachycardia, increased blood pressure ``` Drug Interactions A. Agents that reduce thyroxine bioavailability (must stagger dosing to reduce interaction) -Calcium carbonate -Aluminum hydroxide -Cholestyramine and Colesevelam ``` B. Agents that alter thyroid binding globulin -Estrogen (oral contraceptives, estrogen esters) INCREASE serum thyroid binding globulin **CLINICAL ACTION: may need to increase dose of T4 in patient taking oral contraceptives containing estrogen. Conversely, if a woman stops taking oral contraceptives, then the dose of levothyroxine may need to be decreased. -Glucocorticoids, anabolic steroids DECREASE serum thyroid binding globulin C. Agents that inhibit 5'-deiodinase - propylthiouracil - amiodarone D. Warfarin drug interaction - Warfarin and thyroid hormones: addition of thyroxine INCREASES anticoagulant activity of warfarin. - Thyroxine increases catabolism of Vit K dependent clotting factors. - Must monitor INR values more closely when thyroxine is administered or when thyroid hormone dosing is adjusted.

Answer 143

GRAVES’ DISEASE Treatment 1. NSAIDS or aspirin USED TO TREAT symptoms of inflammation only; 2. Propranolol to block hypermetabolic effects of tachycardia, nervousness, tremor caused by the effects of excess T4 3. Thionamides (Antithyroid agents). There are two agents used in the US PROPYLTHIOURACIL and METHIMAZOLE. **** 4. Radioiodine (I131)** to induce thyroid ablation iodine to suppress thyroid hormone synthesis - CONTAINDICATED IN PREGNANCY

Answer 144

``` ANTITHYROID AGENTS (PROPYLTHIOURACIL and METHIMAZOLE) - PROPYLTHIOURACIL inhibits peripheral 5’ deiodinase (D1) conversion of T4 to T3 ``` Use 1. Hyperthyroidism 2. Methimazole appears more effective than propylthiouracil. a) Methimazole half life is 6 h compared to propylthiouracil half-life of 1 h b) Methimazole intrathyroid level is higher than propylthiouracil. 3. Methimazole and Propylthiouracil used for presurgical treatment prior to thyroidectomy 4. During Pregnancy: Propylthiouracil preferred drug during first trimester of pregnancy**. Propylthiouracil shows less incidence than methimazole to induce fetal abnormalities. Agents must be used with caution during pregnancy to minimize hypothyroid state in fetus. After the first trimester propylthiouracil or methimazole can be used but must consider risk of greater hepatotoxicity with propylthiouracil. Adverse reactions 1. Agranulocytosis Methimazole greater risk than propylthiouracil 2. Propylthiouracil associated with hepatic necrosis and nephritis 3. BLACK BOX WARNING: Propylthiouracil associated with liver injury, liver failure and fatalities (Important to remember)

Answer 145

IODINE Use of IODINE - 131 (4) 1. Hyperthyroidism 2. Thyroid carcinoma 3. Can induce hypothyroidism due to damage to thyroid follicular cells 4. Graves’ disease

Answer 146

D. 131I (Radioiodine) CORRECT ANSWER -Radiodine will concentrate in the thyroid and reduce thyroid hormone production. Propylthiouracil or methimazole can be added with radiodine to provide more rapid response. The propylthiouracil will provide an additional benefit of inhibit conversion of T4 to T3.

Answer 147

A. T3 secretion from thyroid CORRECT ANSWER - Methimazole and propylthiouracil do not inhibit T4 or T3 hormone release. B. Thyroid Peroxidase activity - Thyroid peroxidase is responsible for iodination of tyrosine residues as well as formation of thryoxine and triiodothyronine. Propylthiouracil does inhibit this step C. Iodination of tyrosine residues see B Propylthiouracil does inhibit this step D. Peripheral conversion of T4 to T3 - The D1 isozyme of iodothyronine 5'-deiodinase is inhibited by propylthiouracil. The D1 isozyme is responsible for the majority of circulating T3 in plasma.

Answer 148

B. Oral contraceptive (desogestrel/ethinyl estradiol) CORRECT ANSWER - Estrogens increase serum thryoid binding globulin. Ethinyl estradiol is the most common estrogen component in mixed oral contraceptives. C. Simvastatin Statins do not alter thyroid function. However, another drug used to lower cholesterol, cholestyramine, can reduce the bioavailability of levothyroxine. Cholestyramine and levothyroxine dosing should be staggered to prevent a drug-drug interaction.

Answer 149

Levothyroxine Correct Answer Levothyroxine is the drug of choice. Levothyroxine provides a more consistent response in individuals than liothyronine (T3). T4 has a longer half-life which allows for once a day dosing. The half-life is 6-7 days and it will take 4 half-lives or 4 weeks to attain steady state. T3 is more active than T4 and is more likely to induce side effects of tachycardia and nervouseness.

Answer 150

A. Levothyroxine Correct Answer - T3 is transported in plasma bound to thryoxine binding globulin. - Levothyroxine (T4) is transported bound to thyroxine binding globulin and transthyretin.

Answer 151

DIABETES MELLITUS Prevalence • Between 7 and 8% of the US population has diabetes. • The incidence is expected to increase significantly in the future. • Major public health issue! INSULIN RESISTANCE (type 2 diabetes) • Visceral adipose tissue has high insulin requirements. • Lack of exercise leads to decreased skeletal muscle glucose uptake. • Fat lipolysis even in the fed state.

Answer 152

PREDIABETES; fasting blood glucose >110 • Diabetes is a disorder of adipose tissue – the dysglycemia is an end result of pancreatic damage from excessive insulin demands. • The atherogenic processes associated with diabetes begin long before the sugar reaches the diabetic level. * Potential epidemic in the future! * Potential to reverse the process before irreparable pancreatic damage occurs. * Screening important.

Answer 153

Physical exam • Patients are often obese. • Usually normal. • Small fiber neuropathic changes may be present in the feet. • Retinopathy may be present, visible with ophthalmoscope. Labs • Diabetes diagnosed by fasting sugar >126 on 2 occasions. • Or with random sugar >200. • Glucose tolerance testing may identify diabetes earlier. • Glycosuria occurs when the sugar exceeds 180 – so not a good screening test.

Answer 154

``` Adult diabetes Treatment • Lose weight!! • Exercise (>150 minutes per week). • The possibility exists in younger adults to “turn back” diabetes with lifestyle modification ``` Monitoring • Patients have glucometers and should check sugars daily, ideally before eating. • Monitor Hgb A1c every 3 months, with the goal being <6.5-7.0. • Decisions to start or change medications are based on these levels. Medications • Oral meds are used initially. Most are insulin secretagogues, incretin drugs, or agents to decrease insulin resistance. • Most patients will progress to the point that insulin is required. • Insulin ideally given in split doses, long and short acting. BP and cholesterol • Blood pressure should be targeted to 130/80 in diabetics. • Treat cholesterols to get LDL < 100. • Treating TGs and HDL is recommended, but may be difficult if sugar not controlled.

Answer 155

MICROVASCULAR DISEASE • Retinopathy leads to visual loss. Patients should see an ophthalmologist yearly. • Proteinuria is often the first sign of renal involvement. Control of BP and treatment with ACE i may attenuate this. • Loss of GFR may be up to 10cc per year with aggressive renal disease. MACROVASCULAR DISEASE • DM is a huge risk factor for CAD and CVA. • Patients should be counseled on the signs and symptoms of these disease processes. • PAD is also much more common in diabetics. This is a disease process with microvascular and macrovascular elements.

Answer 156

• Diabetes often complicates the treatment of other illnesses. • Patients requiring steroids will often have marked hyperglycemia. • Infection and stress may worsen hyperglycemia in diabetics. • Need to control BS in hospitalized patients. IMMUNE SUPPRESSION • Diabetics are considered immune suppressed. • Increased risk of adverse outcomes and death in diabetic patients with MI, pneumonia, sepsis, CVA.

Answer 157

* Yearly BS in patients at risk. * Yearly eye exam. * Foot care and foot exams. * Aspirin for secondary prevention of macrovascular disease (primary prevention not well proven).

Answer 158

AUTOIMMUNE DIABETES

Answer 159

HYPERCALCEMIA • Hypercalcemia associated with malignancy. • Most common with advanced NSCC lung, breast. • Usually mediated by PTHrp. • Patients with this are often weakened by the malignancy and may be secondarily dehydrated. • Myeloma causes hypercalcemia by activation of osteoclasts. IL-6 possible involved. • Lymphomas cause hypercalcemia by increased vitamin D production. Treatment • Treat with intravenous saline. (Couple liters. Remember hypercalcemia can cause prerenal failure from vasoconstriction) • Bisphosphonates (zoledronic acid, pamidronate) useful. - osteoclasts bind to the med and can’t do anything • Renal function often improves with hydration since severe hypercalcemia is associated with renal vasoconstriction.

Answer 160

Causes • Malignancy, usually advanced stage. (E.g squamous cell cancer of the lung that secrete PTHrp) • Myeloma (hypercalcemia,anemia, bence jones protein) • Granulomatous disorders (macrophages produce Vit D) • Milk alkali syndrome. • Hyperparathyroidism. • Medications, especially HCTZ (not much increase e.g 10.8, 11) Findings • Many causes of mild hypercalcemia, some very uncommon. • Mental status changes much more common with severe hypercalcemia, > 14mg/dL. • Short QT on EKG. **remember HYPOCALCEMIA will have prolonged QT and can cause torsades de point (low risk tho, if you add sotalol type III the you have increased risk of torsades de point from long QT)

Answer 161

MILK ALKALI SYNDROME • Not common - but not rare • Initially described in patients taking milk and sodium bicarbonate for peptic ulcer disease. • Now more likely to be seen in postmenopausal women taking an excessive amount of calcium carbonate, who may have alkalosis from diuretics or vomiting. • Po4 high, normal, or low! • Vitamin D and PTH usually low.

Answer 162

HYPERPARATHYROIDISM • Common cause of mild hypercalcemia. • 85% have parathyroid adenoma. • 14% with hyperplasia (can be seen with MEN syndromes). • Nephrolithiasis common. • Po4- usually normal. • Increased incidence of gout and hypertension. • Osteoporosis with loss of cortical bone. * “Parathyroid scan” - 99m sestamibi * MRI, ultrasound also useful. * Surgery is definitive, since no medical therapy is effective. * Many patients are monitored until need for surgery. * Criteria for surgery include worsening renal function, age <50, worsening osteoporosis, significant hypercalcemia, significant renal stones. * Surgery can be complicated by hypoparathyroidsim.

Answer 163

VITAMIN D DEFICIENCY • Osteomalacia is decreased mineralization of bone. • X rays show cortical thinning. • Vitamin D (25(OH) D level 3ng/mL (normal undetermined but this is low!). • This patient likely has significant malabsorption of calcium. • Decreased vitamin D level is partially nutritional, but may be worsened by low sunlight exposure. * Severe deficiency replaced more quickly with CALCITRIOL. * Daily oral replacement necessary in many patients. * Mild vitamin D deficiency is very common and underdiagnosed. * Mild deficiency usually asymptomatic. * Still some debate on how much vitamin D should be supplemented. * PTH is high.

Answer 164

HYPOPARATHYROIDISM * Common after thryoid or parathyroid surgery. * Often transient and mild, but can be severe. * Severe hypocalcemia treated with INTRAVENOUS CALCIUM. * Autoimmune hypoparathyroidism. A. Chvostek sign - twitching (stroke the angle of the jaw - hyperexcitability of nerves) B. Trousseau sign - spasm (when you inflate BP cuff for 3 min) - adduction of thumb - flex MCP joints - extend interphalangeal joints - flex the wrist **More specific than Chvostek sign.

Answer 165

HUNGRY BONE SYNDROME

Answer 166

HYPOCALCEMIA ** Treat initially with intravenous calcium. Mild HYPOCALCEMIA • Mild hypocalcemia common in hopsitalized patients. • Check ionized calcium. • Correcting for serum albumin id cheaper

Answer 167

PTH • Abnormalities in serum calcium can be stratified according to PTH. • PTH secretion dependent on extracellular calcium. • PTH increases renal calcium resorption and inhibits phosphate resorption. • PTH increases osteoclast activity. • PTH increased synthesis of calcitriol and impairs its degradation. Vitamin D • Remember that conversion to calcitriol is necessary. • Increased calcium resorption from the gut. • Increased calcium release from bone (PTH mediated). • Decreases renal calcium and phosphate excretion. • PTH and hypophosphatemia increase calcitriol synthesis. • Main action of vitamin D is to keep calcium and phosphate available!****

Answer 168

• Phosphate retention and decrease vitamin D synthesis lead to vitamin D deficiency. Phospahe elevation may also lead to low calcium. • Mildly low calcium and vitamin D (which modulates PTH secretion) lead to mild chronic elevation of PTH (secondary hyperparathyroidism). • Mild metabolic acidosis and secondary hyperparathyroidism lead to bone disease (osteitis fibrosa). • Treated with phosphate binders and oral vitamin D.

Exam 1 Week 2 Endocrine Flashcards

(192 cards)