The Endocrine System

„ Disease of the Pituitary Gland Endocrine System „ Diseases of the Thyroid

Maria Alonso, CDE, PA-C „ Disease of the Adrenal Glands

„ Diabetes Mellitus

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 PITUITARY ANATOMY Pituitary Anatomy •Small pea-sized gland at the base of brain •Located in the “Sella Turcica” •Functions as "The Master Gland" •Attached below hypothalamus by stalk •Large anterior lobe (adenohypophysis) PituitaryPituitary GlandGland •Smaller posterior lobe (neurohypophysis) •The optic chiasm lies directly above •Supplied by internal carotid artery

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Quick Review Quick Review: Hypothalamic Quick Review Pituitary Axis

Hypothalamus „ Neurosecretory cells send messages from Hypothalamus brain to hypothalamus GnRH GHRH SS TRH DA CRH ++ „ Hypothalamus sends chemical hormones + ++__+ to the pituitary gland OxytocinPosterior Pituitary ADH „ Pituitary gland secretes hormones to the FSH/LH GH GH/TSH TSH Prolactin ACTH thyroid gland, adrenal glands, and gonads Anterior Pituitary „ Negative feedback mechanism finishes the Gonadotropin releasing hormone (GnRH). Growth hormone releasing hormone (GHRH) loop Somatostatin (SS), Thyrotropin releasing hormone (TRH), Dopamine (DA) UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course Corticotropin releasing hormone (CRH) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 HYPOPITUITARISM Pituitary Disorders Hypopituitarism- Congenital Causes ACQUIRED CAUSES

„ Hypopituitarism – Congenital causes „ Hypothalamic gene defects „ Tumors are the most common cause in adults „ Pituitary gene defects „ Irradiation for other cranial tumors „ Hormone receptor gene defects „ Vascular: bleed, infarct, Sheehan’s „ Hypopituitarism- Acquired causes Hormone receptor gene defects „ Anencephaly, neural tube defect „ Inflammatory: sarcoidosis, TB „ Pituitary aplasia, usually fatal at birth „ Metabolic: Fe deposits/hemochromatosis, „ Pituitary tumors (adenomas) amyloidosis, illness, malnutrition „ Kallmann syndrome: x-recessive GnRH defect with hypogonadism, delayed **Empty Sella Syndrome: puberty, osteoporosis, anosmia unable to see gland on imaging due to any of above. May have shrunk or flattened UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Pituitary Tumors Types of Adenomas Clinical Manifestations

„ Mass effect „ Microadenomas (<10 mm) „ Prolactinoma prolactin/hypogonadism and galactorrhea (25-40%) (Lactotroph) headaches „ Macroadenomas (>10mm) „ Null cell no active hormone (10-25%) bitemporal hemianopsia „ Rarely malignant „ Somatotroph GH/acromegaly and gigantism (10-15%) Diplopia „ Locally invasive „ Corticotroph ACTH/ Cushing’s (10-15%) destroy hormone producing cells „ Gonadotroph FSH/LH (15-20%) compresses gland or hypothalamus „ Symptoms based on hormone involved „ Thyrotroph TSH/ hyperthyroidism (1%)

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Prolactinoma 25-40% Treatments Prolactin Treatments „ Occurs M/C 20-50 yo „ Medical therapy- „ Hyperprolactinemia „ Dopamine inhibits prolactin secretion decreases hormone and tumor „ Hypogonadism dopamine agonist- Bromocriptine negative effect on GnRH „ Estrogen, TRH, and GHRH positively effect replace hormones (thyroid/adrenal) reduction in LH and FSH prolactin secretion „ Surgical excision „ Females - galactorrhea, oligomenorrhea, amenorrhea Transsphenoidal „ Excess can be caused by lactation, „ Males- headache, visual disturbance, Gamma Knife/ Stereotactic Non-invasive tumors, drugs, hypothyroidism, impotence Radio Surgery impotence hypothalamic dysfunction

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Prolactinoma Excessive Growth Hormone Excessive Growth Hormone „ Work up: Secretion Excessive Growth Hormone BHCG, prolactin level, TSH CT/MRI of the Brain „ Acromegaly – adults „ 98% cases adenomas is the cause „ DDx: excessive exercise After epiphyseal closure Hx chest wall surgery „ Usually mixed cell tumors chest trauma „ Gigantism – children renal failure cirrhosis Before epiphyseal closure (excessive height) „ Increase risk- DM, HTN, CAD „ TX : dopamine agonist- Bromocriptine Surgical excision

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Prominent jaw/ Brow Physical Manifestations Prominent jaw/ Brow Hands doughy / Large hands

„ Enlargement of extremities „ hands doughy / large hands „ Coarse facial features „ prominent mandible, brow, nose, lips, tongue „ Coarse, oily, thick skin „ Organomegaly

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Related Conditions Related Conditions Related Conditions ƒ Musculoskeletal „ Cardiac ƒ Hypertrophy of joint cartilage and „ Musclosketal „ Left ventricular hypertrophy synovial tissue „ Diastolic dysfunction „ Cardiac ƒ carpal tunnel syndrome „ Dysrhythmias ƒ arthritis „ Metabolic „ Hypertension ƒ arthralgia „ Metabolic „ Sleep apnea „ Insulin resistance, glucose intolerance, DM

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Dwarfism Labs/ Diagnostic Tests Treatment Less than 4’10” is height „ Labs „ Surgical (50% success w/macroadenomas) „ GH and IGF-1: 5x normal in acromegaly „Disproportionate- skeletal „ Prolactin, glucose „ Radiotherapy dysplasia „ Liver enzymes, Blood urea nitrogen(BUN) „ Achondroplasia „ Calcium „ Short-trunk dwarf „ Serum FT4 and TSH „ Medical Therapy „Proportionate- medical or „ Glucose Suppression test = Diagnose Dopamine Agonist- (brocriptine) genetic conditions „ Glucose should suppress GH, in acromegaly it GH Receptor Antagnoist- (Pegvisomant) „ Growth hormone does not deficiency „ Imaging: MRI UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) Public domain available at: UMDNJ PANCE/PANRE Review Course http://commons.wikimedia.org/wiki/File:Paul_Steven_Miller_EEOC.jpg (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Growth Hormone Deficiency Achondroplasia Stimulation Test „ Mutations in the FGFR3 gene „ Insufficient GHRH from hypothalamus „ Autosomal dominant „ Insufficient production of GH by pituitary „ Gold Standard Insulin Tolerance Test (ITT), then another agent clonidine, L-Dopa, glucagon, „ Short stature < 4’10” „ Genetic Mutation- GHRHR, GH1 arginine or GhRH should cause an increase in „ Overweight „ Acquired- tumors/irradiation GH levels „ Short limbs „ Idiopathic- M/C „ Stimulation test measures the level of growth hormone (GH) in the blood after stimulation „ Prominent brow „ Genetic disorders- Turner, Noonan, PWS „ The test measures the ability of the pituitary „ Midfacial hypoplasia „ SGA gland to release GH under stimulation

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 GROWTH HORMONE Diabetes Insipidus Central Diabetes Insipidus = REPLACEMENT LOW ADH „ Vasopressin (ADH): Anti-Diuretic Hormone „ Somatotropin given as daily SQ injection Disruption of the normal production, until bone fusion (Bone Age) storage and release of ADH „ Synthesized in hypothalamus: stored and „ May not need further treatment as adults, released from posterior pituitary consider repeating stimulation test „ Two Main forms: „ Primary: No organic lesion, autoimmune „ Central (neurogenic): deficiency of ADH, low „ Side effects include headaches, carpal Central (neurogenic): deficiency of ADH, low „ Secondary: damage to hypothalamus or secretion, most commonly seen tunnel, SKFE, arthralgias, and edema pituitary stalk „ Nephrogenic: resistance to ADH „ Monitor for scoliosis „ Trauma, tumor or illness

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Nephrogenic DI = High ADH Other Rare Causes Clinical Features

„ Congenital Nephrogenic DI: defective •Polydipsia expression of renal vasopressin receptors • Polyuria (5-15L daily) „ Caused by a defect in the kidney tubules „ Familial X-linked trait interferes with water reabsorption, • Colorless urine (dilute) therefore do not respond to ADH „ DI of Pregnancy: Last trimester • Dehydration and electrolyte „ „ Causes: genetic disorder (seen shortly „ Oligohydramnios imbalance after birth), CKD, or drugs (lithium) „ Pre-eclampsia „ Hepatic dysfunction

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Diagnosis HYPOTHALAMIC-PITUITARY -THYROID Diagnosis Treatment of DI AXIS

„ Fluid deprivation test „ excessive intake of fluid (primary polydipsia)

„ defect in ADH production „ Central DI: Desmopressin (DDAVP),

„ defect in the kidneys' response to ADH Carbamazipine „ Desmopressin stimulation test „ U/A „ Nephrogenic: Thiazide diuretics, indomethacin, amiloride (combo) „ Consider MRI „ Diff Dx: psychogenic polydipsia

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Thyroid Gland THYROID ANATOMY FUNCTION „ Largest endocrine gland in body

„ Two lobes connected by “isthmus” „ T4 is the main hormone secreted „ Hypothyroidism „ Protected by thyroid cartilage „ Only 20% of T3 is secreted from thyroid „ Iodine + tyrosine makes the T3 and T4 „ Hyperthyroidism „ T3 is 3-4 times as active as T4 „ T3 and T4 exist as free and protein bound

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 THYROID IMAGING Diseases of the Thyroid Gland Hyperthyroidism

„ Ultrasound (U/S) is useful to identify nodules „ Hyperthyroidism „ Thyrotoxicosis is the clinical syndrome „ U/S guided Fine Needle Aspiration for Dx „ Graves’ Disease „ More common in women, 2% of society „ Nuclear scans with radioactive iodine-123 or „ Thyroid storm „ Most common cause is Graves’ Disease technetium-99m „ Hypothryoidism „ Older patients do not show classic signs „ Radioactive iodine uptake test (RAIU) „ Hashimoto’s thyroiditis evaluates function and helps determine amt. RAI for tx „ Thyroiditis „ Neoplastic Disease

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Hyperthyroidism: Hyperthyroidism in Pregnancy Graves’ Disease „ Other causes: „ Toxic nodules „ Women > Men (8:1) „ Thyroiditis „ Graves’- most frequent cause „ onset 20-40 yrs. „ Iodine induced „ BHCG-a stimulator of thyroid „ Exogenous hormone gland „ Autoimmune disorder „ Decrease TSH & elevated FT4 Thyroid stimulating immunoglobulin antibody „ Neonatal mortality 6% „ Association with other autoimmune disorders SLE, pernicious anemia, RA, DM type 1, MG

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Graves’ Disease Signs Specific to Graves’ EXOPHTHALMOS

„ Mucopolysaccharides/lymphocytes „ Affects TSH receptors „ Ophthalmopathy: Exopthalmos „ Causes protrusion of globe „ TSH secretion „ Look of astonishment „ Pretibial myxedema „ Stimulate glandular growth „ “Stellwag's sign”- infrequent blinking „ Diffuse, symmetric enlargement/goiter „ Upper lid lag on downward gaze „ Thyroid bruit „ Nontender „ Each eye can be affected differently „ May see weak upward gaze, diplopia „ Thyroid cancer can coincide w/ Graves’! „ Excess tearing, photophobia, gritty feel UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Thyrotoxicosis Clinical Features

„ Nervousness, insomnia, irritability „ Hand tremor, hyperactivity, tremulousness „ Excessive sweating, heat intolerance „ Wt. Loss (despite  appetite) „ Diarrhea, freq. defecation Public domain available at: http://commons.wikimedia.org/wiki/ File:Myxedema.jpg „ Palpitations (tachyarrhythmias) „ Muscle weakness „ Menstrual irregularities

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Diagnosis of Graves’ Don’t forget false positives! Treatment Types

„ Drugs „ T3 and free T4 levels elevated „ Auto immunity „ Antithyroid drugs „ „ TSH level extremely low or undetectable „ Acute illness „ Ablation „ Ablation Anti-thyroglobulin antibodies (TGA) „ High estrogen states „ „ Beta blockers – Used to treat symptoms Anti-thyroid peroxidase antibodies (TPO) „ Psychiatric illness Beta blockers – „ „ 24 hr RAIU given orally is increased „ AIDS (T4 can be normal = T3 toxicosis) „ Acute use steroids

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Antithyroid Drugs Radioiodine 131 (RAI) Surgical- Thyroidectomy block conversion of T4 to T3 „ Used in older patients „ Indicated for large obstructing glands, „ Propylthiouracil (PTU) „ Prior PTU/MMI reaction or failure, or poor compliance. malignant nodules, or pregnancy taken three x daily „ Not to be used in pregnancy/nursing used in severe cases, pregnancy and breast feeding „ Must be euthyroid before surgery „ Stop antithyroid meds 3-5 days prior „ Methimazole (Tapazole) „ Potassium iodide may be given prior taken daily, slower to decrease T3 „ RAIU used to determine dosing „ Complications: „ Levels checked 4 weeks after TX started „ Improvement seen after 4-6 weeks „ recurrent laryngeal nerve damage „ recurrent laryngeal nerve damage „ Side effects: „ Almost 80% are cured with one dose Agranulocytosis, thrombocytopenia, anemia, hepatitis, dermatitis, „ bleeding vasculitis, pneumonitis, hypoglycemia, urticaria, „ At least 50% will become hypothyroid in a year „ hypoparathyroidism

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Thyroid Storm Keys to Choosing Tx Clinical Manifestations & Tx „ Rare complication of thyrotoxicosis „ Marked delirium „ Supportive therapy: „ Non-pregnant Graves’ patients „ Precipitating factor: IVF, cooling blankets, „ Methimazole + Beta blocker Stressful illness thyroid surgery „ Severe tachycardia Stressful illness thyroid surgery glucose „ Vomiting „ RAI DKA infection Vomiting „ PTU q 6 H „ Diarrhea „ Preg + Graves’ = PTU (“P’s”) severe trauma childbirth „ Methimazole q 1H „ Dehydration „ High mortality rate: „ Beta blockers „ High fever „ RAI: Elderly with Graves’, solitary toxic 20% pts. (coma or die) „ Iodine nodule „ Hydrocortisone

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Hypothyroidism Primary Hypothyroidism Primary Hypothyroidism Auto immune Iatrogenic „ 0.8-1.0 % population „ Radio Iodine therapy Gland shrinks „ 3 x more common women „ Hashimoto’s thyroiditis „ Onset adulthood and insidious „ Thyroidectomy „ Primary (90-95%) „ Autoimmune associated with other non- „ End-stage Graves’ Disease endocrine abnormalities „ Medications Lithium pernicious anemia, RA, SLE, Sjogren’s, and Myasthenia Gravis. Amiodorone Interferon

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Hashimoto’s Thyroiditis Other Causes Secondary Hypothyroidism „ Chronic Lymphocyte Thyroiditis „ Infiltrative Process „ Most prevalent form of thyroid autoimmune disease „ Genetic propensity Æ HLA-B8 Amyloidosis Failure of the pituitary gland or „ Hypothyroidism initial manifestation hypothalamus Lymphoma „ Hyperthyroidism < 5% patients – self limiting or „ Neoplasm long standing Scleroderma „ Hashitoxicosis, transient hyperthyroidism (severe) „ Surgery „ Graves’ Æ TSI (thyroid stimulating immunoglobulins) „ Sheehan’s syndrome „ Hashimotos ÆTSH receptor blocking antibodies „ Congenital Hypothyroidism defects in enzymes Cause deficiency in TSH or TRHÆ low TSH, low FT4

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Myxedma Coma Hypo: Signs Hypo: Symptoms „ „ Life-threatening hypothyroidism „ Dry skin „ Fatigue, lethargy, weakness „ Coarse hair „ Obtundation, CO2 retention, coma „ Heavy menstrual periods (menorrhagia) „ Thickened puffy features „ Altered mental status is hallmark „ Slight weight gain „ Non-pitting edema Slight weight gain „ Can be precipitated by sepsis „ Carpal tunnel syndrome „ Cold intolerance „ High mortality, treat in ICU „ Slow relaxation of DTR „ Constipation „ Thyroxine bolus 300mcg, then 100mcg daily „ Loss lateral portions of eyebrows „ Slow mentation, inability to concentrate „ Hydrocortisone 100mg IV bolus „ Bradycardia „ Depression „ Goiter (hashimoto: rubbery, non-tender, possibly „ Diminished hearing nodular)

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Hypothyroidism Lab Values Hypothyroidism Treatment Symptoms Key Words Hypo „ Primary: High TSH, Low FT4 Hyper „ „ Secondary: Low TSH or normal, Low FT4 „ •Levothyroxine (T4) Synthroid „ Fatigue/Lethargy „ „ Increase appetite „ Antibody titers: present „ •Dose ranges 25mcg to 200 mcg daily „ Nervous „ Depressed „ Anti-thyroglobulin antibodies (TGA) „ •The T4 is converted into T3 „ Loose stools „ Constipation „ Anti-thyroid peroxidase antibodies (TPO) „ •Start lower in elderly „ Irritability „ Weakness „ •Adjust dose every 4-6 weeks „ T3 not a good test „ Heat intolerance „ Cold intolerance „ „ Subclinical Hypothyroidism: „ •Once stable, check levels twice yearly mild elevated or high normal TSH, serum FT4 normal

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Thyroiditis Nontoxic Goiter Solitary Thyroid Nodules „ Common in population, women>men „ Acute suppurative (rare) „ Thyroid levels are usually normal „ Nodule must be over 1cm to be palpated „ Thyroid adenoma most common benign nodule „ Subacute painful (Dequervain’s) „ Slowly enlarging thyroid gland over years „ Nodule of adenoma is encapsulated „ „ Drug-induced (Amiodarone) 5% of US population „ Follicular adenoma is most common „ Chronic lymphocytic (Hashimoto’s) „ Women > men „ Hürthle (oxyphil) „ Papillary adenoma are very rare „ Fibrous thyroiditis (Riedel’s) „ Usually asymptomatic unless impinging „ Bleeding into nodule causes pain, enlargement „ Endemic in iodine deficient areas Endemic in iodine deficient areas „ Most nodules are benign (95%)

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Solitary Nodule Work Up Thyroid Cancer Thyroid Cancer Types

„ History: Head or neck irradiation „ Physical exam: thyroid, lymph, systemic „ Rapid growing „ Papillary most common, least aggressive „ Tests: labs, US, RAIU, FNA „ Painless „ Follicular type often metastasizes „ Capsular invasion & vessel infiltration are „ Single hard lesion „ Anaplastic type (bad!) mainly >60 yo, hallmarks of malignancy „ More common in women 3:1 least common „ Nodules that concentrate iodine are “hot”, „ Worse in men „ Medullary type- C cells, elevated those that do not are “cold” calcitonin, found with MEN syndrome „ 9% of thyroid cancers are fatal „ Solitary nodules rarely cause extension or „ Thyroid lymphoma seen in Hashimoto’s pressure symptoms

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Treatment of Thyroid Cancer Parathyroid gland Review PTH

„ Increase osteoclastic activity in bone Æ „ Total vs near total thyroidectomy „ Hypoparathyroidism Ca+ into circulation „ Lymph node dissection if needed + „ Increase renal tubular reabsorption of Ca+ „ Radiation therapy „ Inhibits absorption of phosphate and „ Radioactive iodine therapy bicarb by renal tubule „ Chemotherapy as an adjunct „ Hyperparathyroidism „ Synthesis 1,25 dihydroxycholecalciferol by „ T4 replacement will be needed kidney (active form of Vit.D)

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Hypoparathyroidism Clinical Features S&S Think Hypocalcemia!

„ Most commonly seen following thyroidectomy, „ Chovostek’s sign: surgical removal parathyroid adenoma „ Cardiac arrhythmias, „ Cataracts „ Di George’s syndrome prolong QT interval „ Nails – thin, brittle Tapping facial nerve elicits contraction of „ Congenital cardiac anomalies „ Rickets, osteomalacia „ Skin – dry, scaly facial muscles „ Damage heavy metals such as copper Wilson’s disease „ Neuromuscular or iron (hemochromotosis, transfusion hemosiderosis) „ Loss hair irritability (eyebrows) „ Granulomas (eyebrows) „ Circumoral/fingers, „ Trousseau’s sign: „ Defective teeth „ Riedel’s thyroiditis toes numbness, „ Magnesium deficiency (malabsorption chronic ETOH) tingling (childhood) inflating BP cuff to pressure higher systolic „ Pseudohypoparathyroidism „ Tetany: hyperactive BP x 3 minutes to elicit carpal spasms DTR, Chovestek’s Sign, Trousseau’s sign UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Labs and Treatment Hyperparathyroidism Primary Hyperparathyroidism

+ Labs Treatment „ PRIMARY High PTH, High Ca „ Low Calcium „ IV calcium gluconate „ Excessive secretion of PTH by one or more glands „ Low PTH severe „ SECONDARY „ Women 3x more common „ High phosphate „ Pt’s > 50 yo „ Alkaline phosphatase „ Calcium & Vit D „ Single parathyroid adenoma (80%) normal maintenance „ Hyperplasia (20%) „ Carcinoma (<1%)

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Secondary Signs and Symptoms Bones Hyperparathyroidism

„ Bone aches „ Bones „ Arthralgia + „ Stones High PTH, Low or Normal Ca „ Pathologic fx’s – „ Chronic Renal Failure „ Groans „ Osteitis fibrosa cystica „ Vitamin D deficiency „ Psychiatric overtones “brown tumors” or cysts of the jaw „ Other signs

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Stones Groans Psychiatric Overtones (urinary tract manifestations) „ Depression „ „ Muscle pain „ Fatigue „ Renal stones „ „ Weakness „ Anorexia „ Nephrocalcinosis „ „ Pancreatitis „ Sleep disturbance „ Polydipsia „ „ PUD „ Anxiety „ Polyuria „ „ Gout „ Lethargy „ Hypercalcemia induced nephrogenic DI „ Constipation

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Other signs Laboratory Treatment „ + Surgery „ Shortened QT interval (EKG) „ Elevated PTH, Ca+ (confirms diagnosis) + „ Ca+ > 10.5 mg/dL, phosphate < 2.5 mg/dL „ Decreased DTR „ Hypercalciuria, elevated Alkaline „Medical Phosphatase (bone disease) IV hydration „ The best immunoradiometric assay Bisphosphonates Furosemide

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 AVOID: Adrenal Glands Adrenal Hormones

„ „ Large doses of……. „ Cushing’s syndrome „ Glucocorticoids = Cortisol Vit A, Vit D and Calcium „ Mineralcorticoids = Aldosterone

(Antacids/ supplements/additives) „ „ Corticoadrenal insufficiency „ Androgens: precursors of sex steroids „ Catecholamines: epinephrine and „ Thiazide diuretics norepinephrine „ Neoplastic Disease

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Glucocorticoids = Cortisol ACTH „ Help body respond to stress Mineralcorticoids = Aldosterone „ Maintain BP

„ CV function „ Maintains blood pressure „ Slow immune system inflammatory „ Maintains water and salt balance response + + response „ Help kidneys retain Na+, excrete K+ „ Maintain levels of glucose „ Regulate protein/fat/carbohydrate metabolism

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Cushing’s Disease ACTH Causes Excess ACTH

„ Adrenocorticotropic hormone „ Iatrogenic Cushing’s Syndrome (most common cause) „ Cushing’s disease (ACTH excess) is caused „ Hypothalamus ÆCRHÆ pituitary by ACTH secreting pituitary microadenoma „ Pituitary Æ ACTH „ ACTH secreting adenoma of pituitary = Cushings „ Cushing’s syndrome (cortisol excess) is Disease (43%) (second most common cause) „ ACTH stimulates adrenal cortex Æ cortisol the effects of excess cortisol on the body „ Excess ACTH Æ adrenal hyperplasia „ Adrenal Adenoma and Carcinoma (10-15%) „ Women affected 8 times more often Adrenal Adenoma and Carcinoma (10-15%) „ Deficiency ACTH Æ adrenal atrophy „ Cushing’s disease accounts for 70% of „ Cortisol inhibits CRH & ACTH secretion „ Ectopic ACTH (10-15%) Cushing’s syndrome

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 How to Diagnose Cushings What is my source of ACTH? Cushing’s Disease Disease?

„ Central obesity „ Easy bruising High dose Dexamethasone Suppression test „ Initial screening „ Hirsutism „ Supraclavicular fat „ „ Low dose Dexamethasone suppression test > 50% suppression cortisol Æ pituitary „ Moon face pads „ „ 24 hour free urinary cortisol level „ MRI of pituitary „ “buffalo hump” „ Protuberant abdomen „ „ Purple striae „ < 50% suppression cortisol Æ ectopic Purple striae „ Thin extremities „ Lanugo hair ACTH tumor „ HTN „ Acne „ CT of appropriate region „ Increase infections

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Ectopic ACTH producers Treatment of Cushing’s Ectopic ACTH producers Treatment of Cushing’s Corticoadrenal Insufficiency

„ Small cell carcinoma (lung) “Oat cell” „ Iatrogenic Cushing’s: Taper steroids “Addison’s disease”

„ Thyroid, thymomas „ Pituitary Cushing’s: transsphenoidal removal of pituitary adenoma

„ Pancreatic islet cell „ Adrenal adenoma or carcinoma: adrenalectomy

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Causes of Cortiocadrenal Insufficiency Destruction or Dysfunction “Addison’s disease” Clinical Features of Adrenal Cortices „ Autoimmune destruction most common cause Addison’s „ GI symptoms: anorexia, N/V, vague 80% spontaneous cases abdominal pain, wt. loss Primary (ACTH independent) Secondary (ACTH dependent) „ Primary Secondary „ Infectious diseases – tuberculosis „ Mental: lethargy, confusion, psychosis „ Autoimmune „ Steroids most common cause worldwide „ Hypoglycemia „ Adrenalectomy „ Hypopituitarism „ Iatrogenic „ Hypotension (orthostatic) „ Infection (TB/fungal) „ Trauma B/L adrenalectomy „ Hyperpigmentation – knuckles, elbows, „ Bleed „ ACTH deficiency Hyperpigmentation – knuckles, elbows, „ Metastatic knees, post. neck, palmar creases, nail „ Metastatic knees, post. neck, palmar creases, nail „ beds (primary insufficiency) „ Congenital Secondary adrenal insufficiency beds (primary insufficiency) abrupt cessation of exogenous steroids „ Other: irregular or absent menses

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Cosyntropin test (stimulation) Diagnostic Labs Treatment

+ „ Serum Na+ low (90%) „ Give ACTH (cosyntropin- parenterally) Hydrocortisone - glucocorticoid + „ Serum K+ high (65% primary disease) „ Measure serum cortisol 30-60 min „ Prednisone 20-40mg po QD „ Hydrocortisone 50-100mg q6hr IV (“stress”situations) „ Fasting glucose low „ Normal rise to at least 20 mcg/dL Hydrocortisone 50-100mg q6hr IV „ Low levels of AM cortisol (<3 mcg/dL), „ Less than rise of 20 mcg/dL – suspicious high ACTH (> 200 mg/dL) = diagnostic for adrenal insufficiency Fludrocortisone – mineralocorticoid „ Florinef 0.1-0.2mg po QD „ Low ACTH = secondary „ Ensure adequate salt intake „ Eosinophilia, neutropenia, lymphocytosis

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Presentation and Laboratory Pheochromocytoma Treatment Values

„ Rare cause of HTN, age 40-60 onset „ Family Hx of pheochromocytoma or MEN „ Adrenergic blockade for 3-4 weeks „ Most are due to unilateral medullary tumor „ First do 24hr urine catecholamines (avoid –Phenoxybenzamine PO „ Bilateral type tends to run in families caffeine, vanilla, fruits) –Phentolamine IV „ Rule of 10’s: 10% bilateral, 10% extra-adrenal, „ False (+): shock, hypoglycemia, stress, clonidine 10% malignant, 10% familial, 10% pediatric, withdrawal, TCAs, and MAOIs „ Surgical laparoscopic adrenalectomy 10% show no HTN „ Clonidine suppression test if above equivocal „ Follow up catecholamine testing needed „ Palpitations, diaphoresis, and headache „ Adjunctive radiation and chemotherapy „ Picture of refractory or labile HTN

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 An 8 yr. old boy presents with his mother who states that he An 8 yr. old boy presents with his mother who states that he A 28 yr. old presents to the ED with confusion and agitation. has become overweight during the past year and has little has become overweight during the past year and has little He appears intoxicated and is unable to provide a history. On energy, sleeps more, and is cold all the time. His growth energy, sleeps more, and is cold all the time. His growth exam he has mild proptosis, is tachycardic with regular curve has fallen from the 50th% to the 5th% for height, but his curve has fallen from the 50th% to the 5th% for height, but his rhythm, neck fullness, a fine tremor, and brisk reflexes. While weight has increased from the 50th% to 90th%. On PE he is weight has increased from the 50th% to 90th%. On PE he is in the ED he vomits x 3. All labs are normal. obese, has thin hair, immature facies, and slowed reflexes. obese, has thin hair, immature facies, and slowed reflexes. What is the most likely diagnosis? What is the cause of his symptoms? What is the cause of his symptoms? 1. Addison’s disease 1. Acromegaly 1. Acromegaly 2. Diabetic ketoacidosis 2. Cushing’s syndrome 2. Cushing’s syndrome 3. Thyroid storm 3. Dwarfism 3. Dwarfism 4. Toxic adenoma 4. Hypothyroidism 4. Hypothyroidism

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 A 28 yr. old presents to the ED with confusion and agitation. He appears intoxicated and is unable to provide a history. On Where is thyroid-stimulating hormone Where is thyroid-stimulating hormone exam he has mild proptosis, is tachycardic with regular rhythm, neck fullness, a fine tremor, and brisk reflexes. While (TSH) produced? (TSH) produced? in the ED he vomits x 3. All labs are normal. What is the most likely diagnosis? 1. Anterior pituitary 1. Anterior pituitary 2. Posterior pituitary 2. Posterior pituitary 1. Addison’s disease 3. Zona fasciculata 3. Zona fasciculata 2. Diabetic ketoacidosis 4. Zona glomerulosa 4. Zona glomerulosa 3. Thyroid storm 4. Toxic adenoma

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Over the past year a 21 yr. old female has developed Over the past year a 21 yr. old female has developed A 25 yr old presents with extreme weakness and amenorrhea and milky nipple discharge. She is not taking any amenorrhea and milky nipple discharge. She is not taking any dizziness. On PE he appears depressed; BP 90/70. He medications and is sexually active but doesn’t wish to become medications and is sexually active but doesn’t wish to become has dark skin and hyperpigmented creases on his pregnant. Her serum HCG is negative; prolactin 300 mg/dL; pregnant. Her serum HCG is negative; prolactin 300 mg/dL; palms. Labs: low sodium; high potassium, calcium and MRI reveals a 3 mm mass in the pituitary. What is the most MRI reveals a 3 mm mass in the pituitary. What is the most appropriate therapy at this time? appropriate therapy at this time? urea. What is the most likely diagnosis?

1. Addison’s disease 1. Bromocriptine (Parlodel) 1. Bromocriptine (Parlodel) 2. 2. Monthly IM 2. Monthly IM 2. Cushing’s syndrome medroxyprogesterone medroxyprogesterone 3. Pheochromocytoma 3. Sequential OC’s 3. Sequential OC’s 4. Primary 4. Transphenoidal tumor 4. Transphenoidal tumor hyperaldosteronism resection resection

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 A 25 yr old presents with extreme weakness and A 46 yr old male complains that he has developed A 46 yr old male complains that he has developed dizziness. On PE he appears depressed; BP 90/70. He coarse facial features and a large prominent jaw. He coarse facial features and a large prominent jaw. He has dark skin and hyperpigmented creases on his states that his shoe size has increased over the last states that his shoe size has increased over the last palms. Labs: low sodium; high potassium, calcium and year despite no weight gain. What additional finding year despite no weight gain. What additional finding urea. What is the most likely diagnosis? will most likely be found on PE? will most likely be found on PE?

1. Addison’s disease 1. Atrophy of the digits 1. Atrophy of the digits 2. 2. Cushing’s syndrome 2. Deepening voice 2. Deepening voice 3. Pheochromocytoma 3. Dry skin 3. Dry skin 4. Primary 4. Enlarged testes 4. Enlarged testes hyperaldosteronism

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 A 19 yr. old male presents to the ED with acute A 19 yr. old male presents to the ED with acute fatigue, vomiting, diarrhea, and anorexia. On PE he fatigue, vomiting, diarrhea, and anorexia. On PE he has postural dizziness and pigmented buccal mucosa. has postural dizziness and pigmented buccal mucosa. Labs indicate hyponatremia, hyperkalemia and Labs indicate hyponatremia, hyperkalemia and glucose of 50 mg/dL. glucose of 50 mg/dL. What is the most likely diagnosis? What is the most likely diagnosis?

1. Adrenal insufficiency 1. Adrenal insufficiency Diabetes Mellitus 2. DM, type 1 2. DM, type 1 3. Myxedema 3. Myxedema 4. Pheochromocytoma 4. Pheochromocytoma

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 What is Diabetes Mellitus? Classification Epidemiology

„ Type 1 - little or no endogenous insulin „ Nearly 26 million people in the US have „ A disorder of carbohydrate metabolism production diabetes, 7 million of whom may be „ Lack of insulin undiagnosed and unaware of their „ Type 2 – insulin resistance and/ or condition „ Insulin resistance deficiency „ Research examining A1C levels found that „ Both insulin deficiency and resistance „ Gestational 35% of U.S. adults aged 20 years or older „ LADA (type 1.5)- latent autoimmune had pre-diabetes (50% of those aged 65 diabetes in adults (+) GAD years or older are considered pre- diabetic); an estimated 79 million „ MODY- maturity onset diabetes of the Americans aged 20 years or older have

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Pathogenesis of DM type 1 Pathogenesis of DM type 2 Type I vs. Type II

„ Hereditary predisposition (HLA-DR gene) „ „ Genetically linked „ Onset: Sudden „ Onset: Gradual „ Autoimmune (90% islet cell AB) „ Inadequate insulin secretion „ Age: Typically young „ Age: Mostly adults „ Islet Cell Cytoplasmic Autoantibodies (ICA) „ Body: Usually thin „ Body: usually obese „ Glutamic Acid Decarboxylase Autoantibodies (GADA) „ Peripheral insulin resistance Body: Usually thin Body: usually obese „ Insulinoma-Associated-2 Autoantibodies (IA-2A) „ Accelerated hepatic glucose production „ Ketosis: Common „ Ketosis: Rare „ Insulin Autoantiboidies (IAA) „ Autoantibodies: „ Autoantibodies: „ Autoimmune destruction of beta cells Present Absent „ Endogenous insulin: „ Endogenous insulin: „ Infiltration of pancreas with T- low or absent normal, increased, lymphocytes lymphocytes decreased UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Diagnostic Criteria Screening Guidelines Risk Factors Screening Guidelines „ Asymptomatic individuals with risk factors „ Age (> 45 years old) Age (> 45 years old) FBS GTT A1C should be screened for diabetes if they are „ Obesity Normal Blood overweight (BMI > 25 kg/m2) and have <100 mg/dL <140 mg/dL <5.7% „ Sedentary Lifestyle Sugar additional risk factors „ Ethnicity (African-American, Hispanic, Asian) Prediabetes 100-125mg/dL 140-199 mg/dL 5.7-6.4% „ Beginning at age 45 for those without „ Family history other risk factors „ HTN, hypercholesterolemia, high triglycerides Diabetes >126mg/dL >200mg/dL >6.5% „ Those with normal results and low risk „ Gestational diabetes, having a child >9lbs should be re-tested at three-year intervals „ „ PCOS „ Adapted from the ADA Standards of medical care in diabetes-2011. Diabetes Care. 2011;34 (suppl 1):S11-S61. American Diabetes Association. Standards of Medical Care in Diabetes - 2010. Diabetes Care 2010:33;S11-61 UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Testing Recommendations: Child Signs & Symptoms Diabetes Complications

„ Polyuria, polydipsia, polyphagia „ Overweight, Age 10 yrs or onset of puberty „ : „ Infections Microvascular Complications: „ BMI > 85th percentile for age and sex th „ Retinopathy „ Weight for height > 85 percentile „ Weakness „ Weight > 120% ideal for height „ Neuropathy „ Lethargy „ Nephropathy „ Plus 2 risk factors „ Family history „ Numbness and tingling „ Macrovascular Complications: „ Race 0 „ Acanthosis nigricans, HTN, dyslipidemia, PCOS, SGA „ Blurry vision „ CVD- atherosclerosis – 1 cause of death „ Maternal history of DM or GDM „ Weight loss „ Poor immune function „ Frequency every 3 years „ Complicated infections

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Morbidity and Mortality Diabetic Neuropathy „ Leading cause of kidney failure, Diabetic Retinopathy nontraumatic lower-limb amputations, and „ Cataracts new cases of blindness among adults in „ Peripheral neuropathy ( LE > UE ) „ Glaucoma the US distally symmetric,“stocking glove pattern” loss sensation „ Proliferative retinopathy „ Autonomic „ Major cause of heart disease and stroke neovascularization, scarring Gastroparesis, urinary retention, postural hypotension, „ 1 in 3 suffer from severe periodontal „ Non-Proliferative retinopathy impotence, fecal incontinence disease hemorrhages, exudates, microaneursyms, venous dilatation „ Seventh leading cause of death in the US Silent MI

„ *CDC National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of DM leading cause of Blindness Health and Human Services, Centers for Disease Control and Prevention, 2011.

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Diabetic Nephropathy Systemic Vascular Changes Poor immune function „ High glucose levels cause polyuria-

renal hyperfiltration „ Atherosclerosis „ Vaginitis „ Chronic hyperfiltration leads to kidney „ Hypertension „ Periodonitis damage „ CAD „ UTI „ Proteinuria – early indicator of renal „ PVD „ Sinusitis disease „ Stroke „ Otitis externa/ media „ Rapid progression to dialysis once „ Cellulitis creatinine reaches 3-4 mg/dl ESRD-DM most common reason for HD Public domain available at: http://commons.wikimedia.org/wiki/File:Cellulitis_Left_Leg.JPG UMDNJ PANCE/PANRE Review Course Public domain available at: UMDNJ PANCE/PANRE Review Course Public domain available at: UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) http://commons.wikimedia.org/wiki/File:Diffuse_proliferative_lupus_nephritis.jpg (becoming Rutgers July 1, 2013) http://commons.wikimedia.org/wiki/File:Aorta.jpg (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Complicated Infections Diabetic immunosuppression Hypoglycemia „ Gram negative pneumonias „ Signs and Symptoms „ Infected ulcers „ Fungal infections „ FS- < 70 mg/dL „ Thrush „ Tachycardia, sweating, tremors, nausea, „ Gram negative sepsis hunger, anxiety „ Aspergilliosis „ Confusion, coma, seizure, death „ Cholecystitis/ cholangitis Tx: 15 grams of glucose „ pyelonephritis 4 oz OJ or soda, 3-4 glucose tabs, 5-6 hard candies, glucagon IM

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Hyperosmolar Hyperglycemic State DKA- Diabetic Ketoacidosis DKA- (HHS) „ Usually occurs in type 1 (insulin insufficiency) Treatment of DKA „ Usually occurs in type 2 (osmotic diuresis due to „ Diagnostic criteria- hyperglycemia -> dehydration, insulin secretion suppresses ketolysis „ PG >250 „ Regular insulin IV 0.1 units/ kg bolus - then 0.1 „ K+, Mg+, are lost along w/Water & Na+ „ Ph <7.35 units/kg/hr „ Severe dehydration „ Bicarb <15 cardiac profusion compromise: tachycaridia, low C.O., low Mg+ & K+ „ Fluid replacement w/ normal saline 3-4 L/8 hrs cardiac profusion compromise: tachycaridia, low C.O., low Mg+ & K+ „ High anion gap „ Diagnostics Criteria- „ Serum/ urine ketones „ Sodium bicarb if pH <7.0 „ PG >600 mg/dL

„ Serum osm >310 „ Signs/Symptoms- „ Potassium replacement (20-30 meq/ 2-3 hrs after Serum osm >310 „ No acidosis „ Polyuria, polydipisia therapy started) „ No ketones „ Weakness, stupor ( Kussmaul breathing) „ Glucose < 250md/dL add 5% dextrose to fluids „ Bicarb >15 „ Tachycardia, tachypnea (to compensate pH) „ Nausea/ vomiting „ Triggers: infection, AMI, pancreatitis, poor compliance „ Fruity breath UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Treatment Dawn Phenomenon Somogyi Effect Hyperosmolar Hyperglycemic State Somogyi Effect „ End result of a combination of natural body changes that occur during sleep „ "rebound hyperglycemia” „ Saline replacement - (6-10 L) „ Between 3 AM & 8 AM, your body starts to „ The cause is more "man-made" - a result „ Regular Insulin IV (15 units/ IV, 15 units SQ) increase the amounts of counter- of poor diabetes management „ Potassium (10 meq to initial fluids) regulatory hormones (GH, cortisol, & „ Refers to pattern of high morning sugars catecholamines). „ Magnesium (2 gm to initial fluids) preceded by an episode of hypoglycemia „ These combined events cause your body's „ Once glucose <250md/dL – 5% dextrose „ Check blood sugars between 2-3 AM to fluids blood sugar levels to rise in the morning „ M/C in type 1 UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Treatment & Management of DM Self Monitoring Balanced Diet „ Moderate caloric restriction „ Used to adjust „ Self monitoring „ Moderate weight loss 5-9 kg goals medication „ Spacing meals (especially carbs) „ Insulin/ oral medications „ Improves glycemic „ Approach depends on lifestyle „ control Diet and exercise „ Very low calorie diet usually NOT effective „ Patient’s involvement Patient’s involvement for long term goals! „ Patient education in their care

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Exercise Oral Anti-diabetic Agents (OAD) Oral Anti-diabetic Agents (OAD) „ Improves glucose „ Sensitizers- Inhibit the release of glucose tolerance tolerance from the liver; improve sensitivity to „ Secretagogues- Stimulate the release of „ Promotes good circulation insulin insulin from the pancreas „ Maintains good muscle „ tone „ Biguanides- Metformin (Glucophage, „ Sulfonylureas (SU) „ Glipizide (Glucotrol), Glimepiride (Amaryl), „ Helps maintain normal Fortamet, Glumetza, etc) Glipizide (Glucotrol), Glimepiride (Amaryl), Glyburide (DiaBeta, Glynase) body weight „ * Lactic Acidosis, elderly „ Reduces insulin „ Meglitinides „ Thiazolidinediones (TZD) PPARy (gamma) requirements „ Repaglinide (Prandin), Nateglinide (Starlix) „ Rosiglitazone (Avandia),Pioglitazone (Actos) „ Recommendation „ *Bladder Cancer, CHF 150min/week

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Non-insulin Injectables Human Insulin Profiles Oral Anti-diabetic Agents (OAD) (Rapid and Intermediate Acting, Premix) „ Amylin mimetics- It slows the rate at which INSULIN ONSET PEAK DURATION glucose is absorbed from the intestine, reduces the ƒ Dipeptidyl peptidase-4 inhibitors (DPP-4)- production of glucose by the liver by inhibiting the action Novolin® (R), 30-60 min 2-4 hrs 5-8 hr inhibitors inhibit the degradation of incretins (GLP- of glucagon Humalin® (R) 1 and GIP) „ Pramlintide (Symlin) Regular ƒ Saxagliptin (Onglyza), Sitagliptin (Januvia), Novolin® (N), 1-3 hrs 4-10 hrs 18-24 hrs „ Incretin mimetics- GLP-1 agonist- Enhances Linagliptin (Tradjenta) Humalin® (N) Linagliptin (Tradjenta) insulin secretion by the pancreatic beta-cell, suppresses NPH ƒ Alpha-glucosidase inhibitors (AGI)- Slow inappropriately elevated glucagon secretion, slows ® the breakdown of starches and some sugars gastric emptying which produces satiety Humulin 30-60 min Varies Up to 24hrs ® „ Liraglutide (Victoza), Exenatide (Byetta), 70/30, Novolin ƒ Acarbose (Precose), Miglitol (Glyset) Exenatide extended-release (Bydureon) 70/30 UMDNJ PANCE/PANRE Humalin® 50/50 30-60 min Varies Up to 24hrs UMDNJ PANCE/PANRE Review Course Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Insulin Analogs Basal (Long-acting) Bolus (Fast-acting) Treatment in DM Preventive Care INSULIN ONSET PEAK DURATION „ Type I: Insulin (basal / bolus) Levemir® 1 hr Steady over Up to 24 hrs „ Hgb A1C every 6 mo „ Dilated eye exam (insulin detemir) time (if controlled) yearly „ Type II: Lantus® 1 hr Steady over Up to 24 hrs „ FBS, AC & HS+ „ Foot exam each visit 1. Diet and Exercise (First Step) (insulin glargine) time bedtime (yearly DPM) 2. Oral medication ® Novolog 5-15 min 30-90 min 3-5 hr 3. Insulin (if no glycemic control, severe „ Microalbuminuria „ Cholesterol yearly (insulin aspart) hyperglycemia fasting BG > 240) yearly „ BP each visit Apidra® 5-15 min 30-90 min 3-5 hr „ BUN/Cr yearly „ Stop smoking (insulin glulisine) ***Start with one Lifestyle changes- then add Metformin (drug of choice) if fails, use second ® Metformin (drug of choice) if fails, use second Humalog® 5-15 min 30-90 min 3-5 hr agents different class (insulin lispro) UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Hypoglycemia Metabolic Syndrome Lipid Disorders

„ Self induced: medications Need 3 of 5 to diagnose „ Hyperlipidemia „ Immunopathologic (rare) – anti-insulin „ HDL < 40 male, < 50 female antibodies to insulin receptors „ ETOH related hypoglycemia „ Elevated BP ≥ 135/85 „ Hypertriglyceridemia „ Tumors – pancreatic B-cell, extra-pancreatic „ Elevated Triglycerides ≥ 150 mg/dL „ Symptoms at or below 60 mg/dL, impairment of brain function 50 mg/dL „ Fasting BG 100-125 mg/dL „ Whipple’s Triad: hx of hypoglycemic symptoms, „ Waist Circumference- fasting blood glucose of 40 mg/dL or less, immediate recovery upon admin. glucose > 35"F, >40"M

UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course Public domain available at: (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) http://upload.wikimedia.org/wikipedia/commons/9/9e/Obesity-waist_circumference.PNG

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 First Step: Hyperlipidemia Values and Risk Assessment Screening and Risk Assessment

„ LDL „ Most important and modifiable risk factor for CAD Æ „ All adults ≥ 20 yrs. fasting lipoprotein profile Æ „ Total < 200 „ < 100 = desirable accelerates atherosclerosis Every five years „ 100-129 = above optimal „ 130-159 = borderline high „ 160-189 = High „ LDL < 100 (no CAD) „ ≥ 190 very high „ Primary Disorder: Familial Dyslipidemia Syndrome „ LDL Levels alone

„ Cigarette smoking „ HDL Cholesterol „ LDL < 70 (+CAD) „ < 40 Low „ HTN (BP ≥ 140/90 or on HTN med) „ Secondary Disorder „ ≥ 60 High „ Endocrine: hypothyroidism, DM, Cushings „ Low HDL < 40 mg/dL „ Total Cholesterol „ Triglycerides < 125 „ Nephrotic syndrome, Chronic liver disease „ Family History of premature CAD (CAD in male „ < 200 = desirable „ Medications: steroids, estrogen, thiazide diuretics first degree relative < 55, female first degree „ 200- 239 = borderline high „ ≥ 240 = high ≥ 240 = high „ „ Pregnancy relative < 65) „ TC:HDL ratio < 4.5 „ Age Men > 35, women > 45 UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Drug Treatment of Hyperlipidemia Screening and Clinical Features Treatments

„ HMG CoA reductase inhibitors (statins) „ Most potent Lower LDL ** Drug choice Lower LDL „ Monitor LFT’s, may elevate CPK „ No risk factors (if „ Asymptomatic „ Dietary Changes previously not screened) „ Severe hyperlipidemia „ Lowering fat intake „ Niacin „ Decrease TG levels, Decrease LDL, Increase HDL „ 35 Men (saturated fats), cholesterol „ Xanthelasma: yellow „ No use in Diabetics „ 45 women plaques on eyelids „ Food rich Omega 3-fatty „ Most potent ↑HDL, ↓TG levels acids (fish) „ Flushing effect „ Family Hx „ Xanthoma – hard yellow „ Second line agent for LDL, First line for hypertriglyceridemia masses on tendons „ Fiber „ HTN „ Bile acid-binding resins (cholestyramine, colestipol) „ Increases TG levels „ Smoking „ Good for use in combo with statins or niacin in high risk pts. „ Exercise: Increase HDL „ Third line agent for LDL „ DM „ GI side effects „ Low HDL „ Drug Therapy „ Fibrates (gemfibrozil) „ Lower VLDL, Increase HDL „ Age „ Used if above fail „ GI side effects, gynecomastia, gallstones, wt.gain UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course Public domain available at: UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) http://commons.wikimedia.org/wiki/File:Nordic_walking_on_treadmill.jpg (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 A 42 yr. old obese woman with a hx of Type 2 DM x A 42 yr. old obese woman with a hx of Type 2 DM x Treatment of Hypertriglyceridemia 4 mos. presents for follow-up after initial attempts at 4 mos. presents for follow-up after initial attempts at diet and exercise for control. She has gained 10 lbs diet and exercise for control. She has gained 10 lbs and her BMI is now 30.5. On this visit her HgbA1c and her BMI is now 30.5. On this visit her HgbA1c „ Reduce weight is 8; serum creatinine is normal. is 8; serum creatinine is normal. „ Reduce amount saturated fat, trans fat, What is the best management? What is the best management? cholesterol in diet 1. Bedtime insulin 1. Bedtime insulin „ Reduce ETOH use (NPH) (NPH) „ Exercise 2. Metformin 2. Metformin „ Lower carbohydrate intake (glucophage) (glucophage) „ Increase meats high in Omega-3 fatty acids 3. Glipizide (Glucotrol) 3. Glipizide (Glucotrol) „ LOVAZA® (omega-3-acid ethyl esters) „ SE: burping, infection, flu-like symptoms, upset 4. Continue diet & 4. Continue diet & stomach, and change in sense of taste exercise efforts exercise efforts UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 A 66 yr old male was found wandering the streets by the A 66 yr old male was found wandering the streets by the Which of the following glucose-lowering police. There are no signs of trauma. Vitals: BP 90/54, P 115, police. There are no signs of trauma. Vitals: BP 90/54, P 115, R 12. PE reveals mild dehydration and mental confusion w/o R 12. PE reveals mild dehydration and mental confusion w/o agents acts by decreasing insulin resistance focal neurological findings. Labs are: glucose 759, Na 124, focal neurological findings. Labs are: glucose 759, Na 124, and increasing glucose utilization?

K 3.0, Cl 102, CO2 37, BUN 63, CR 1.0. What is the most K 3.0, Cl 102, CO2 37, BUN 63, CR 1.0. What is the most appropriate first step in treatment? appropriate first step in treatment? 1. Acorbase (Precose) 2. Glipizide (Glucotrol) 1. Glucagon 1. Glucagon Glipizide (Glucotrol) 2. Insulin 2. Insulin 3. Metformin (Glucophage) 3. Phosphate 3. Phosphate 4. Saline 4. Saline 4. Pioglitazone (Actos)

UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 Which of the following glucose-lowering A 15 yr. old male presents with extreme fatigue and A 15 yr. old male presents with extreme fatigue and agents acts by decreasing insulin resistance frequent urination day and night which he attributes frequent urination day and night which he attributes and increasing glucose utilization? to increased water intake to “quench his thirst.” Exam to increased water intake to “quench his thirst.” Exam indicates a slender male with postural hypotension. indicates a slender male with postural hypotension. What is the best initial step to What is the best initial step to 1. Acorbase (Precose) establish a diagnosis? establish a diagnosis? 2. Glipizide (Glucotrol) 1. ACTH 1. ACTH 3. Metformin (Glucophage) 2. HgbA1C 2. HgbA1C 4. Pioglitazone (Actos) 3. Plasma glucose 3. Plasma glucose 4. Serum AM cortisol 4. Serum AM cortisol

UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 A 50 yr. old male presents for a routine visit. He A 50 yr. old male presents for a routine visit. He A 49 yr. old with a hx of Type 2 DM presents after states that he could “stand to lose a few pounds” but states that he could “stand to lose a few pounds” but receiving a non-fasting cholesterol of 235 at a is otherwise in good health. PMH and family hx reveal is otherwise in good health. PMH and family hx reveal community health fair. Which of the following is no risk factors. Exam reveals abdominal obesity no risk factors. Exam reveals abdominal obesity the best management? (waist circumference 45 in.) and BP 142/90. What (waist circumference 45 in.) and BP 142/90. What additional finding would confirm a dx of metabolic additional finding would confirm a dx of metabolic 1. Diet & exercise syndrome? syndrome? advice 1. Fasting glucose 98 mg/L 1. Fasting glucose 98 mg/L 2. Fasting lipid profile 2. HDL 45 hg/dL 2. HDL 45 hg/dL HDL 45 hg/dL HDL 45 hg/dL 3. HMG Co_A 3. LDL 120 mg/dL 3. LDL 120 mg/dL reductase inhibitor 4. Triglycerides 200 mg/dL 4. Triglycerides 200 mg/dL 4. Reassurance that results are OK

UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 A 49 yr. old with a hx of Type 2 DM presents after A 52 yr old postmenopausal woman presents with A 52 yr old postmenopausal woman presents with receiving a non-fasting cholesterol of 235 at a chest pain suggestive of angina. Exercise stress test is chest pain suggestive of angina. Exercise stress test is community health fair. Which of the following is positive. Fasting labs: glucose 92, T. Chol. 271, positive. Fasting labs: glucose 92, T. Chol. 271, the best management? LDL 127, HDL 31, Trigl. 375. What is the best therapy LDL 127, HDL 31, Trigl. 375. What is the best therapy for this patient? for this patient? 1. Diet & exercise

advice 1. Atorvastatin (Lipitor) 1. Atorvastatin (Lipitor) 2. Fasting lipid profile 2. Cholestyramine 2. Cholestyramine (Questran) (Questran) 3. HMG Co_A reductase inhibitor 3. Estradiol 3. Estradiol 4. Niacin 4. Niacin 4. Reassurance that results are OK

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UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013 References A Compreshensive Review for the Certification and Recertification Examinations for Physician Assistants, 3rd/4th edition. Claire Babcock O’Connell, Sarah F. Zarbock „Thank you and good luck! Evidence- Base Endocrinology. 2nd edition. Pauline M. Camacho, Hossein Gharib, Glen W. Sizemore.

2012 Current Medical Diagnosis and Treatment. 51th edition. Michael W. Rabow, Stephen J. McPhee, Maxine A. Papakis.

Cecil Text book of Medicine, 22nd Edition. Lee Goldman, MD, Dennis Ausiello, MD.

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UMDNJ PANCE/PANRE Review Course (becoming Rutgers July 1, UMDNJ PANCE/PANRE Review Course 2013) (becoming Rutgers July 1, 2013)

UMDNJ PACE/PANRE Review Course becoming Rutgers July 1, 2013