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What are the etiologies of panhypopituatarism?
surgery, radiation, tumors (primary,mets), infection, infiltration (sarcoid,hemachromatosis), autoimmune, ischemia (inc Sheehan's syndrome), carotid aneursym, cavernous sinus thrombosis, trauma
SECONDARY (i.e. causes affecting hypothalamic or stalk), tumor (craniopharyngioma), infection, infiltration, radiation, surgery, trauma
How does panhypopituatarism clinically present?
HORMONAL (acute): fatiguable, hypotension, polyuria, polydipsia, (chronic): wt. loss, bradycardia, sexual dysfxn, loss of axillary & pubic, amenorrhea
MASS EFFECT: HA, visual field changes, cranial nerve palsies, galactorrhea
APOPLEXY: sudden HA, N/V, visual field changes, cranial nerve palsies, meningismus, AMS, hypoglycemia, hyptotension
How do you work up hypopituatarism?
chronic: dec target gland hormone, dec/nl pit hormone
acute: target gland hormone may be nl
(partial more common than panhypopit)
How do you treat hypopituatarism?
Replace deficient hormones (most importantly, adrenal insufficiency and hypothyroidism. If both, give glucocorticoids first, then thyroid to avoid risk of adrenal crisis)
What are the hormones of hypopituatarism?
(1) Dec ACTH (compared to primary: aldosterone preserved, no hyperpigmentation)
(2) Dec TSH (compared to primary: no goiter, dx with both TSH and T4, as TSH may be low, inapprop normal)
(3) Dec Prl
(4) Dec GH (chronic - fatigue, weight gain, osteoperosis. dx with failure of inc GH with stimulus like insulin tolerance test, glucagon stim)
(5) Dec FSH, LH (Sx: dec libido, impotence, a- or oligomenorrhea, infertility. Sx: dec testicular size, lose off axillary, pubic hair. Dx: dec a.m. testoseterone or estradiol, dec FSH/LH - also dec in any acute illness)
(6) Dec ADH (usually in hypothalamic, stalk disease- diabetes insipidus: severe polyuria, mild hyponatremia - Dx: Posm, Uosm, volume status)
What is the etiology of hyperpituatarism?
Adenoma - 60-70% are functional. May cause deficiencies in some trophic hormones via compression.
How does hyperpituatarism present clinically?
Hormone oversecretion: hyperprolicnemia, acromegaly, Cushing's disease, central hyperthyroidism (v. rare)
Mass Effect: HA, visual changes, diplopia, crania neuropathies.
How do you work up hyperpituatitary syndrome?
hormone levels: (PRL, IGF-1, suppression of GH in response to OGT test, ACTH)
consider: visual field testing, MEN1 testing
watch and wait if: <10mm, no mass effect, no hormonal effects, f/u in 3-6 months
How does hyperprolactinemia present? How do you work it up?
(1) Presents with: amenorrhea, galoctorrhea, infertility, decreased libido, impotence
(2) Work up: PRL, r/o pregnancy, exogenous estrogen, hypothyroidsm, dopamine agonists (psych meds, antiemetic), renal failure (dec clearance), cirrhosis, stress, inc carb diet.
MRI, visual field testing
How do you treat hyperprolactinemia?
(1) if asx, <10mm, follow with MRI
(2) if sx, >10mm
-medical: bromocriptine, cabergoline (dopamine agonist). side effects: n/v, orthostasis, nasal congestion
-surgical: if failed medical, GH co-secretion, neuro sx not improving- transhenoidal surgery
-radiation: if above failed/not tolerable
What is the clinical manifestation of excess GH? How do you work it up?
inc IGF-1-> acromegaly
P/W increased soft tissue, arthralgias, jaw enlarged, HA, carpal tunnel syndrome, macroglossia, hoarse, sleep apnea, amenorrhea, impotence, DM, acanthosis/skin tags, inc sweating, HTN, colonic polyps
W/U: IGF-1 inc, GH not suppressed to OGT
What is the treatment and prognosis for Acromegaly?
TREATMENT: surgery, octreotide, dopamine agonists (if also Prl consecration) pegvisotmant (GH receptor antagonist), radiation
PROGNOSIS: w/o tx, 2-3x inc in mortality, r/o pituatary insufficiency, colon cancer.
What is MEN Type I?
genetics: inactivation of MENIN
Pancreatic islet Cell (neoplasia-> gastrin, VIP, insulin, glucagon)
Pituatary adenoma (fxn or not)
What is MEN Type 2A?
genetics: RET proto-oncogene
Medullary thyroid carcinoma
What is MEN Type 2B?
genetics: RET proto-oncogene
Medullary thyroid carcinoma
Mucosal & gastrointestinal neuromas
What is PGA Syndrome Type 1?
Polyglandular Autoimmune Syndrome - children
What is PGA syndrome Type II
Polyglandular Autoimmune Syndrome - adults
autoimmunte thyroid disease
DM type 1
TSH: what is best for? what may interfere with its interpretation?
Best for primary hypo and hyperthyroidism
(inappropriately normal in central etiologies)
Decreased by dopamine, steroids, severe illness
What does T3 and T4 immunoassays immunoassays measure? What is it influenced by?
Measures the total* serum concentration.
It is influenced by TBG.
What is TBG, and what increases or decreases it?
THyroxine-binding globulin, will cause correlating inc or dec in T4
inc from: estrogens, OCP, pregnancy, hepatitis, opioids, hereditary
dec from: androgens, glucocorticoids, nephritic syndrome, cirrhosis, acromegaly, nicotinic acid, hereditary.
What is the general lab work up approach to thyroid disorders?
TSH-> (if high or low)-> Free T4
if primary hyperthyroidism (low TSH, high FT4)-> RAIU. if no RAIU take up- > serum thyroglobulin
Decreased TSH, increased FT4?
Primary hypERthyroidism -> RAUI
if diffuse, homogeneous take up: Graves
if diffuse, heterogeneous take up: Toxic multi nodular goiter
If focal take up: functioning adenoma
if no take up-> serum thyroglobulin -
if dec: thyrotoxicosis factitia
if inc: thyroiditis strum avarii or Iodine load
Increased TSH, decreased FT4
- consider anti-TPO, anti-Tg Abs for Hashimoto's
Increased TSH, increased FT4
TSH secreting adenoma (central hypERthyroidism)
or - thyroid hormone resistance
What are causes of hypothyroidism?
PRIMARY (>90%) - dec FT4, inc TSH
- Goitrous: Hashimoto's, s/p thyroiditis, iodine deficiency, Li, amiodarone
- Nongoitrous: surgical destruction, s/p radioactive iodine or XRT, amiodarone
CENTRAL- dec FT4, nl or slight inc TSH
-hypothalamic or pituitary failure (TSH can be of any level, but functionally inactive due to abnormal glycosylation)
How does hypothyroidism present clinically?
weakness, fatigue, arthralagias, myalgias, HA, depression, cold intolerance, weight gain, constipation, menorrhagia, dry skin, coarse hair, brittle nails, carpal tunnel syndrome, delayed DTR, diastolic HTN, hyperlipidemia
slow speech, hoarseness, loss of outer third of eyebrows, myxedema (inc glycosominoglycans), periorbital puffiness, bradycardia, pleural, pericardial and peritoneal effusions, atherosclerosis.
hypothermia, hypotension, hypoventilation, AMS
possible hyponatremia, hypoglycemia, anemia, inc LDL, dec HDL, and inc CK
How do you treat overt hypothyroidism?
Levothyroxine, f/u in 5-6 weeks to titrate
Sx can take months to resolve
start low if risk of ischemic heart disease
inc dose for: pregnancy, HRT, dec GI absorption (Fe/Ca supplements, PPI, sucrasulfate, celiac dz, IBD)
MYXEDEMA COMA: First adrenal replacement therapy, T4 IV load then daily, consider T3 if unstable
What are the causes of Hyperthyroidism?
- Graves Disease
- Thyroiditis (subacute/granulomatous, painless/lymphocytic)
- Toxic adenoma (single or multi nodular)
- TSH-secreting pituatary tumor/pituatary resistance to thyroid hormone
- MEDS: amiodarone, iodine-induced, thyrotoxicosis factitia,
- OTHER TUMORS: struma ovarii (3% ovarian dermoid, teratomas), hCG-secreting tumors (e.g. choriocarcinoma), large deposits of metastatic follicular thyroid tumors
What are the specific clinical manifestation of Grave's disease? What are the antibodies involved?
usually women, usually 40-60
-goiter: diffuse, nontender, w/ bruit
-ophthalmopathy: periorbital edema, lid retraction, proptosis, conjunctivitis, diplopia. A/w smokig.
-pretibial myxedema (infiltrative dermopathy)
TSI or TBII, anti-TPO, anti-thyroglobulin, ANA
What is the clinical presentation of hyperthyroidism? What lab work up would you do?
weight loss, restlessness, sweating, tremor, moist warm skin, fine air, tachycardia, AF, inc frequency of stools, menstrual irregularities, hypereflexia, osteoporosis, stare and lid lag (sympathetic overactivity.
APATHETIC THYROTOXICOSIS - elderly may present with lethargy
THYROID STORM (rare) - delirium, fever, tachycardia, systolic htn w/ wide pulse pressure and dec MAP, GI sx, 20-50% mortality
WORKUP: TSH, FT3, FT4, RAIU scan. Antibodies only in pregnancy
may see hypercalciuria, maybe hypercalcemia, increased AP, anemia
How would you treat hyperthyroidism?
Beta blockers (dec tachy, propanolol dec conversion of T4 to T3)
GRAVES DZ: - methimazole (MMI)- side effects pururitis, rash, arthralgia, fever, N/V, agranulocytosis
- propylthiouracil (PTU) -2nd line, slower, TID. side effects hepatocellular necrosis.
both - high risk of recurrence, check LFTs, WBC, TSH baseline and f/u
- RAI, surgery
TOXIC ADENOMA/TMG - RAI, surgery
THYROID STORM - beta blocker, PTU, iopanoic acid or iodine (using Wolff-Chaikoff effect - thyroid hormone reduced after large iodine load)
OPTHALMOPATHY- ca worsen after RAI, pretreat with prednisone in high risk
SUBCLINICAL- controversial, consider if TSH < 0.1, inc risk for CV dz, osteoporosis
What are causes of thyroiditis?
ACUTE: bacterial infection (rare in US)
SUBACUTE: transient thyrotoxicosis -> transient hypothyroidism -> nl fx
-painful: viral, granulomatouss, de Quervaine (inc ESR, tx NSAIDs, ASA, steroids)
-silent: postpartum, autoimmune, lymphocytic (+anti-TPO)
-other: amiodarone, radiation, palpation thyroiditis (from mechanical damage)
CHRONIC: Hashimoto's, Riedel's (idiopathic fibrosis)
What is Sick Euthyroid Syndrome?
Patient has TFT abnormalities due to severe nonthyroidal illness (may be acquired transient central hypothyroidism)
if working up thyroid in critically ill patients: TSH not reliable, have to measure T4, FT4, T3.
Replacement thyroxine in critically ill not usually helpful unless other s/s of hypothyroidism
What is the risk of thyroid disease in patients on Amiodarone?
Higher dose has higher risk
HYPOTHYROIDISM: 10%, more common in iodine replete areas
HYPERTHYROIDISM: 3% or 10-20% in iodine deficient areas.
What are the risk factors associated with malignancy in a thyroid nodule?
Age: <20 or >70
h/o nec xrt
Exam: hard, immobile mass, size is large
U/S: hypoechoic, solid, irregular borders, microcalcification, central blood flow
What are the features associative with benign thyroid nodules?
FHx: autoimmune thyroid dz or goiter
hypo- or hyperthyroidism
When would you do a screening U/S for thyroid nodules?
FHx of MEN2 or medullary thyroid cancer
PHMx neck XRT
When would you do an FNA of a thyroid nodule?
if >10mm (or >8mm with irregular borders), micro calcifications, central vasculature. Hx of neck XRT, FHx of MEN2, MTC
What is the clinical approach to thyroid nodule?
Hx: thyroid sx, h/o neck XRT, FHx of MEN2, MTC, autoimmone thyroid dx, goiter
if TSH Low, RAUI
if TSH normal, RAUI cold, or other RF - FNA
Cold nodules, malignant FNA - surgery
Hot nodules: benign toxic adenoma- ablate, resect, or meds
bening: observe or meds, monitor
What is Cushing syndrome versus Cushing's disease?
CUSHING SYNDROME: cortisol excess
CUSHING'S DISEASE: Cushing's syndrome secondary to pituatary ACTH hypersecretion
What are the etiologies of hypercortisolism?
(1) Iatrogenic-exogenous glucocorticoids (most common)
(2) Cushing's disease: pituitary adenoma or hyperplasia
(3) Adrenal tumor: adenoma, (rarely) carcinoma
(4) Ectopic ACTH: SCLC, islet cell tumors, MTC, pheo
How does hypercortisolism present?
NONSPECIFIC: DM, Htn, obesity, oligomenorrhea, osteoperosis
MORE SPECIFIC: central obesity, extremity wasting, dorsocervical fat, moon fancies
MOST SPECIFIC: easy bruising, proximal myopathy, wide striae, hypokalemia
OTHER: depression, insomnia, psychosis, impaired cognition, facial flushing, acne, hirsutism, hyperpigmentation (if also inc ACTH), fungal skin infxn, nephrolithiasis, polyuria
How do you work up Cushing's Syndrome?
(1) SCREEN - 3 options
-24 hr urine free cortisol
-overnight low dose dexamethasone suppression test
-11pm salivary cortisol
(2) Positive in EtOH, acute illness, depression (possible pseudo-Cushings): recheck after resolution or combine 48 hr LD DST + CRH
(3) Positive, or continued strong clinical suspicion
recheck 24hr UFC, THEN
(4) ACTH high/nl: ACTH dependent
->48hr o/n HIGH dose DST or CRH test
a. NO supression/neg stim: chest & and RI, somatostatin scan: + (ectopic ACTH) - (->Bilat inferior petrosal sinus vein sampling, assess petrosal: peripheral ACTH ratio - will determine if ectopic ACTH or Cushing disease)
b. YES suppress/pos stim: pituatary MRI: + Cushing Dz, - (->BIPSS)
(5) ACTH low: ACTH independent
adrenal CT/MRI for adrenal tumor
How do you treat Cushing's Syndrome?
(1) Tumors (pituatary, adenoma, adrenal, ectopic) - surgery
(2) if not successful
-medical adrenalectomy w/ mitotane or b/l surgical adrenalectomy
-ketoconazole, +/- metyrapone to dec cortisol
(3) Glucocorticoid replacement therapy 6-36 mo for Transphenoidal, lifetime (+mineralocorticioid) if adrenalectomy)
What are the etiologies of Hyperaldosteronism?
PRIMARY: adrenal d/o, renin independent increases
-adrenal hyperplasia 70%, adenoma (Conn's syndrome) 25%, carcinoma 5%, glucocorticoid-remediable adosteronism (GRA)
SECONDARY: extra-adrena d/o, inc is renin dependent
-primary reninism: rening secreting tumor (rare)
-secondary reninism: renovascular disease (Renal artery stenosis, malignant hypertension), dec arterial volume due to edema (CHF, cirrhosis, nephrosis), hypovolemia, diuretics, DM2, Bartter's (=loop diuretic), Gitelman's (=thiazide diuretic)
NONALDOSTERONE MINERALOCORTICOID EXCESS: mimics hyperaldesteronism
-11Beta-HSD deficiency (hydroxysteroid dehydrogenase)
- black licorice (inhibits, 11Beta-HSD), extreme hypercorisolism (overwhelmed 11beta-HSD
- Liddle syndrome (inc distal tubular renal Na channel)
-exogenous mineralocorticoids, some CAH
How does Hyperaldosteronism present?
Mild to moderate Htn (refractory to 3 drugs)
HA, muscle wekaness, polyuria, polydipsia.
hypokalemia (or nl), metabolic alkalosis, mild hypernatremia
How do you work up hyperaldosteronism?
suspected (esp if Htn + hypokalemia, adrenal mass, or its refractory)
-> AM plasma renin and aldosterone
(1) low renin, low aldosterone: NON-ALDOSTERONE MINERALOCORTICOID EXCESS
(2) low renin, high aldosterone, high aldo:renin ratio: PRIMARY HYPERALDOSTERONISM
-> Adrenal CT/MRI:
(a) unilateral: adenoma or carcinoma
(b) none or bilateral--> adrenal vein sampling (if no localizations: hyperplasia, GRA)
(3) high renin, high aldosterone, low ratio: SECONDARY HYPERALDOSTERONISM
How do you treat hyperaldosteronism?
Adenoma/carcinoma - surgery
GRA- glucocorticoids +/- spironolactone
What are the etiologies of adrenal insufficiency?
PRIMARY (Addison's Dz - adrenocortical dz)
-vascular (hemorrhage esp in setting of sepsis, thrombosis, trauma)
-infection (TB, CMV, histoplasmosis)
-autoimmune (including PGA)
-infiltrative (sarcoid, amyloid, hemochromatosis)
-tox (ketoconazole, etomidate, rifampin, anticonvulsants
SECONDARY (pituatary, failure of ACTH - aldo is still intact, given RAALS)
-any cause of hypo-pit
-glucocorticoid therapy, megestrol (progestin w/ corticoid activity)
How does adrenal insufficiency present?
weakness, fatigue, anorexia
PRIMARY ONLY (from no aldo, inc ACTH): orthostatic hypotension (vol. depleted), hyperpigmentation, hyperkalemia
SECONDARY ONLY +/- other hypo-pit sx
How do you work up adrenal insufficiency?
(1) Early am serum cortisol
(2) Standard dose cosyntropin stimulation test (assess whether more ACTH increases cortisol-abnl in primary and chronic secondary, where adrenals atrophied)
(3) Specialized tests of HPA axis: insulin-induced hypoglycemia, metyrapone
(4) other lab abnl: hypoglycemia, eosinophilia, lymphocytosis, +/- neutropenia
(5) ACTH levels
(6) consider imaging: pituitary MRI, adrenal CT
CRITICALLY ILL PT
if hypotension + abs adrenal insuf -> ACTH stim test ASAP
-start corticosteroid early
How do you treat Adrenal Insufficiency?
(1) Acute insufficiency: IVF + hydrocortisone IV
(2) Chronic insufficiency: hydrocortisone PO + fludrocortisone PO (only in primary) + back up dexamethasone
What are the clinical manifestations of pheochromocytoma?
THE 5 P'S:
Pressure (htn, paroxysmal, severe, refractory)
Pain (HA, CP)
Palpitation (tachy, tremor, wt loss, fever)
RULE OF 10
10% extra adrenal (paraganglioma-more likely to recur, be malignant)
10% in children
10% multiple or bilateral
What syndromes are associated with pheochromocytoma?
MEN 2A, 2B
Von Hippel Lindau
Neurofibromatosis type 1
How do you work up Pheochromocytoma?
(1) 24 hr urine fractionated metanephrines & catecholamines (very Se/Sp)
- false + w/ very ill, Renal failure, OSA, labetalol, TCA, meds w/ sympathomimetics
(2) Plasma free metanephrines (lower specificity)
(3) Adrenal CT/MRI, consider MIBG scintigraphy, PET
(4) Consider genetic testing
How do you treat Pheochromocytoma?
First: alpha blockade (phenoxybenzamine)
+/- beta blockade (usually propanolol)
What is the differential diagnosis of Adrenal Incidentalomas?
(1) NONFUNCTIONING MASS
-adenoma, cysts, abscesses, granuloma, hemorrhage, lipoma, myelolipoma, primary or metastatic malginancy
(2) FUNCTIONING MASS
-pheochromocytoma, adenoma (cortisol, aldosterone, or sex horones), nonclassical CAH, other endocrine tumor, carcinoma
(3) NONADRENAL MASS
-renal, pancreatic, gastric, artifact
How do you work up an Adrenal incidentaloma?
(1) R/O SUBCLINICAL CUSHINGS IN EVERYONE
- 1 mg o/n Dex test. If abnl, do confirmatory studies
(2) R/O HYPERALDOSTERONISM IF HTN
- plasma aldo and renin
(3) R/O PHEO IN EVERYONE
- 24hr urine fractionated metanephrines and catecholamines, or plasma free metanephrines
(4) R/O METS or INFECTION if suspicious
- history, CT guided biopsy
What are CT and MRI characteristics that may suggest adenoma vs. carcinoma in adrenal incidentalomas?
BENIGN: small (<4cm), smooth margins, homogenous, hypodense. - follow with periodic scans
SUSPICIOUS: large (>4 cm) or expanding in repeat scans, irregular margins, heterogeneous, dense or vascular, h/o malignancy, young age. - FNA biopsy, repeat in 3 months, or resection
What are the the hypercalcemic disorders that correlate to these lab findings?
(1) High Ca, v. High PTH, low PO4
(2) High Ca, hi or nl PTH, low PO4
(3) high Ca, low PTH, low PO4
(4) high Ca, low PTH, high PO4
(5) high Ca, low PTH, unpredictable PO4
(1) Hyperparathoridism, primary and tertiary
(2) Familial hypocalciuric hypercalcemia
(3) Milk-alkali syndrome, thiazides
(4) Increased bone turnover OR Vit D excess
What are the hypocalcemic disorders that correlate to these lab findings?
(1) low Ca, v. high PTH, high PO4?
(2) low Ca, high PTH, low PO4
(3) low Ca, high PTH, high PO4
(4) low Ca, low PTH, high PO4
(5) low Ca, variable PTH, variable PO4
(2) Vit D deficiency
(3) chronic renal failure (secondary hyperparathyroidism)
(5) acute calcium sequestration
What are limitations in measuring calcium?
(1) Only ionized calcium reflects physiologic Ca. Serum Ca is influenced by albumin (need to correct or measure directly)
(2) alkalosis increases albumin binding
What are etiologies of hyperparathyroidism (primary and secondary?)
adenomas (85%), hyperplasia (spont vs MEN 1/2A), carcinoma (<1%)
after long standing secondary hyperpara (renal failure)-> autonomous nodule (require surgery)
Lithium (inc PTH)
What are the etiologies of familial hypocalciuric hypercalcemia (FHH)?
(1) Inactivating mutation in Ca sensing rec in parathyroid and kidney--> inc Ca set point +/- inc PTH (to a lesser degree than primary hyperpara)
(2) Acquired from autoAb to Ca sensing rec (rare)
What are the etiologies of malignancy leading to hypercalcemia?
(1) PTH-related peptide (PTHrP)--> humoral inc Ca of malignancy (e.g. squamous cell cancers, renal, breast bladder)
(2) Cytokines and 1,25 (OH)2D3 (hematological malignancies)
(3) local osteolysis (breast, myeloma)
What are the etiologies of Vitamin D excess hypercalcemia?
grandulomas (sarcoid, TB, histo, Wegener's)--> Inc 1-OH-> inc 1,25 (OH)2D
Vit D intoxication
What is the cause of hypercalcemia due to increased bone turnover?
immobilization + Paget's Dz
What are the etiologies of Hypercalcemia? What is most common in the inpatient population?
Hyperparathyroidism (primary and tertiary)
Familial Hypocalciuric hypercalcemia (FHH)
Vitamin D excess
Inc Bone Turnover
Milk Alkali Syndrome
Inpatients: 45% cancer, 25% primary hyperpara, 10% chronic kidney disease--> tertiary hyperapara
What is the clinical manifestation of of hypercalcemia?
BONES, STONES, ABD GROANS, PSYCHIATRIC OVERTONES
(1) bones: osteopenia, fractures, oseitis fibrosa cystic (if severe, inc osetoclast activity->cysts, fibrous nodules, "salt and pepper" on x ray)
(2) stones: nephrolithiasis, nephrocalcinosis, nephrogenic DI
(3) Abd groans: pain, anorexia, N/V/C, pancreatitis, PUD
(4) Psych: fatigue, weakness, depression, confusion, coma, Dec DTR, short QT interval
HYPERCALCEMIC CRISIS: (Ca>13-15): polyuria, dehydration, AMS (Ca toxic to renal tubules, blocks ADH-> vasoconstriction->dec GFR->polyuria but with inc Ca reabsorption-> inc serum Ca-> inc nephrotoxicity and CNS sx)
CALCIPHYLAXIS (calcific uremic arteriopathy): calcification fo media of small-med vessels of dermis & SC fat--> ischemia and skin necrosis
a/w uremia, inc PTH, inc Ca, inc PO4
dx biopsy, poor prognosis
tx: wound care, keep Ca & PO4 nl, avoid supplements
What are the diagnostic studies for Hypercalcemia?
Ca, albumin, ionized Ca, PTH, PO4.
perhaps: PTHrP, 25(OH)2D, Alk Phos, Uca, SPEP, UPEP, ACE, CXR/CT, mammogram
What are the treatments for Hypercalcemia?
(1) NL SALINE (onset hours, duration during Rx, natriuresis inc renal Ca excretion)
(2) FUROSEMIDE (hours, duration during Rx, use only if volume overloaded)
(3) BISPHOSPHONATES (onset 1-2d, lasts 2-3d, inhibits osteoclasts, good for malignancy, careful in renal failure, risk of jaw osteonecrosis)
(4) CALCITONIN (onset hours, lasts 2-3 d, quickly develop tachyphylaxis)
(5) GLUCOCORTICOIDS (onset ays, lasts days, maybe useful in some malignancy, granulomatous disorders and vit D intox)
What is the treatment for asymptomatic primary hyperparathyroidism?
Surgery if young (<50), high serum Ca (>1mg/dL), low kidney function (Cr Cl <60), low bone density (DEXA T score < -2.5)
What are the etiologies of Hypocalcemia?
-sporadic, familial, iatrogenic (thyroid surgery, radiation), Wilson's, hemochromatosis, hypoMg, activating Ca-sensing rec auto-Ab
-Ia and Ib (PTH end organ resistance, thus inc serum PTH), Ia (skeletal abnl, short stature, retardation)
-pseudopseudohypoparathyroidism (1a syndrome but nl Ca & PTH)
(3) VIT D DEFICIENCY (or RESISTANCE)
-nutritional/sunlight, GI dz/fat malabs, drugs (anticonvulsants, rifampin, ketoconazole, 5-FU/leucovorin), genetic (1alpha-hydroxylase, VDR mutations)
(4) CHRONIC RENAL FAILURE (low 1,25(OH)2D production, high PO4 from low clearance)
(5) ACCELERATED NET BONE FORMATION
-postparathyroidectomy, Rx of severe vit D deficiency or Paget's dz, osteoblastic mets
(6) CALCIUM SEQUESTRATION
-pancreatitis, citrate excess (after blood transfusion), acute and severe inc PO4 (ARF, rhabdo, tumor lysis) bisphosphonates
What are the clinical manifestations of Hypocalcemia?
(1) Neuromuscular irritability: perioral paresthesis, cramps, Chvostek's sign (tap facial nerve->contract facial muscles), Trousseau's sign (inflate BP cuff->carpal spasm), laryngospasm; irritibility, depression, psychosis, inc ICP, seizures, inc QT
(2) Rickets/Osteomalacia: chronic dec Vit D-> dec Ca, PO4-> dec bone mineralization, growth failure, bone pain, muscle weakness
(3) Renal osteodystrophy (dec Vit D, inc PTH in renal failure), osteomalacia, and osteitis fibrosa cystica (due to inc PTH)
What are the diagnostic studio for hypocalcemia?
Ca, alb, ionized Ca, PTH, 25-(OH)-D, 25-(OH)2-D (if renal failure or rickets), Cr, Mg, PO4, Alk Phos, Uca
How do you treat hypocalcemia?
-IV Ca gluconate + calcitriol (most effective in acute, but takes hrs) +/- Mg
(2) ASYMPTOMATIC OR CHRONIC
-oral Ca + Vit D. If +calcitriol, consider thiazide
(3) CHRONIC RENAL FAILURE
-phosphate binder + oral Ca, calcitriol or analog (calcimimetic later to prevent hypercalcemia)
What is the definition of Diabetes Mellitus?
(1) Fasting glc >/= 126
(2) random glc >/= 200 x 2 (or once if very high + metabolic decompensation)
(3) 75 g OGTT w/ 2h glc >/= 200 (not the routine OGTT)
(4) NOT OFFICIAL: HbA1C>6.5
What is the definition of "prediabetes"? How do you proven progression to dm?
(1) impaired fasting glc: 100-125
(2) impaired glc tolerance: 140-199 2h after 75 g OGTT
Diet and exercise (58% dec), metformin (31% dec), TZD (60% dec)
What are the categories of Diabetes?
(1) Type I: islet cell destruction, abs insulin deficiency, ketosis if no insulin, inc risk with FHx, HLA associations, usually childhood onset (not always), have anti-GAD, anti-islet cell, anti-insulin autoantibodies. Prevalence is 0.4%
(2) Type II: insulin resistance + relative insulin deficiency; gradual onset later in life; inc risk if +FHx, obesity, sedentary, no HLA association. prevalence is 8%
(3) Type II DM p/w DKA (ketosis prone type 2 diabetes): most often i nonwhite, +/- anti-GAD Ab, eventually may not need insulin
(4) MODY (mature onset diabetes of the young): autosomal dominant, forms of DM due to defects in insulin secretion genes, heterogeneous
(5) Secondary causes of DM: exogenous glucocorticoids, glucogonoma (3Ds: DM, DVT, diarrhea), pancreatic (pancreatitis, hemochromatosis, CF, resection), endocrinopathies (Cushing's, acromegaly), gestational, drugs (PI, atypical antipsychotics)
What are the diabetes treatment options?
(1) Diet (carb counting, wt reduction, exercise)
(4) Thiozolididnediones (PPAR gama agonists)
(7) alpha-glucosidase inhibitors
(9) DPP-4 inhibitor
Metformin: what is its effect, adverse effects, contraindication, general use?
EFFECT: dec hepatic gluconeogenesis, dec HbA1C ~1.5%
ADVERSE: weight neutral, N/V/D, rare lactic acidosis
CONTRA: renal (Cr > 1.5) or liver failure
USE: first line Rx with lifestyle for all T2D wit HA1C>7%
Sulfonylureas: what is its effect, adverse outcomes?
EFFECT: inc insulin secretion, dec HbA1C 1.5%
ADVERSE: weight gain, hypoglycemia
Thiazolidinediones (PPAR gamma agonists): what is its effect, adverse effects, contraindication?
EFFECT: inc insulin sensitivity in muscle, adipose, dec HbA1C 1%
ADVERSE: Weight gain, hepatotoxicity, fluid retention, CHF, bone factures, ?inc risk of MI (rosiglitazone, not pioglitazone)
CONTRA: liver disease, NYHA III-IV, monitor LFTs
Glinides: effect, adverse effects?
EFFECTS: inc insulin secriteion, dec HbA1C 1.5%
ADVERSE: hypoglycemia (less than SU), wt gain
Exenatide: effect, adverse effects?
EFFECTS: inc glc depend insulin secretion (GLP-agonist), dec HbA1C 0.5%
ADVERSE: wt loss, N/V/D, pancreatitis (rare)
alpha-glucosidase inhibitor: effect, general use?
EFFECTS: dec intestinal CHO absorption, dec HbA1C 0.5-0.8%
GENERAL USE: as adjunctive Rx w/ insulin in T1D or T2D
Insulin: adverse effects, use?
ADVERSE: hypoglycemia, weight gain
USE: T1D - intermed/long acting (NPH or glargine) and short/rapid (regular or lispro)
T2D- consider if mono oral Rx not adequate (esp if high HbA1C), start if combo oral Rx not adequate
What is the onset, peak, duration and time of use of Lispro and aspart?
ONSET: 5-15 min
PEAK: 60-90 min
DURATION: 2-4 h
USE: immediate before a meal
What is the onset, peak, duration and time of use of Regular insulin?
ONSET: 30-60 min
PEAK: 2-4 hr
DURATION: 5-8 h
USE: 30 min before a meal
What is the onset, peak, duration and adverse effects of use of NPH?
ONSET: 1-2 h
PEAK: 4-8 h
DURATION: 12-18 h
SIDE EFFECT: can cause protamine Ab production
What is the onset, peak, duration and time of use of glargine?
ONSET: 2 h
PEAK: no peak
DURATION: 20-24 h
USE: Once daily (am or pm)
What are the types, presentation of diabetic retinopathy? What is the treatment?
-"dot & blot", retinal hemorrhages, cotton-wool/protein exudates
- neovascularizations, vitreious hemorrhage, retinal detachment, blindness
TREATMENT: photocoagulation, surgery
What is the usual progression of diabetic nephropahty? What is the histological pattern? How is it related to retinopathy? What is the treatment?
(1) microalbuminuria--> proteinuria +/- nephrotic syndrome -> renal failure
(2) diffuse glomerular basement membrane thickening/nodular pattern (Kimmelstiel-Wilson)
(3) Accompanies retinopathy. If not, suspect other cause
(4) strict BP control with ACEI or ARB, low protein diet, dialysis or transplant.
What are the types of diabetic neuropathy?
(1) symmetric peripheral: symmetric distal sensory loss, paresthesias +/- motor loss
(2) Autonomic: gastroparesis, constipation, neurogenic bladder, ED, orthostasis
(3) mononeuropathy: sudden-onset peripheral or CN deficit (e.g. foot drop, CNIII>VI>IV)
What are the common infectious risks of diabetes?
UTI, osteomyelitis of foot, candidiasis, mucormycosis, necrotizing external otitis
What are the dermatologic risks of diabetes?
- necrobiosis lipoidica diabeticorum
What are the complications of Diabetes?
ATHEROSCLEROSIS (coronary, cerebral, peripheral)
What are the Outpatient screening and treatment goals of Diabetes?
(1) HbA1C <7%
(2) Yearly microalbuminuria test, Spot microalbumin/Cr ratio <30%
(3) Cardiovascular: BP <130/80, LDL <100, TG<150, HDL >40.
(4) Consider: Statins helpful even w/o CAD, ASA if age >50 (men)/>60 (women)
(5) Retinal, foot exam yearly
Overview: What is the management of hyperglycemia in Inpatients?
(1) Reversible causes? (IVF, steroids, post op, carb diet)
(2) Tests: BG (fasting, qAC, qHS or q6h if NPO), HA1C
(3) Goals: avoid hypoglycemia, and extreme hyperglycemia <180
(4) Modify outpatient treatment
- T1D: maintain basal insulin (or risk DKA)
- T2D: stop PO DM meds
(5) Inpt insulin, use outpt as guide. If naive:
- total daily=wt(kg) / 2
- half as basal (long acting), target fasting
- half as short acting (pre-meal, sliding scale) (then adjust)
(6) Discharge plan: keep outpatient unless indication otherwise.
What are the likely precipitants of DKA?
The 6 I's :
INFECTION (pna, uti) )
INFLAMMATION (pancreatitis, cholecystitis)
ISCHEMIA/INFARCTION (mi, cerebral, gut)
INTOXICATION (etoh, drugs)
What is the pathophysiology of DKA?
occurs in T1D/ketosis prone T2D
(1) inc glucagon, dec insulin
(2) hyperglycemia: inc glucneogenesis, glycogenolysis, dec uptake into cells
(3) ketsosis: insulin def-> mobilize, oxidize FA, inc substrates for ketogenesis, inc ketogenic state of liver, dec ketone clearance
How does DKA present?
(1) polyuria, polydypsia
(2) dehydration: tachycardia, hypotn, dry
(3) N/V/abd pain (from inc abd pressure, dka), illeus.
(4) Kussmaul respirations (deep, to compensate metabolic acidosis) with acetone odor,
(5) change MS (somnolence, stupor, coma)
- mortality ~1%
What are the things you should track in DKA?
Ketones (betaOHB, or acetaldehyde by nitroprusside)
How does DKA present on diagnosistic studies?
(1) anion gap metabolic acidosis (later non-AG from urinary loss of ketones and fluid resusc with chlorine)
(2) ketosis: in urine and serum (beta-OHB, or acetaldehyde if measured by nitroprusside) Urine ket may be + in nl fasting patients
(3) Inc serum glc, BUN/Cr (dehydration)
(5) inc or dec K (dec* total body K), dec total body phos
(6) inc WBC, amylase
how do you correct for pseudohyponatremia in DKA?
corrected Na= measured Na + [2.4x(measured glc-100)/100]
how do you treat DKA?
(1) r/o precipitants
(2) aggressive hydration: NS 10-14 ml/kg/h (adjust for dehydration and CV)
(3) Insulin (10 U IV push, then 0.1 U/kg/h - cont until AG normal
-if glc <250, AG still high, add dextrose too)
(4) Electrolyte repletion
- K: 20-40meq/L IVF if K <4.5 (note insulin promotes K entry to cells, will see dec in serum K)
-HCO3? if pH<7, cardiac instability
-PO4: if <1
What is the definition of Hyperosmolar hyperglycemic state? precipitants?
-extreme hyperglycemia, w/o ketoacidosis
-ms changes in T2D (typically elderly)
(2) 6Is, but also, dehydration, renal failure
What is the pathophysiology of hyperosmolar hyperglycemic state?
hyperglycemia-> osmotic diuresis -> vol depeltion ->prerenal azotemia -> inc glc, etc
how does hyperosmolar hyperglycemia present (including studies)?
volume depletion, MS change
inc serum glc (>600)
inc serum osm (>320)
- effective Osm = 2 x Na (mEq/L) + glc (mg/dL)/18
no ketoacidosis (usually inc BUN/Cr)
How do you treat hyperosmolar hyperglycemia?
(1) r/o preciptants (15% mortality from these)
(2) aggressive hydration NS, then 1/2NS, avg body fluid loss is 8-10 L
(3) Insulin (10 u IV push, then 0.05-0.1 u/kg/h)
What are the etiologies of hypoglycemia?
(1) excess meds, missed meals, renal failure (dec med clearance)
-beta blockers mask sx of hypoglycemia
(2) inc insulin (exogenous, sulfonyureas, insulinoma, anti-insulin antibodies)
(3) dec glucose production: hypopit, AI, glucagon def, heaptic failure, renal failure, CHF, etoh-ism, sepsis
(4) Inc IGF-II: non-islet tumor
(5) post-parandial (esp postgastrectomy, gastric bypasss, excess response to glc load)
(6) low glc w/o sx can be normal
What are the clinical manifestations of hypoglycemia?
(1) CNS: ha, visual change, ms change, weakness, sz, LOC (neuroglycopenic sx)
(2) Autonomic: diaphoresis, palpitations, tremor (adrenergic)
How do you evaluate hypoglycemia? (nondiabetic)
check BUN, Cr, LFTs, TFTs, IGF-I/II ratio as needed
-72h fast with monitored glc (stop for neurolgycopenic sx)
-At time of hypoglycemia, check insulin, C peptide (up w/insulinoma, sulfonylureas, down w/ exogenous insulin), beta-OHB, solfonylurea
-at end of fast, give 1 mg glucagon IV, measure plasma glc response before feeding
How do you treat hypoglycemia?
(1) POs: juice, paste, glc tablets
(2) IV 25-50g D50
(3) no IV: glucagon 0.5-1 mg IM or SC (side effect N/V)
What is a lipoprotein?
lipids (cholesterol esters & trigycerideds)
include: chylomicron, VLDL, IDL, LDL, HDL, Lp(a)
How is cholesterol measured and what are some relevant considerations?
(1) measure after 12 hr fast
(2) LDL is calculated = TC - HDL - (TG/5) but if LDL >400, order direct since calc is inaccurate.
(3) lipid levels stable up to 24 hr after ACS/acute illness, then dec (up to 6wk to normalize)
What are the criteria for metabolic syndrome?
At least 3 of these:
(1) waist >/= 40" (m) or 35" (w)
(2) TG >/=150, HDL <40 (m) or <50 (w)
(3) BP >/= 130/85
(4) FBG >/= 100
What are the secondary dyslipidemias?
-DM2 (high TG, low HDL)
-hypothyroidism ( inc LDL, inc TG)
-hyperthyroidism (dec LDL)
-cushing/exogenous steroids (inc TG)
-RF (inc TG)
-nephrotic syndrome (inc LDL)
-cholestasis, PBC (inc LDL)
-Liver failure (dec LDL)
-acute hepatitis (inc TG)
-obesity (inc TG, dec HDL)
-sedentary (dec HDL)
-etoh (inc TG, inc HDL)
-tobacco (dec HDL)
-thiazides (inc LDL)
-beta blockers (inc TG, dec HDL)
-estrogens (inc TG, inc HDL)
-protease inhibitors (inc TG)
What are they primary dyslipidemias?
(1) FH - familial hypercholesterolemia (1:500) deffective LDL rec, super high chol, nl TG, inc CAD
(2) FDB- familial defective apoB100 (1:1000) similar
(3) FCH - familial combined hyperlipidemia (1:2000) polygenic, inc chol, TG, CAD, dec HDL
(4) FDBL - familial dysbetaliproteinemia (1:10K) apo E eta2/eta2 + DM, obesity, renal dz, etc - inc chol, TG, CAD; tuberoeruptive and palmar striated xanthomas
(5) FHTG - familial hypertriglyceridemia (1:500): inc TG, +/- inc chol, dec HDL, pancreatitis
What are the physical exam findings in lipid disorders?
(1) Tendon xanthomas-achilles, elblows hands (LDL >300)
(2) eruptive xanthomas: pimple like lesions on extensor surface (TG>1000)
(3) xanthelesma: yellowish streaks on eyelids in various dyslipidemias
(4) corneal arcus: esp in older peeps, if in younger implies hyperlipidemia
What is the pay off for reducing LDL? What are the goals?
Every 39mg/dL dec LDL-> 21% redux major vascular event (CV death, MI, stroke, revasc)
GOALS -from NCEP guidelines, framingham 10 yr CHD risk
HIGH RISK (chd, cvd, pad, aaa, dm, or >/= 2RF & 10y risk>20%)
goal LDL <100 or <70 if very high risk
MOD HIGH >/=2RF &10y risk 10-20%
goal LDL <130 (optional 100)
MODERATE >/=2RF &10y risk <10%
goal LDL <130
goal LDL <160
RF: >/=45 yo (m), 55yo (w); smoking; htn; +FH; HDL <40. If HDL>60 -1RF
What is the expected effect and side effects, other considerations of statins?
dec LDL: 20-60%
inc HDL: 5-10%
dec TG: 10-25%
inc aminotransferases 05-3% of peep, risk dose dependent
(check LFTs before, 8-12 wks, the q6mo)
myalgias <10% (not always inc CK), myositis 0.5%, rhabdo <0.1%, dose dependent
dbl dose -> 6% dec in LDL
What is the expected effect and side effects, other considerations of ezetimibe?
dec LDL: 15-20%
What is the expected effect and side effects, other considerations of fibrates?
dec LDL: 5-15%
inc HDL: 5-15%
dec TG: 35-50%
myopathy risk increases w/ statin
What is the expected effect and side effects, other considerations of niacin?
dec LDL: 10-25%
inc HDL: ~30%
dec TG: 40%
flushing (tx w/ASA)
severe hepatitis (rare)
What is the expected effect and side effects, other considerations of resins?
dec LDL: 20%
inc HDL: 3-5%
dec TG: ?inc
bloating, binds other meds
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