Week 6 Flashcards
1
Q
Primary adrenal insufficiency
patho, presentation, clinical features
gradual vereus rapid
A
- Pathophysiology: damage to the cortical cells (90% of cortex lost) that produce aldosterone and cortisol (adrenal medulla is preserved) → increased ACTH
- Presentation:
- Rapid (Waterhouse-Friderichsen): adrenal crisis due to hemorrhage → hypovolemic shock/coma → treat with glucocorticoids immediately
- Etiology: DIC secondary to N. meningitidis (children)
- Gradual (basal cortisol may be normal): Addison’s disease
- Rapid (Waterhouse-Friderichsen): adrenal crisis due to hemorrhage → hypovolemic shock/coma → treat with glucocorticoids immediately
- Clinical features: weakness, fatigue, loss of appetite, N/V, abdominal pain, weight loss, hyperpigmentation of skin (elevated ACTH → melanocyte production)
2
Q
Primary adrenal insufficiency
labs and etiology
A
- Labs: ACTH is elevated, hypoglycemia, hypotension, hyponatremia, hyperkalemia, eosinophilia (low cortisol effect), increased BUN/creatinine (volume depletion)
- Etiology: Autoimmune (majority), adrenal hemorrhage (due to anticoagulant therapy), infections, metastatic disease, adrenoleukodystrophy (X-linked, defect in fatty acid metabolism → very long chain fatty acids accumulate in organs), infiltrative diseases (i.e. amyloidosis), drugs (i.e. ketoconazole)
3
Q
Autoimmune polyglandular syndrome
1 versus 2
patho, etiology, Sx
A
- APS-1: Primary AI with hypoparathyroidism and mucocutaneous candidiasis
- Pathophysiology: autosomal recessive disease that is characterized by autoantibodies against cholesterol cleavage enzyme
- Etiology: mutation in autoimmune regulatory gene (AIRE)
- Sx: hepatitis, alopecia, vitiligo, hypogonadism, hypothyroidism
- APS-2: Primary AI with DM I and autoimmune thyroid disease
- Pathophysiology: anti-adrenal antibodies against 21-alpha-hydroxylase
- Associated with: genetic susceptibility linked to HLA-DR3/DR4
- Sx: less commonly alopecia, vitiligo, hypogonadism, celiac disease
4
Q
Secondary adrenal insufficiency
patho, etiology,
A
- Pathophysiology: deficient pituitary ACTH secretion → low ACTH → decreased cortisol and adrenal androgens, but NO aldosterone deficiency
- Early: basal cortisol is normal (decreased reserve or recent pituitary surgery)
- Late: further loss of ACTH secretion → atrophy of adrenal cortex → decreased basal cortisol
- Etiology: exogenous steroids (majority), hypothalamic/pituitary tumors (HA, vision changes, look for loss or hypersecretion of other pituitary hormones)
5
Q
Secondary adrenal insufficiency
sx, labs
A
- Sx: NO hyperpigmentation, NO hypotension, fatigue, loss of appetite, nausea, vomiting
- Labs: ACTH is low, hyponatremia (low cortisol → increased ADH → excessive water uptake), NO hyperkalemia, hypoglycemia, eosinophilia
6
Q
4 ways to diagnose AI
and how do they work
A
- AM cortisol (assesses basal cortisol): reasonable initial screening test, but may be normal in partial/early AI
- ACTH stimulation test (assesses adrenocortical reserve): normal peak cortisol >18 mcg/dL
- If abnormal cortisol response to test, check ACTH
- High ACTH → primary adrenal insufficiency
- Low ACTH → secondary adrenal insufficiency
- If abnormal cortisol response to test, check ACTH
- Metyrapone Test: evaluates HPA axis’ response to stress
- MOA: Metyrapone blocks the 11β-hydroxylase enzyme which converts 11-deoxycortisol to cortisol → decreased cortisol synthesis → stimulates ACTH → increases 11-deoxycortisol
- 11-deoxycortisol > 7 and ACTH > 100 → normal pituitary ACTH secretion and adrenal function
- MOA: Metyrapone blocks the 11β-hydroxylase enzyme which converts 11-deoxycortisol to cortisol → decreased cortisol synthesis → stimulates ACTH → increases 11-deoxycortisol
- Insulin-induced hypoglycemia test: evaluates entire HPA axis’ response to stress
- MOA: Hypoglycemia → increases CRH release → increases ACTH secretion → increases cortisol secretion
- Normal response is a peak cortisol > 18mcg/dL
- MOA: Hypoglycemia → increases CRH release → increases ACTH secretion → increases cortisol secretion
7
Q
Treatment of adrenal insufficiency
A
- Tx of acute adrenal crisis: IV glucocorticoids, IV fluids
- Tx of chronic AI: hormone replacement (glucocorticoids/hydrocortisone and/or mineralocorticoids/fludrocortisone)
8
Q
ACTH independent versus dependent Cushing syndrome
compare eitiologies
A
- ACTH-dependent Cushing syndrome:
- Cushing disease: due to ACTH secreting pituitary tumor → increased ACRH and bilateral adrenal hyperplasia (majority of syndrome)
- Ectopic ACTH or CRH secretion by non-pituitary tumors (small-cell carcinoma) → increased ACTH (hyperpigmentation) and bilateral adrenal hyperplasia
- ACTH-independent Cushing syndrome:
- Exogenous corticosteroid treatment → decreased ACTH and bilateral adrenal atrophy
- Primary adrenal adenoma, hyperplasia, carcinoma → produce cortisol → decreased ACTH → leads to atrophy of uninvolved adrenal gland
- Ectopic receptors in adrenal gland (respond to GIP/food dependent or HCG/pregnancy dependent) → Cushing syndrome
- Primary pigmented nodular adrenal disease (Carney complex)
9
Q
Cushing
sx, lab, path
A
- Symptoms: central obesity with thin extremities, moon facies, fat pad, thinning of skin → easy bruising and purple abdominal striae, osteoporosis, amenorrhea/hirsutism (women), proximal muscle weakness, immunosuppression, HTN, hypogonadism, decreased libido/impotence (men)
- Labs: low eosinophils (cortisol), possible hypokalemia, hyperglycemia (diabetes)
- Pathology: chronic high cortisol → pituitary cells accumulate cytokeratin filaments (hyaline material) → displacement of secretory granules to periphery (looks like rings)
10
Q
Diagnosis of Cushing Syndrome:
what is the intial screenign tests
what happens if those are positive
what is IPS
A
- Initial screening: increased 24 hour urine free cortisol, increased late night salivary cortisol, inadequate suppression of cortisol following 1mg dexamethasone overnight
- If initial screening is positive, proceed to measure ACTH
- Low ACTH → ACTH independent Cushing → perform CT of adrenal gland
- High ACTH → ACTH dependent Cushing
- High dose dexamethasone suppression test: no suppression (ectopic) or adequate suppression (Cushing)
- CRH stimulation test: increased ACTH and cortisol (Cushing) or no increase in ACTH and cortisol (ectopic)
- Inferior petrosal sinus (IPS) sampling: recommended if MRI does not reveal pituitary adenoma
- MOA: simultaneously measure IPS and peripheral ACTH before and after CRH
- IPS ACTH:peripheral ACTH > 2 before CRH, and >3 after CRH → pituitary ACTH-secreting tumor
- Drainage of blood: anterior pituitary → cavernous sinuses → IPS → jugular vein
- MOA: simultaneously measure IPS and peripheral ACTH before and after CRH
11
Q
Adrenal tumor-mediated hypertension
name 5 etiologies
explain each
A
- Cushing Syndrome
- Pheochromocytoma (functional chromaffin tumors from adrenal medulla → excess epi and norepi)
- Sx: episodic episodes of headaches, diaphoresis, and palpitations (classic triad)
- 5 P’s: pressure, pain, palpitations, pallor, and perspiration
- Etiology: germ line mutation (NF-1, VHL, RET)
- Epidemiology (rule of tens): 10% are malignant, bilateral, extra-adrenal, calcified, and in children
- Dx: increased serum metanepherines and increased 24 hour urine metanephrines and vanillylmandelic acid
- Tx: phenoxybenzamine
- Sx: episodic episodes of headaches, diaphoresis, and palpitations (classic triad)
- Primary hyperaldosteronism → excess aldosterone (zona glomerulosa)
- Etiology: aldosterone secreting adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia
- Sx/signs: HTN, hypokalemia, hypernatremia, metabolic alkalosis
- Labs: high aldosterone, low renin (high aldo:renin ratio)
- Secondary hyperaldosteronism: high aldosterone, high renin (aldo:renin ratio < 10)
- Etiology: cirrhosis, heart failure, nephrotic syndrome, renovascular HTN, renin secreting tumor
- Low aldo and low renin: CAH, exogenous mineralocorticoids, Cushing, Liddle syndrome (mutation in sodium channel → Na reabsorption), 11 beta hydroxysteroid dehydrogenase 2 deficiency (inactivation of cortisol to cortisone)
12
Q
Describe the gross anatomy, blood supply, and innervation of the adrenal glands
A
- Gross anatomy: left adrenal gland is bigger than right adrenal gland
- Blood supply:
- Adrenal glands are supplied by inferior phrenic aa, superior adrenal aa, and middle adrenal aa.
- Adrenal glands are drained by inferior phrenic vv, and adrenal vv.
- Innervation:
- The adrenal medulla is the only case in which the organ is directly innervated by preganglionic neurons (allows for quick fight and flight response)
13
Q
what are the layers of the adrenal gland
A
- Cortex (outer to inner): zona glomerulosa (G), fasiculata (F), reticularis (R),
- Medulla (M)
14
Q
Discuss the synthesis and regulation of catecholamines in the chromaffin cell
A
- Synthesis of catecholamines in chromaffin cells:
- Tyrosine (via tyrosine hydroxylase) → DOPA → dopamine → enter chromaffin granule → norepinephrine → exits chromaffin granule → epinephrine via PNMT → enters chromaffin granule
- Regulation of catecholamines:
- Ach driven sympathetic innervation (triggered by stress) → catecholamine synthesis
- Cortisol maintains PNMT gene expression
15
Q
Explain the action of catecholamines on different adrenergic receptors
A
- Catecholamine MOA: binds to GPCRs
- Norepinephrine: tends to be agonist for alpha receptors
- Epinephrine: tends to be agonist for beta receptors
- Catecholamine effect on receptors
- Alpha1 (Gq): vasoconstriction (systemic and to GI specifically)
- Alpha2 (Gi): glucagon release
- Beta1 (Gs): inotropic effect on heart
- Beta2 (Gs): vasodilation (muscles), bronchodilation, decreased insulin (pancreas), gluconeogenesis/glycogenolysis/ketogenesis (liver and muscles)
- Beta3 (Gs): lipolysis
16
Q
CAH: 11-beta-hydroxylase deficiency
A
- Leads to a deficiency of cortisol and aldosterone and an increased production of testosterone
- Sx: virilization (testosterone), HTN/hypokalemia (increased 11-DOC)
17
Q
21-hydroxylase deficiency
A
- Leads to deficiency of aldosterone and cortisol and increased testosterone
- Sx: virilization, salt wasting (salt is excreted w/o aldosterone)
18
Q
CAH: 17-alpha-hydroxylase deficiency:
A
- Leads to deficiency of cortisol, testosterone, DHEAS (lack of secondary sexual characteristics) and increased production of aldosterone (high-normal levels due to negative feedback)
- Sx: HTN/hypokalemia (both due to increased 11-deoxycorticosterone), abnormal sexual development (infertility), dysmenorrhea
19
Q
Describe the physiologic actions of cortisol, aldosterone, DHEAS,
A
- Cortisol
- Regulation: HPA axis (negative feedback), produced in paraventricular nucleus (follows circadian rhythm of release, highest right before waking up), released in response to stress/excitation
- Pathway: PVN releases CRH → anterior pituitary releases ACTH → cortisol is released by the adrenal glands (zona fasiculata)
- Effects: Acute/mins (mobilization of cholesterol and elevated pregnenolone), chronic, chronic/hrs (increased expression of genes for steroidogenic enzymes), trophic/months (hypertrophy of zona fasiculata/reticularis)
- DHEAS (bimodal elevations at birth and puberty)
- Pathway: ACTH → zona reticularis → DHEAS release
- No negative feedback on HPA axis, not associated with cortisol levels
- Pathway: ACTH → zona reticularis → DHEAS release
- Aldosterone
- Regulation: RAAS pathway (renin secreted by juxtaglomerular apparatus)
- Hyperkalemia → aldo increases, HTN → ANP increase → aldo decreases
- Effects: Na+ reabsorption, K+ excretion, pro-inflammatory effect on LV of heart
- Regulation: RAAS pathway (renin secreted by juxtaglomerular apparatus)
20
Q
what is the action on insulin
and structure
A
- Actions of insulin:
- Activate: glucose uptake, glycolysis, glycogen synthesis, protein synthesis, uptake of ions
- Inhibit: gluconeogenesis, glycogenolysis, lipolysis, ketogenesis, and proteolysis
- Structure of pro-insulin from beta cells
- A-chain and B-chain make up pro-insulin (bound by disulfide bonds)
- C-peptide is cleaved from A-chain and B chain to activate insulin
- Due to long half-life, c-peptide can be used to determine amount of insulin
21
Q
what is whipples triad
A
- Whipple’s triad: presence of symptoms (TIRED: Tachycardia, Irritability, Restlessness, Excessive hunger, Diaphoresis), documented low blood glucose, and eventual resolution of symptoms with raising blood sugar
22
Q
Endogenous hyperinsulinemia
name some etiologies
A
- Endogenous hyperinsulinemia (i.e. insulinoma, nesidioblastosis/beta cell hyperplasia, Roux-en-Y gastric bypass)
- Roux-en-Y gastric bypass: due to excess GLP-1 secretion from bypassed duodenum
- Dx: fast patient to achieve low blood glucose → take labs (insulin, proinsulin, C-peptide, cortisol, free FA)
- Labs: look for decreased blood glucose and increased C-peptide (increased insulin:glucose ratio and increased proinsulin:insulin ratio)
- Tx: pancreatectomy (nesidoblastosis) or tumor resection (insulinoma)
23
Q
how does AI lead to hypoglycemia
A
- Adrenal insufficiency: low cortisol → low blood glucose without hyperinsulinemia
24
Q
what are non-endocrine causes of hypoglycemia
3 overarching ways
A
- Liver and renal disease
- Normal: These organs contain glucose-6-phosphatase → releases glucose into circulation (therefore decreased cell mass → hypoglycemia)
- Liver: ethanol shuts down gluconeogenesis → hypoglycemia
- Renal: disease → alters insulin clearance → hypoglycemia
- Tumor and malignancies
- Tumors → insulin growth factor (IGF) expressed → increased glucose uptake → hypoglycemia
- Dx: no detectable insulin levels (IGF ≠ insulin)
- Tumors → insulin growth factor (IGF) expressed → increased glucose uptake → hypoglycemia
- Antibodies/immunologic
- Etiology:
- Pathway 1: anti-insulin antibody binds to insulin → pancreas produces more insulin → antibodies release insulin → LOTS of insulin → hypoglycemia
- Pathway 2: anti-insulin receptor antibodies act as insulin agonist → acts as insulin → hypoglycemia
- Associated with: SLE, biliary cirrhosis, and myasthenia gravis
- Etiology:
25
Q
- Drug-induced hypoglycemia
A
- Interference with metabolism, binding, or clearance of anti-diabetes drug:
- Adrenergic blocking drugs, heptotoxins, nephrotoxins, quinolones (i.e Cipro)
- Stimulation of K+ and/or Ca++ in beta cells:
- Anti-arrhythmic, macrolides, antihistamines
26
Q
- Jamaican vomiting sickness
A
- Etiology: Unripe Ackee fruit produces hypoglycin A/B → hypoglycemia
27
Q
- Factitious hypoglycemia
A
- Etiology: self-induce hypoglycemia caused by:
- Insulin injections, sulfonylureas, meglitinides
- Dx: mimics finings of endogenous hyperinsulinemia (NO elevated proinsulin:insulin ratio)
- Labs: high insulin, low c-peptide
28
Q
Non-pathologic hypoglycemia
3 types
A
- Reactive hypoglycemia
- Mechanism: high carb meal → excess insulin release → hypoglycemia
- Types
- Alimentary: post GI surgery due to dysfunctional glucose absorption → longer insulin release
- Prediabetic: delayed first phase insulin release → build-up of insulin during non-fed states → hypoglycemia
- Idiopathic post-prandial syndrome (not hypoglycemia)
- Mechanism: exaggerated catecholamine release in response to insulin → hypoglycemic-like symptoms without low blood sugar
- Somatostatinoma
- Mechanism: somatostatin releasing tumor → inhibition of insulin, glucagon, gastrin, GIP, CCK, secretin, GH, TSH → hypo or hyper-glycemia
- Sx: gallstones, steatorrhea, achlorhydria
29
Q
Glucagonoma
A
- Glucagonoma → hyperglycemia
- Mechanism: glucagon releasing tumor from alpha cells→ severe hyperglycemia
- Sx: depression, diarrhea, declining weight, dermatitis, DVT and anemia
- Necrolytic migratory erythema
- Description: erythematous blisters and swelling in areas of increased friction (present in majority of cases) – similar rash seen in zinc deficiency
- Necrolytic migratory erythema
30
Q
what is obesity
how to measure and what are the different BMI categories
A
- Obesity: storage of excess calories as fat
- Possible measurement techniques: BMI (can be misleading based on muscle mass), hip-to-waist ratio, Edmonton Obesity Staging System (most accurate – assesses obesity based on medical, mental and functional co-morbidities)
- BMI categories
- Under 16.5 (severely underweight), 16.5-18.4 (underweight), 18.5-24.9 (normal), 25-29.9 (overweight), 30-34.9 (class 1 obesity), 35-39.9 (class 2 obesity), 40 and over (class 3 obesity)
31
Q
thrifty gene versus set point theory
A
- Thrifty gene hypothesis: premise that humans evolve to store fat efficiently, burn energy slowly, spare muscle breakdown, and desire for calorically dense foods (i.e. ice cream)
- Set point theory: the body’s ability to restore to the physiological “setpoint” by changing intake, expenditure, and fat stores
32
Q
what are peptides/hormones involved with body weight
A
- Leptin: hormone produced by adipocytes leading to satiety
- Ghrelin: neuropeptide produced by stomach epithelial cells in response to shrinking of stomach → hunger
- MCH (melanin concentrating hormone): direct stimulation of appetite
- AgRP (Agouti related peptide): normally causes loss of appetite suppression
- NPY (neuropeptide Y): potent stimulus for hunger
- POMC gene: gives rise to MSH (melanocyte stimulating hormone) → appetite suppression
- Mutations of POMC gene → early childhood onset obesity (sx: AI)
- FTO gene: discovery of gene that is associated with adiposity (decides to store fat vs burning) independent of caloric intake → BMI is partially inherited
55
Q
DM type 1 vs 2
patho, characterisitics of each
A
65
Q
comapare DKA and HHS
A
70
Q
difference between insulins
- humulog/novolog
- novolin
- long acting
A
