Unit 4 week 2 Flashcards
1
Q
Presentation of adrenal insufficiency (BOTH primary and secondary adrenal insufficiency)
A
1) Hyponatremia
2) Hypotension
3) Hypovolemia
4) Tachycardia
5) Hypoglycemia
6) Eosinophilia
+ fatigue, weakness, postural dizziness, anorexia, nausea, vomiting, diarrhea, abdominal pain, weight loss, myalgias, arthralgias, headache
2
Q
Presentation of adrenal insufficiency ONLY present with primary AI
A
1) Hyperkalemia
2) Hyperpigmentation
3) Salt craving
3
Q
Adrenal Crisis
symptoms (6) and treatment
A
EMERGENCY
-nausea, vomiting, fever, syncope, hypotension, tachycardia
GIVE STRESS DOSE STEROIDS (Hydrocortisone 100 mg IV every 8 hrs)
4
Q
Tests for diagnosis of adrenal insufficiency (4)
A
1) Cortisol level (7-8am cortisol not > 16-18 → check ACTH with cortrosyn)
2) Cortrosyn (synthetic ACTH): stimulation test of adrenal reserve
- Baseline serum cortisol + IV injection of ACTH → serum cortisol at 30 and 60 minutes
3) Adrenal CT scan
4) Serum ACTH level
5
Q
Primary vs. Secondary Adrenal Insufficiency
A
Primary = adrenal gland is not producing cortisol
Secondary = any cause upstream of adrenals
- ACTH NOT being produced
- adrenals are normal and respond normally to AGII –> normal aldo levels
6
Q
Causes of Primary adrenal insufficiency
A
1) Addison’s Disease (autoimmune destruction)
2) Infectious - TB (most common cause in developing countries), Fungi, HIV
3) Amyloid infiltration of adrenals
4) Hemorrhagic, Metastatic, Surgical destruction of adrenals
7
Q
Presentation of Primary adrenal insufficiency (4)
A
1) Hyponatremia
2) Hyperkalemia
3) Hypotension
4) Hyperpigmentation
8
Q
Why do patients with primary AI have hyperkalemia? Why do they have hyperpigmentation?
A
Hyperkalemia due to lack cortisol AND ALDOSTERONE → hyponatremia, hyperkalemia
Hyperpigmentation due to Increased POMC (large ACTH precursor molecule)
–> increased ACTH and MSH (melanocyte stimulating hormone)
9
Q
Diagnosis of Primary AI
4 tests and their findings
A
1) *Serum cortisol < 5ug/dL at baseline
2) *Plasma ACTH > 100 pg/ml
3) *Serum cortisol < 20ug/dl after Cosyntropin (ACTH stim test)
4) Adrenal CT Scan:
Small glands → autoimmune, metabolic
Large glands → all other causes
10
Q
Treatment of primary adrenal insufficiency
A
glucocorticoids and mineralocorticoid replacement
- Hydrocortisone or prednisone (GC)
- Fludrocortisone (MC)
11
Q
Causes of secondary adrenal insufficiency (3)
A
1) Supraphysiological exogenous glucocorticoids for > 3 weeks
2) Opioids
3) Hypothalamic/pituitary lesions (tumor, surgery, radiation, infection, hemorrhage, infiltrative, metastatic)
12
Q
Presentation of secondary adrenal insufficiency
A
1) Hyponatremia
2) Hypotension, hypovolemia
3) NORMOkalemic (preserved aldo synthesis)
4) Low ACTH
5) No hyperpigmentation
13
Q
Diagnosis of secondary adrenal insufficiency (4)
tests + results
A
1) Serum cortisol < 5ug/dl baseline
2) Serum cortisol < 20ug/dl after Cosyntropin (chronic secondary AI - may have normal ACTH response if this is new onset of AI and adrenals haven’t atrophied)
3) Plasma ACTH low or normal
4) MRI pituitary may show pathology
14
Q
Treatment of secondary adrenal insufficiency
A
replace GCs only
No MC replacement required
15
Q
Adrenal medullary catecholamines synthesis
what is rate limiting step?
what step does cortisol effect?
A
Tyrosine → DOPA (via tyrosine hydroxylase = RATE LIMITING STEP)
DOPA → DA → NE
NE → epinephrine (via PNMT = UPREGULATED BY CORTISOL)
16
Q
Pheochromocytoma
A
Tumor of dark chromaffin cells → excess NE and epinephrine
17
Q
Paraganglioma
A
pheochromocytoma outside the adrenal medulla
18
Q
Genetics of pheochromocytoma
A
commonly associated with genetic abnormalities and familial syndromes
MEN (2A, 2B) - Ret gene mutation
VHL
NF-1
SDHB
SDHD
19
Q
SDHB vs. SDHD genes in pheochromocytoma
A
SDHB = gene that significantly increases risk for malignant pheochromocytoma
- Dopamine secreting tumor associated with malignancy
- B FOR BAD
SDHD = AD, paternal inheritance
D FOR DAD
20
Q
RET gene and pheochromocytoma
A
mutated in MEN2A, 2B
RET cell surface receptor somatic mutation → constitutive activation
Glial-derived neurotrophic growth factor (GDNF) binds RET → intracellular signaling stimulating cell synthesis of NE and EPI
21
Q
Constellation of findings in: MEN2A (3)
A
Pheochromocytoma
Medullary thyroid carcinoma (Calcitonin-secreting C cells)
Hyperparathyroidism
22
Q
Constellation of findings in: MEN2B (3)
A
Pheochromocycoma
Medullary thyroid carcinoma
Mucosal neuromas
23
Q
Constellation of findings in: VHL (6)
A
pheochromocytoma RCC renal/pancreatic cysts CNS hemangioblastomas islet cell tumors retinal angiomas
24
Q
Constellation of findings in: NF-1 (5)
A
pheochromocytoma hyperparathyroidism duodenal carcinoids medullary thyroid carcinoma optic nerve tumors
25
Clinical manifestations of pheochromocytoma
triad of symptoms + 3 other findings
TRIAD = headache, palpitations, diaphoresis
Hypertension (a1 vasoconstriction)
-Severely resistant to treatment
Increased HR, sweating and tremulousness (B1 receptors increase inotropic and chronotropic heart effects)
Vasodilation in muscle beds (B2 receptors)
26
Diagnosis of pheochromocytoma (3 tests)
1) 24 hour urinary collection
2) CT/MRI to localize tumor
3) I-123 MIBG scan: localization for extra-adrenal, recurrent, and metastatic tumors
27
24 hour urine collection in pheochromocytoma
- Catecholamines (Epi, NE) --> Not as reliable, needle stick can cause a rush of catecholamines
- Metabolites (metanephrines, normetanephrines, VMA) (can do serum also)
28
Medications that can interfere with 24 hr urine levels of catecholamines and metabolites (4)
Interfering medications: can falsely elevate catecholamines / metabolites
Acetaminophen
SSRIs, SNRIs
Marijuana and other illicit drugs
29
Treatment of pheochromocytoma
1) Surgical removal
2) Alpha-adrenergic blocker (phenoxybenzamine)
3) B-blocker (labetalol)
DO NOT start B-blocker before a-blocker
4) Ca2+ channel blocker
30
Licorice ingestion and hyperaldosteronism?
(pseudohypoaldosteronism): licorice prevents inactivation of cortisol in kidney
→ HTN and hypokalemia
31
Causes of secondary aldosteronism (2)
Cirrhosis
| Heart failure
32
Primary aldosteronism (Conn’s Syndrome)
Adrenal cortex (glomerulosa) primarily secretes too much aldosterone
- Low renin and angiotensin II (under normal feedback mechanisms)
- RAAS feedback loop is perturbed
Most common cause of secondary hypertension
33
Primary aldosteronism (Conn’s Syndrome)
Presentation (6)
1) Resistant hypertension
- HTN at a young age, HTN resistant to multiple anti HTN meds, stage 2 HTN (>160/100)
2) Hypokalemia - may be very severe or normal
3) Metabolic alkalosis
4) Muscle weakness
5) Mild hypernatremia
6) Presence of adrenal adenoma possible
34
Primary aldosteronism (Conn’s Syndrome)
Diagnosis (4)
1) Aldosterone:Renin Ratio: ratio > 20
- High plasma aldosterone, low plasma renin
2) IV saline suppression test
-IV saline should suppress aldosterone, but if they have primary aldosteronism → no aldo suppression
Aldo > 10 ng/dL confirms dx
3) CT or MRI to look for adenoma or hyperplasia
4) Adrenal Vein Sampling (AVS) for lateralization (look for difference in aldosterone levels between R and L adrenal vein)
35
Which medications should be stopped before getting plasma renin and aldosterone levels?
Must STOP interfering medications before testing (spironolactone, eplerenone)
36
Treatment of primary aldosteronism
Surgical cure
Bilateral adrenal hyperplasia or non-surgical candidate → treat with mineralocorticoid antagonist (spironolactone or eplerenone)
37
4 types of primary aldosteronism
1) Aldosterone producing adenoma (34%)
2) Idiopathic hyperaldosteronism (bilateral adrenal hyperplasia) (66%)
3) Glucocorticoid remediable hyperaldosteronism
4) Aldosterone-producing carcinoma
38
Glucocorticoid remediable hyperaldosteronism
mechanism?
genetic rearrangement fusing regulatory promoter of 11-B hydroxylase with structural component of aldosterone synthase → aldosterone synthase under positive control of ACTH
--> increased aldosterone synthesis in response to ACTH
39
3 main categories of Cushing's Syndrome
1) Iatrogenic (chronic administration of GCs - most common)
2) ACTH dependent
3) ACTH independent: high cortisol production, low ACTH, feedback mechanism still works
40
Causes of ACTH dependent Cushing's Syndrome
1) Pituitary adenoma (Cushing’s Disease)
| 2) Ectopic ACTH Syndrome (small cell lung cancer)
41
Pituitary adenoma (Cushing's Disease)
ACTH and cortisol levels
High ACTH, high cortisol
| Feedback mechanism does not turn off ACTH
42
Ectopic ACTH Syndrome
ACTH and cortisol levels
VERY high ACTH, VERY high cortisol
| Feedback mechanism does not turn off ACTH
43
Causes of ACTH independent Cushing's Syndrome
Adrenal Adenoma
Adrenal Carcinoma
Nodular Adrenal Hyperplasia
high cortisol production, low ACTH, feedback mechanism still works
44
3 steps for working up Cushing's syndrome
1) Establish patient has Cushing’s syndrome
```
2) Determine etiology of hypercortisolism
ACTH level (ACTH dependent vs. independent)
```
3) 3) Determine if ACTH is ectopic or from pituitary
45
Tests that can establish if a patient has Cushing's syndrome (3)
1) 24 hr urinary free cortisol
2) 1 mg dexamethasone suppression test (cortisol should be low after dexamethasone)
3) Midnight salivary cortisol elevated (cortisol should be LOWEST at midnight)
46
What test can distinguish between ACTH dependent vs. independent Cushing's Sydrome
ACTH level
47
How can you determine if ACTH production is ectopic or from pituitary? (3 tests)
1) CT, MRI, ultrasonography, isotope scanning
2) 8 mg dex suppression test
3) Inferior petrosal sinus sampling
48
8 mg dex suppression test - for what? tells you what?
determine if ACTH production is ectopic or from pituitary
Pituitary source: cortisol suppresses to < 5 ng/dL because still some sensitivity of pituitary corticotroph cells
Not very reliable
49
Inferior petrosal sinus sampling
measure baseline ACTH at intervals after stimulation with CRH
Pit source → ACTH should be higher in petrosal sinus than central IVC
Ectopic source → ACTH similar in sinus and central IVC
50
Adrenal incidentalomas
adrenal gland tumors are common, most clinically insignificant, majority are non-functioning
51
Initial evaluation of Adrenal incidentalomas must exclude:
1) Benign or Malignant? Radiographic appearance
| 2) Functional or nonfunctional?
52
Determining benign or malignant nature of adrenal incidentaloma
Malignant: size? shape? lipid density? signal intensity?
```
Benign:
< _______ size
_______ with ________ borders
HU is ______ on noncontrast CT
_______ lipid content
__________ occurs on out of phase imaging
```
Malignant: Large, irregular, lipid-poor lesion with higher signal intensity (high HU, > 10)
Benign:
-< 4 cm in size
-Homogenous with smooth/regular borders
-HU < 10 on non-contrast CT
-High intracellular lipid content, density closer to water and fat
-Signal dropout on out of phase imaging
Rapid enhancement of contrast, rapid loss of contrast (>50% washout)
MRI is as effective as CT scanning for distinguishing benign from malignant lesions
53
Adrenal incidentalomas
Functional or nonfunctional?
what tests should you order to determine this? (3)
1) Plasma metanephrines or 24 hr urine mets/cats
SCREEN FOR PHEOCHROMOCYTOMA
2) 1 mg overnight dex suppression test
SCREEN FOR HYPERCORTISOLISM
3) If patient is hypertensive, screen for primary aldosteronism with aldosterone/plasma renin level
54
Adrenocorticosteroids:
____________ effects can NOT be separated from anti-inflammatory effects and ___________ effects cannot be separated from immunosuppressive effects
Metabolic effects can NOT be separated from anti-inflammatory effects and anti-inflammatory effects can NOT be separated from immunosuppressive effects
55
Hydrocortisone
MC:GC Activity
Route of administration
Clinical Use
MC:GC Activity: 1:1
Route of administration: TOPICAL, oral, injectable
Clinical Use:
- Used in PHYSIOLOGIC replacement regimens
- Must be given several times daily
56
Prednisone
MC:GC Activity
Route of administration
Clinical Use
MC:GC Activity: 1:5
Route of administration: oral (NOT TOPICAL)
Clinical Use: most commonly used oral agent for steroid burst therapy
57
Dosing considerations with prednisone?
MUST be activated to prednisolone in liver**
Cannot be given topically
58
Dexamethasone
MC:GC Activity
Route of administration
Clinical Use
Adverse effects
MC:GC Activity: 0:30 → all GCC activity
Route of administration: oral, injectable, TOPICAL
Clinical Use: used for anti-inflammatory/immunosuppressive actions
- Most potent anti-inflammatory agent
- Used in cerebral edema, chemo-induced vomiting
- Big suppression of ACTH secretion from pituitary
Adverse effects: Significant metabolic side effects
59
Triamcinolone
potent systemic agent with excellent topical activity
NO MC action
60
Fludrocortisone
MC:GC Activity: 125-200:10 → Primarily MC activity without GC / anti-inflammatory activity
High doses can cause hypokalemia
61
Treatment of Addison's Disease
reat with physiologic replacement therapy (MC and GC replacement required)
Cortisol (GC replacement) + Fludrocortisone (MC replacement) + DHEA (sex steroid replacement for women)
62
3 main categories of drugs that can be used to treat Cushing's Syndrome
1) ACTH secretion inhibitors
2) Cortisol synthesis inhibitors
3) Cortisol Receptor Antagonist
63
ACTH secretion inhibitors (2)
Cabergoline (D2 agonist)
Pasireotide (SST analog)
64
Ketoconazole
Cortisol synthesis inhibitor
inhibits CYP450 androgen synthesis in testes and inhibits cholesterol → pregnenolone, reduces cortisol synthesis
Adverse effects: headache, N/V, gynecomastia, impotence, reversible hepatotoxicity
65
Mifepristone
Cortisol Receptor Antagonist
-anti-progestational drug that blocks GC receptors at higher doses
Not first line
Used to control hyperglycemia secondary to hypercortisolism
Contraindicated in pregnancy
66
Treatment of Primary aldosteronism
goal is to normalized hypokalemia and BP before surgical removal of tumor
Aldo antagonists: Spironolactone, eplerenone
BP meds: Ca2+ channel blockers, ACEI, ARB
67
Metyrosine
competitive inhibitor of catecholamine synthesis
used to treat pheochromocytoma that is non-surgical
68
Thyronine
backbone of THs with 3, 5, 3’, and 5’ positions that can be iodinated
69
Thyroxine (T4) vs. T3
Thyroxine (T4) = 3, 5, 3’, 5’ tetraiodothyronine
T3 = 3, 5, 3’ triiodothyronine
70
Iodide trap
Membrane pump on basal side of follicular cell promotes accumulation of iodide in thyroid 30-40x concentration in serum
71
4 steps of iodine uptake by thyroid gland
1) Na+/I- symporter + Na/K ATPase on basal side brings I- into cell
2) Iodide diffuses from basal (blood) → apical (lumen) side of follicular cell
3) Iodide oxidized (I- → I2) by thyroid peroxidase
4) Organification of I2 (incorporation of iodide into tyrosyl residues on thyroglobulin) occurs at follicular cell-colloid interface
72
Thyroperoxidase
membrane bound glycoprotein/enzyme in thyroid that catalyzed iodination of thyroglobulin, organification of I2, and coupling of DITs/MITs
73
Synthesis and Release of Thyroglobulin
Thyroglobulin synthesized in RER of follicular cell and transported to Golgi apparatus to be glycosylated and packaged into secretory vesicles
Secretory vesicles released from apical follicular cell into lumen (colloid)
Undergoes iodination and coupling reactions to synthesize TH at tyrosyl residues
74
Steps of Thyroid Hormone Synthesis
thyroperoxidase catalyzes iodination of tyrosyl moieties on TG → mono/di- iodotyrosine (MIT/DIT) formed on TG
Thyroperoxidase also catalyzes coupling of 2 DITs or 1 DIT and 1 MIT to form iodothyronines
75
Steps of thyroid hormone release
Drops of colloid endocytosed into follicular cells → coalesce with lysosomes → lysosomal enzymes act on TG to cleave T4 and T3 from TG
10-20x more T4 removed than T3
76
Thyroid Hormone Transport
Most thyroid hormone in a protein bound form
Some exist in free form (0.03% of T4, and 0.4% of T3)
77
thyroid hormone in a protein bound form
binds with what 3 proteins?
what is the effect of protein binding?
Thyroid binding proteins:
1) Thyroid binding globulin (TBG)
2) Thyroid binding pre-albumin (TBPA)
3) Albumin
Delay, buffer and prolong effects of TH action
78
half life of T4 vs. T3
T ½ for T4 is 7 days, and T3 is 1 day because TBG has a higher affinity for T4
79
Free thyroid hormone
Free form is active form
Must measure plasma TH values for bound or free form in addition to total TH in blood
80
How is T4 converted to T3?
T4 → T3 by 5’-deiodinase in the target cell
81
Cellular actions of thyroid hormone
- T3 has a higher affinity for TH receptor, so is more active than T4
- T3/T4 enter cell by ACTIVE TRANSPORT
T4 → T3 by 5’-deiodinase
T3 enters nucleus → interacts with nuclear receptors → T3-receptor complex acts on DNA to direct transcription of specific mRNAs
82
5 main actions of thyroid hormone
1) Metabolic rate
2) Fetal and neonatal brain development
3) TH and GH necessary for normal growth
4) Enhance response to catecholamines
5) Metabolic effects
83
How does thyroid hormone effect metabolic rate?
THs increase basal metabolic rate and increase oxygen consumption = Calorigenic effect
Mostly due to Na/K pump upregulation
84
Thyroid hormone and catecholamines
TH enhances response to catecholamines: TH mimics effects of SNS by increasing number of B-adrenergic receptors = permissive effect
85
Thyroid hormone and metabolic effects
low/moderate dose of TH vs. high dose of TH
Low/Moderate doses of TH → anabolic
-Promote conversion of glucose → glycogen
High doses of TH → catabolic
-Increased fuel consumption, protein breakdown, muscle wasting, glycogenolysis, and lipolysis
86
TSH and its actions on the thyroid gland
TSH → thyroid gland where it interacts with membrane receptor, stimulating thyroid hormone synthesis via increases in cAMP
TSH stimulates:
1) Iodide pump
2) Thyroperoxidase
3) Endocytosis of colloid
4) Iodide organification
5) Coupling of iodotyrosines
6) TG synthesis and its proteolysis following endocytosis
7) Follicular cell proliferation, elongation, and enlargement
87
3 drugs that block thyroperoxidase and conversion of T4 to T3 in target cells
Thioureas, propylthiouracil, methimazole
88
Signs/Symptoms of Hyperthyroidism (10)
```
BMR
Nervousness
Pretibial myxedema (Graves)
Heat intolerance
Muscle weakness
Goiter
Palpitations
Exophthalmos (Graves)
Lid retraction (Graves)
Tachycardia
```
89
In what cases would you have an elevated total T4/T3, but a normal free T4/T3?
Total T4/T3 can be elevated with increases in thyroid binding proteins (e.g. high estrogen states), but free T4/T3 will not be affected
90
4 causes of high uptake aka "TRUE" Hyperthyroidism
Graves Disease (autoimmune thyrotropin receptor antibody)
Toxic adenoma
Toxic multinodular goiter
Tumors of pituitary or thyroid
91
What is low uptake "hyperthyroidism"?
release of preformed T3/T4 into blood (NOT TRUE HYPERTHYROIDISM) → thyroid scan will be dark, no need for scan
92
Causes of low uptake "hyperthyroidism" (7)
1) Granulomatous thyroiditis (viral) = de Quervain’s → tender thyroid
2) Chronic lymphocytic thyroiditis (Hashimoto’s)
3) Postpartum thyroiditis
4) Radiation, infectious thyroiditis → tender thyroid
5) Drug-induced thyroiditis
6) Excess TH administration (Factitious)
7) Struma ovarii (ovarian tumor that produces thyroid hormones)
93
Grave’s Disease
symptoms?
antibodies against TSH receptor → stimulate excess T4/T3 production
Symptoms:
-Ophthalmopathy (thyroid eye disease) and pretibial Myxedema
94
Why does pretibial myxedema and ophthalmopathy occur in Grave's disease?
Occurs due to TSH receptor on fibroblasts → fibroblast overproduction of glycosaminoglycans (GAGs)
95
Tests that indicate Grave's disease
Homogenous uptake, “hot scan” on radioactive iodine scan
| Low TSH, high free T4 and T3
96
4 treatment options for Grave's Disease
1) Antithyroid drugs (methimazole, propylthiouracil) → inhibit TH synthesis
2) Beta blockers → reduce systemic hyperadrenergic symptoms
3) Radioactive Iodine
4) Surgery
97
Thyroiditis
Types: subacute/granulomatous thyroiditis, postpartum thyroiditis
High release of preformed/stored T3/T4 as thyroid cells are damaged → high free T3, T4 and suppress TSH
Once destruction as resolved, there is no ability to secrete thyroid hormone → high TSH, low thyroid hormone = hypothyroid
NOT true hyperthyroidism (no overproduction of TH)
98
Signs/Symptoms of Hypothyroidism (10)
```
BMR
Lethargy, weakness
Myxedema
Cold intolerance
Slow speech
Goiter
Hoarseness
Mental slowness
Psychosis
Bradycardia
```
99
Causes of Hypothyroidism (10)
1) Hashimoto’s Thyroiditis (chronic autoimmune)
2) Transient hypothyroidism
3) Iatrogenic: Thyroid surgery/thyroidectomy, Radioactive iodine, External neck irradiation
4) Iodine deficient diet or excess
5) Starvation, severe illness, severe stress, neonatal period (Euthyroid sick syndrome (nonthyroidal illness)
6) Liver or kidney disease (decreased serum protein binding)
7) Drugs (glucocorticoids, propranolol, amiodarone, radiocontrast dyes)
8) Infiltrative disease (TB, hemochromatosis, sarcoidosis, amyloidosis)
9) Cretinism
10) Pituitary tumor (central hypothyroidism)
100
why does Starvation, severe illness, severe stress, neonatal period cause hypothyroidism?
→ Inhibit conversion of T4 → T3 (active form) by blocking type 1 or type 2 deiodinase and activating type 3 deiodinase (converts T4 → rT3, inactive form)
101
Hashimoto’s Thyroiditis
Autoimmune destruction of thyroid gland
- most common cause of hypothyroidism in regions where iodine levels are adequate
- associated with HLA-DR5
Autoimmune destruction of follicular cells → initial dumping of thyroid hormone out of cells (hyperthyroidism) and progress to hypothyroidism
102
Cretinism
deficiency in neonates and infants
severe mental and growth retardation
short stature, skeletal abnormalities, coarse facial features, enlarged tongue, umbilical hernia
-can be caused by maternal hypothyroidism during early pregnancy, thyroid agenesis, dyshormonogenetic goiter, and iodine deficiency
103
__________ and __________ antibodies are often present in Hashimoto Thyroditis as a sign of thyroid damage
Antithyroglobulin
| Antithyroid peroxidase antibodies
104
Histological presentation of Hashimoto's thyroditis (2 main features
chronic inflammation with germinal centers and Hurthle cells (eosinophilic metaplasia of cells that line follicles)
105
Increased risk for _________ with Hashimotos thyroditis
B-cell (marginal zone) lymphoma
presents as an enlarging thyroid glans late in disease course
106
Subacute granulomatous (De Quervain) Thyroditis
Granulomatous thyroiditis that follows a viral infection
Presents as a tender thyroid** with transiet hyperthyroidism
Self-limited
*rare progression to hypothyroidism
107
Riedel fibrosing thyroiditis
chronic inflammation with extensive fibrosis of thyroid gland
- presents as hypothyroidism + "hard as wood", non-tender thyroid gland
- fibrosis may extend to involve local structures
- mimics anaplastic carcinoma
- classicaly seen in young female patient
108
Myxedema Coma
Complication of chronic, severe hypothyroidism (typically Hashimoto)
true endocrine emergency - decrease CO, bradycardia, respiratory depression, edema, AMS, hypothermia, metabolic derangements
High mortality rate
109
3 main tests used to evaluate thyroid dysfunction
1) Thyroid Stimulating Hormone
2) Free T4 (not free T3)
3) Radioactive iodine uptake and scan
110
TSH testing:
Primary hypothyroidism vs. primary hyperthyroidism
when is TSH level unreliable?
best test to screen for thyroid dysfunction
Primary hypothyroidism → elevated TSH, low thyroid hormone
--> Lack of negative feedback by thyroid hormone
Primary hyperthyroidism → low TSH
--> Excessive negative feedback by thyroid hormone
CANNOT rely on TSH when pituitary gland is abnormal
111
When should you check a T4?
Check T4 if TSH is low
112
Radioactive iodine uptake and scan
Normal/elevated iodine uptake in setting of low TSH → ?
Low iodine uptake in setting of low TSH → ?
Normal/elevated iodine uptake in setting of low TSH → autonomous production of thyroid hormone = true hyperthyroid state
Low iodine uptake in setting of low TSH → thyroid hormone excess due to high release of preformed thyroid hormone → destructive / inflammatory etiology (e.g. early Hashimoto's, thyroditis)
113
thyroid adenoma
Benign thyroid nodule
Typically solitary nodule
Must carefully evaluate capsule (with biopsy) - cannot be differentiated follicular adenoma from follicular carcinoma with FNA
114
Papillary Thyroid Carcinoma
- Most common type of thyroid carcinoma (80%)
- Associated with ionizing radiation in childhood
- Well-differentiated
- Lymphatic spread
- Excellent prognosis
115
Follicular Thyroid Carcinoma
- Malignant proliferation of follicles surrounded by fibrous capsule WITH INVASION THROUGH CAPSULE = hallmark
- -> can distinguish from follicular adenoma (via biopsy, NOT FNA)
-metastasizes HEMATOGENOUSLY
116
Anaplastic Thyroid Carcinoma
- Highly invasive undifferentiated malignant tumor of thyroid
- seen in elderly
- very aggressive, poor survival
- rapidly growing mass with necrosis and hemorrhage
117
Medullary Thyroid Carcinoma is a malignant proliferation of what cell type?
what will it stain with immunostain?
what can deposit in the tumor?
Malignant proliferation of parafollicular C cells (neuroendocrine cells that secrete calcitonin)
- can get amyloid deposition of calcitonin in tumor
- Immunostains: thyroglobulin -, calcitonin +, chromogranin +
**Associated with MEN2**
118
Papillary Thyroid Carcinoma
Histology - 3 main features
1) papillae lined by cells with clear "ORPHAN ANNIE EYE" nuclei
2) Nuclear grooves
3) Papillae often associated with psammoma bodies
119
Anatomic imaging modalities (3)
Detect or characterize palpable or incidentally found thyroid nodule on other modalities
1) Ultrasound
2) CT Neck
3) MRI
120
Ultrasound used for work up of thyroid disease how?
no radiation, real time, doppler capability
* Best modality to detect/characterize thyroid nodule
* Best modality to detect lymph node metastasis in post-op patient of thyroid cancer
Used for real time guidance for FNA
121
CT Neck used for work up of thyroid disease how?
Useful to define local extension of cancer in adjacent structures
Detect abnormal lymph nodes in areas not visualized by US
Distant metastasis
122
MRI used for work up of thyroid disease how?
Useful in identifying infiltrative disease particularly in post-therapy neck where anatomy is distorted
Detection of invasion of adjacent structures and deep nodal disease
NOT used to detect or characterize thyroid nodule
123
Iodine scanning can be used for what in working up thyroid dysfunction?
Functional imaging
Evaluate for function of thyroid gland or nodule in patient with abnormal thyroid function
Evaluate for distant metastatic disease
124
I-123 vs. I-131 iodine scans
I-123 scan: evaluate function of thyroid gland and thyroid nodule in patient with abnormal thyroid function (diagnostic only)
I-131 scan: diagnostic and therapeutic role
- Detect local/distant thyroid cancer metastasis
- Treatment of hyperthyroidism and well differentiated thyroid cancer
125
On a CT neck, the normal thyroid is _________ on noncontrast and _________ with IV contrast
Hyperdens on noncontrast
Hypervascular with IV contrast
126
Fetal thyroid gland arises from 2 distinct embryonic lineages
1) Follicular cells (endodermal pharynx) → produce thyroxine (thyroid hormone)
2) Parafollicular cells (neural crest) → produce calcitonin
127
After descent, thyroid follicular cells differentiate to express genes essential for ________________
thyroid hormone synthesis
128
Thyroid follicular cells trap iodide and secrete thyroid hormone by ________ wks.
Maternal ______ crosses the placenta for hormone synthesis
______ and ______ levels gradually increase to term
Trap iodide, secrete thyroid hormone, and TSH by 10-12 wks
Maternal iodine crosses placenta for hormone synthesis
TSH and T4 levels gradually increase to term
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Hypothalamus-Pituitary-Thyroid axis is functional with feedback control by __________ wks
25 weeks
130
Thyroid gland originates as proliferation of _________ cells on median surface of __________ between ____ and ____ arches
Initially hollow → becomes solid and bilobed
Thyroid gland originates as proliferation of endodermal epithelial cells on median surface of pharyngeal floor between 1st and 2nd arches
Initially hollow → becomes solid and bilobed
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Thyroid gland is connected to the ______ via the ________ as it descends. It completes this descent by the ______ week.
two problems that can arise due to thyroglossal duct problems?
Thyroid connected to TONGUE via THYROGLOSSAL DUCT as it descends
Completes descent in 7th gestational week
Can have arrested descent of thyroid or thyroid duct cyst
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What if fetus doesn’t make thyroid hormone? How can fetus still get some thyroid hormone?
Placenta allows small amount of maternal T4 and iodine across → maternal T4 converted to T3 by type II deiodinase in fetal brain
→ minimizes adverse effects of fetal hypothyroidism
133
Transcription Factors Important for Thyroid Development (3)
1) PAX8
2) TITF1
3) TITF2
134
PAX8
paired box gene 8 transcription factor
Mutation causes thyroid dysgenesis
AD pattern of inheritance
Phenotypes vary from mild to severe hypoplasia (compensated or overt hypothyroidism)
Can be associated with renal agenesis
135
TITF1
Mutation can cause thyroid dysgenesis
Also expressed in lung, forebrain, and pituitary gland
Heterozygous mutation → CH, respiratory distress, neuro disorders
136
TITF2
thyroid transcription factor 2
Mutation can cause thyroid dysgenesis
Homozygous mutation → Bamforth Lazarus Syndrome
137
Bamforth Lazarus Syndrome
Congenital Hyothyroidism, cleft palate, spiky hair, bifid epiglottis, choanal atresia
138
Congenital hypothyroidism
lack of thyroid hormones present from birth
If not detected/treated early, can cause irreversible neurological problems and poor growth
Associated with other congenital abnormalities
139
4 causes of Congenital hypothyroidism
1) Thyroid Dysgenesis
2) Thyroid dyshormonogenesis
3) TSH resistance
4) Transient forms
5) Central Hypothyroidism
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Thyroid Dysgenesis
- defect in what?
- causes ____% of congenital hypothyroidism
- due to _____, ______ or ______ (most common)
- female:male ratio?
-caused by defects in what transcription factors?
defect in thyroid gland development
85% of congenital hypothyroidism
Aplasia, hypoplasia, or **ectopy (most common - thyroid gland arrests in descent)
Female:Male 2:1
Caused by transcription factor defects (PAX8, TITF1, TITF2)
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Thyroid dyshormonogenesis
- defect in what?
- causes ____% of congenital hypothyroidism
- can be caused by a mutation in what genes?
defect in thyroid hormone synthesis
10-15% of congenital hypothyroidism
Can be caused by mutations in genes coding for proteins involved in thyroid hormone synthesis
Most common is thyroid peroxidase gene mutation
AR inheritance
Goiter may be present
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Pendred Syndrome
Type of thyroid dyshormonogenesis
AR mutation in SLC26A4 encoding pendrin protein that mediates iodide efflux from follicular cell to colloid
Goiter
Sensorineural congenital deafness (dilated semicircular canals on CT)
Thyroid phenotype mild and depends on nutritional iodine intake
Does not present in newborn period
143
TSH resistance
mutation in TSH-R transmembrane receptor on surface of follicular cells
Mediated effects of TSH
Critical for development and function of thyroid gland
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TSH resistance:
- heterozygous loss of function mutation --> ?
- Homozygous TSH-R mutations →
Heterozygous loss of function mutations → partial resistance with normal size gland and TSH elevation
Homozygous TSH-R mutations → congenital hypothyroidism with hypoplastic gland and decreased T4 synthesis
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Transient forms of congenital hypothyroidism (4)
1) Maternal TSH-R blocking abs
2) Maternal iodine deficiency or excess
3) Maternal radioiodine administration
4) Maternal medications (amiodarone, propylthiouracil, methimazole)
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Central Hypothyroidism
(Hypothalamic/Pituitary Deficiencies)
Usually in setting of multiple pituitary hormone deficiency especially growth hormone deficiency
Must evaluate other pit. hormones and obtain cranial MRI
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Treatment of congenital hypothyroidism
start treatment with levothyroxine AS EARLY AS POSSIBLE
148
Newborn screening for congenital hypothyroidism
Best to do after 2-3 days of age due to initial TSH surge after birth
1) Primary T4 screening (most common)
or
2) Primary TSH screening
Follow screening with confirmatory labs
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Primary T4 screening in newborn screen
If T4 in lowest 10% of results on a given day → measure TSH
- If TSH > 20 = abnormal → call PCP
- If TSH < 20 could still be abnormal, but will not call PCP
Total T4 = bound + free
Can get inaccurate results in presence of extreme variations in concentrations of thyroid-binding proteins
150
Normal TSH secretion in first week of life:
Within 30 minutes of birth, TSH rapidly peaks to 60-80 uU/ml, then decreases → peak in T4 and T3 levels by 24 hours
151
T3-Uptake screening:
T3 uptake and T4 in SAME direction → ?
T3 uptake and T4 in OPPOSITE direction →?
used to differentiate central hypothyroidism and thyroid binding globulin deficiency
T3 uptake and T4 in SAME direction → thyroid disease
-Low uptake and low T4 = hypothyroid
T3 uptake and T4 in OPPOSITE direction → TBG abnormality
-High uptake and lw T4 → TBG deficient
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Signs/Symptoms of Congenital Hypothyroidism (8)
**Baby appears normal at first - sx may not develop for weeks
Large posterior fontanel
Prolonged jaundice
Macroglossia
Umbilical hernia
Hypotonia
Feeding difficulties
Hoarse cry
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Thyroid hormone reversibly bound in plasma to thyroid-binding-globulin (TBG), and only unbound hormone has metabolic activity
what drugs can increase TBG binding? (3)
what drugs can decrease TBG binding? (5)
* Increase binding with: estrogens, SERMs, Tamoxifen
* Decreased binding with: salicylates, anti seizure meds (phenytoin, carbamazepine), androgens, glucocorticoids, furosemide
154
T4 must be activated to T3, biologically active thyroid hormone, done by _________ in _______
T4 must be activated to T3, biologically active thyroid hormone, done by 5’-deiodinase in liver
155
drugs that can decrease activity of 5-deiodinase (4)
glucocorticoids, B-blockers, propylthiouracil, amiodarone
156
Levothyroxine (T4)
drug of choice for thyroid hormone replacement therapy
Use: hypothyroidism, myxedema coma (end state of untreated hypothyroidism)
Narrow therapeutic index
Takes 6-8 weeks of maintenance dose to reach steady-state plasma levels
Oral or IV, generic and cheap
Use same levothyroxine product throughout treatment for any individual patient
157
Levothyroxine (T4)
Adverse reactions (1) + caution starting this med in what patients?
symptoms of hyperthyroidism
Use caution initiating therapy if underlying cardiac disease
158
Bioavailability of Levothyroxine can be modified by impaired absorption caused by what drugs? (3)
Metal ions (antacids, calcium and iron supplements)
Ciprofloxacin
bile acid sequestrants
159
Liothyronine
(T3):
Well absorbed, rapid action, shorter duration
Allows for quicker dosage adjustments
NOT recommended for routine replacement (plasma level fluctuates)
Higher potential for cardiovascular side effects during initiation of therapy
More expensive
160
Liotrix
(T3, T4 mixture):
| More expensive, no real advantage, not really used
161
Thyroid USP
porcine thyroid extract
Disadvantages: protein antigenicity, product instability, variable T4/T3 ratio may produce unexpected toxicity
Use in hypothyroidism NOT recommended
162
Thionamides
drug names?
Mechanism?
combine with what other med?
Methimazole, Propylthiouracil (PTU)
Mechanism: block iodine organification AND coupling of iodotyrosines → prevent T4/T3 synthesis
Pros: leaves gland intact
Combine with B-blocker (Propranolol blocks T4 → T3 conversion)
163
Methimazole
generally preferred over PTU
Efficacy at lower doses
Once-daily dosing
Fewer side effects
164
PTU preferred in __________
pregnancy
165
PTU and Methimazole
Side effects
Caution in pregnancy (can cross placenta) - PTU more protein bound so crosses less freely
Pruritic rash, GI intolerance, arthralgias
Agranulocytosis
Rare hepatotoxicity
166
Iodides (I-)
mechanism?
use?
disadvantages?
Mechanism: inhibit hormone synthesis and hormone release through inhibition of thyroglobulin proteolysis
Use: Rapid effects, used in thyrotoxicosis and thyroid storm
Disadvantages: variable effects, can worsen hyperthyroidism
167
Radioactive iodine (131I)
Mechanism?
Advantages?
Disadvantages?
Concentrated in thyroid → slow inflammatory process that destroys parenchyma of gland over weeks to months
Advantages: easy administration (oral), effective, inexpensive, no pain
Permanent resolution of hyperthyroidism
Disadvantages: slow onset of effects, radiation thyroiditis, may worsen ophthalmopathy, can cause hypothyroidism (80% require replacement therapy)
168
Treatment of Graves’ Disease:
1) ________ and _________ → modify tissue response, symptomatic improvement
2) ________ and _________ → interfere with hormone production
3) ________ and _________ → glandular destruction
1) B-blockers, corticosteroids → modify tissue response, symptomatic improvement
2) Thioamides, iodides → interfere with hormone production
3) Surgery, radioactive iodine → glandular destruction
169
Treatment of Myxedema Coma (end state of untreated hypothyroidism)
1) Large IV loading dose T4 + daily IV dosing
| 2) Hydrocortisone to prevent adrenal crisis as T4 increase may increase endogenous hydrocortisone metabolism
170
Treatment of thyroid storm:
4 meds and why?
Beta-Blockers: Propranolol → control CV symptoms
Sodium iodide IV + Potassium iodide → slow RELEASE of hormones
PTU → block hormone synthesis and T4 → T3 conversion
Hydrocortisone → block T4 to T3 conversion
171
Thyroidectomy
rarely used due to effective radioactive treatment
| Advantage: rapid, permanent cure of hyperthyroidism
172
Diabetes and mood:
depression
bipolar disorders
Depression: 2-3x general population, worsens control of blood sugar
Bipolar Disorders: increased risk of also having DM2
- Higher rate of obesity for pts with bipolar
- Treatments for bipolar disorder → metabolic effects, weight gain
- Sleep apnea worsens insulin resistance
173
Hypercortisolemia and psych symptoms (6)
Psych symptoms may predate physical:
```
Depressive symptoms
Anxiety
Hypomanic/manic symptoms
Psychosis
Memory problems and other cognitive symptoms
```
174
what can occur in both hypo and hypercalcemia?
PSYCHOSIS****
175
Hyperparathyroidism with hypercalcemia:
pscyh symptoms?
Common: irritability, low mood, apathy, lethargy
Severe: delirium, psychosis, catatonia, coma
176
Hypocalcemia
psych symptoms
Common: anxiety, paresthesias, irritability
Severe: psychosis, manic symptoms, tetany, seizures
177
Addison’s disease
and psych symptoms
primary adrenal insufficiency
Psych symptoms: apathy, anhedonia, fatigue, depression
178
Acromegaly and psych symptoms
increased growth hormone
Psychiatric symptoms: irritability, mood lability, depressive symptoms, personality changes
179
Thyroid problems and psych symptoms interact how?
Thyroid hormone interacts with NE, serotonin, dopamine
| Thyroid hormones appear to be capable of modulating phenotypic expression of illness
180
Hypothyroidism and psych symptoms
depression*, lethargy, forgetfulness (can be confused with dementia especially in older women), psychosis (later stages)
**Can have subclinical hypothyroidism unresponsive to antidepressants, and thyroid replacement may improve outcomes
181
Hyperthyroidism and psych symptoms
anxiety disorder, depressive disorder, mania when thyrotoxic
182
In Worrisome Growth you are worried about children having abnormal __________ or __________
height or growth velocity
183
What is considered worrisome growth for height?
short stature, height below 2 SD (3%) for age and gender OR height more than 3.5 inches below the midparental target height
184
What is considered worrisome growth for growth velocity
abnormally slow linear growth velocity or dropping across two major centile lines on the growth chart
185
Midparental target
97% of children fall within 3.5 inches of target
Boys → (Mom height + 5 inches + Dad height) / 2
Girls → (Dad height - 5 inches + Mom height) / 2
186
Skeletal maturation
direct correlation between degree of skeletal maturation and time of epiphyseal closure
Greater bone age delay = longer time before epiphyseal fusion ceases growth
Can be used to predict height by using child’s height and bone age BUT predictions NOT accurate in children with growth disorders
187
Normal variant of short stature (2)
1) Familial short stature
| 2) Constitutional growth delay
188
Familial short stature
children who have normal growth velocity and height that are within normal limits for parents’ heights
Initially will have decrease in growth rate between 6 and 18 months of age --> then track growth chart, but just lower than other people because their parents are short
189
Constitutional growth delay
aka "late bloomers"
born at normal weight/length with growth deceleration during first 2 years of life --> followed by normal growth paralleling lower percentile curve throughout prepubertal years
Should NOT be falling off after age 2-3 yrs
Skeletal maturation delayed**
Catch-up growth achieved by late puberty and delayed fusion of growth plates
Usually end up at lower end of normal height range for families
190
Treatment of Constitutional growth delay
Boys: testosterone if bone age > 11.5 yrs
Girls: estrogen
191
Failure to thrive
infants and toddlers < 2 years of age with:
Deceleration of weight gain < 3% or fall in weight across 2 or more major percentiles
-Typically primary weight issue with later height drop off
Non-organic causes most common (poor nutrition, psychosocial factors)
May look like constitutional growth delay
192
Nutritional growth retardation
linear growth stunting from poor weight gain in children > 2 yrs of age
May be secondary to systemic illnesses (celiac, IBD, CF), or stimulant medications
Hard to distinguish from constitutional growth delay/thinness
Weight typically falls off before height
193
Hypothyroidism and worrisome growth
profound growth failure, lacks common sx of hypothyroid seen in adults
Growth chart patterns: can have profound drop off on height + weight drop off
194
Cushing’s and worrisome growth
excessive weight gain, with falling off on height
195
small for gestational age
< 2SD for birth weight or length
Most healthy infants with SGH achieve catch-up in height by 2yr
Typically grow along a stable trajectory, but have height projection less than their genetic target
May have early or rapid puberty (compromises height)
**No delayed bone age - INTRINSIC short stature
196
Treatment for small for gestational age (SGA)
growth hormone treatment for kids who fail to have catch-up growth by age 2 years
197
Pathological causes of short stature
Nutritional (zinc, iron, anorexia, IBD, celiac disease, CF)
Endocrine:
1) Hypothyroid
2) Growth hormone deficiency
3) Cushing
4) Rickets
* *Two or more endocrine deficiency = BRAIN TUMOR until proven otherwise
Chromosomal:
1) Turner syndrome
2) Down syndrome
3) Prader-Willi Syndrome: GH deficient
4) Noonan syndrome
Others: skeletal dysplasias, metabolic, chronic diseases, psychosocial deprivation, drugs (stimulants, glucocorticoids)
198
Growth hormone deficiency
congenital and acquired causes
Congenital causes: Hypothalamic-pituitary malformations
1) Holoprosencephaly/Schizencephaly
2) Isolated cleft lip or palate
3) Septo-optic-dysplasia
4) Optic nerve hypoplasia
5) Empty sella syndrome
Acquired: trauma, CNS infection, hypophysitis, CNS tumors (craniopharyngioma, germinoma), cranial irradiation
199
Growth hormone deficiency
presentation
1) abnormal growth velocity with exclusion of other causes
2) Decreased muscle build
3) Increased subcutaneous fat (truncal)
4) Face immature for age
5) Prominent forehead, depressed midface
6) Small phallus (males)
7) Other midline facial defects
8) Prolonged jaundice +/- hypoglycemia in newborn period
200
Evaluation of growth hormone deficiency for worrisome growth (4)
1) Bone age
2) IGF-1
May be reduced due to malnutrition regardless of GH status
Can test IGFBP-3 instead - less affected by nutrition
3) Stimulation testing - clonidine, arginine, glucagon, L-dopa
4) MRI to evaluate for brain tumor, empty sella, etc. - high suspicion with other hormone deficiencies for tumor
201
Turner Syndrome (45X)
Haploinsufficiency of SHOX genes → Skeletal and growth abnormalities
Most common sex chromosome abnormality of females (1/2000)
No bone age delay (intrinsic short stature)
Will end up short, even with treatment with GH - no potential to reach height normal for their family
Not due to GH deficiency, due to SHOX gene deficiency
202
Presentation of turner syndrome
1) Short stature
2) Increased carrying angle
3) Short neck
4) Micro or retrognathia
5) Lymphatic obstruction (lymphedema)
6) Low hairline
7) Webbed neck
8) Cardiac abnormalities (bicuspid aortic valve, coarctation or aorta)
9) Renal - horseshoe kidney
10) Ovarian insufficiency
11) Hypothyroidism / celiac disease
Otitis media, hearing loss
12) Nonverbal learning disability
203
Short stature in Turner Syndrome
(final height 20 cm < target height if untreated)
Significant initial drop off on turner syndrome initially, and then have a secondary fall off around 5-6yrs, but if they have tall parents can be around 10-12yrs (can go unnoticed)
204
Treatment of growth in Turner Syndrome
growth hormone therapy (significantly improves growth and final adult height)
Start treatment as early as possible
205
8 tests you can do when evaluating worrisome growth
1) Bone age (left hand and wrist) → determine growth potential
2) Metabolic panel → rule out RTA, rickets
3) CBC → rule out anemia, chronic disease, skeletal dysplasia
4) TSH and T4
5) IGF-1 or IGFBP-3
6) Karyotype in girls → rule out Turner
7) TTG and IgA → rule out Celiac
8) ESR → rule out IBD
206
“FDA-approved” uses of growth hormone (9)
```
1985 - GH deficiency
1993 - chronic renal insufficiency
1996 - Adult growth hormone deficiency
1997 - Turner Syndrome
2000 - Prader-Willi Syndrome
2001 - small for gestational age (< 2 SDs)
2003 - idiopathic short stature
2006 - SHOX deficiency
2007 - Noonan syndrome
```
207
Side effects of GH treatment
slipped capital femoral epiphysis (hip or knee pain), intracranial hypertension (pseudotumor cerebri), insulin resistance
208
Determining a Good Clinical Practice Guideline:
8 steps/points of assessment
1) Transparency
2) Management of conflict of interests
3) Guideline group composition
4) Collaboration and coordination between systemic review and guideline development
5) Evidence foundation for recommendation
Judge certainty of net benefit based on evidence
6) Articulation of recommendation
7) External review
8) Update
209
____________ should be the first thing to look for when you are looking for how to treat a patient
Evidence based practice guideline
210
What is the best research evidence?
systematic reviews of RCTs
211
Systematic reviews
summary of best available evidence to address a focused question
212
Standard methods designed to reduce bias in systematic reviews
1) Focused question
2) Sources/search explicit, comprehensive
3) Selection is criterion based
4) Appraisal is critical
5) Synthesis is systematic
6) Inferences are evidence based
213
How do you critically appraise something?
3 questions to ask
Are results valid
Are valid results meaningful
Are the valid, meaningful results relevant to my patient
214
What kind of error can you have in a systematic review?
systematic error (bias) that causes results to be consistently distorted in one direction because of nonrandom factors
215
Two main types of bias in systematic reviews:
1) Publication bias
| 2) Location bias
216
Publication bias
tendency for published studies to differ systematically in their results from unpublished studies → significant studies more likely to be published
217
Location bias
tendency for high profile, widely disseminated studies to differ systematically in their results from low profile, less widely disseminated studies
Significant studies are easier to find
218
How to reduce publication and location bias? (4)
Avoid language restrictions
Search more than one electronic database
Search other types of documents
Check references of other studies
Contact experts or organizations
219
Meta-analysis is a ________ synthesis of data
Meta-analysis: QUANTITATIVE synthesis of data
220
Meta-analysis
STATISTICAL method for combining effect estimates of multiple studies to produce a single common estimate of effect
Improves precision by combining all available data
May or may NOT be part of a systematic review
Studies must have same outcome and be measured in similar ways
221
Disadvantages of meta-analysis
Does not control for bias
May inappropriately combine heterogeneous studies (adding apples to apples)
Problems in interpretation
222
Narrative review articles
structured summary and discussion of individual study characteristics and effect estimates
ALL relevant results should be presented
Use structured approach to presentation
223
How to deal with statistical heterogeneity: (4 strategies)
1) Do not pool at all
2) Ignore heterogeneity (use fixed effect model)
3) Allow for heterogeneity (use random effects model)
4) Explore heterogeneity through special statistical methods
