Endo/repro Flashcards
0
Q
How are Cortisol and Aldosterone measured?
A
Cortisol: urine free cortisol (reflects unbound, physically active level)
Aldosterone: 24 hr. urine aldosterone
1
Q
In terms of enzymes, how does the zona glomerulosa of the adrenal gland differ from the zona fasciculata and reticularis?
A
- Lacks 17a-Hydroxylase: can’t form cortisol and androgens
2. Has Aldosterone Synthase (CYP11b2): able to form mineralcorticoid - Aldosterone from corticosterone
2
Q
When are stimulation and suppression tests of the adrenal gland done?
A
Stimulation: when hormone deficiency suspected
Suppression: when hormone excess suspected
3
Q
When do cortisol levels reach high and low levels
A
Acording to circadian rhythm:
High: 6-7am
Low: 11pm
4
Q
What are normal daily levels of Cortisol, DHEA, and Aldosterone secretion?
A
Cortisol: 15-30 mg/day
DHEA: 15-30 mg/day
Aldosterone: 0.050-0.250 mg/ day
5
Q
When measuring urine levels of hormones, what other substance should be considered?
A
Creatinine - ensure kidney secretory function is normal
6
Q
What is a cosyntropin test and how is it performed? Results?
A
Cosyntropin: ACTH (1-24) given IV w/ cortisol and aldosterone levels checked before and at 30 and 60 minutes post-admin
Normal: cortisol elevation >18mcg/dL (min normal is 9 or more mcg/dL)
Primary adrenal insufficiency: no increase in cortisol or aldo
Long standing secondary: no increase in cortisol but increase in aldo
Recent onset secondary: usually normal result (no time for atrophy)
7
Q
What binds cortisol in the blood and to what extent?
A
Corticosteroid Binding Globulin (CBG / transcortin): 90%
Albumin: 7%
Free 3%
8
Q
What binds aldosterone in blood and to what extent?
A
Corticosteroid Binding Globulin (CBG): 17%
Albumin: 47%
9
Q
How are androgens (DHEA, DHEA-SO4, Testosterone) transported in blood?
A
DHEA, DHEA-SO4: Albumin
Testosterone: 95% bound to SHBG (TeBG)
10
Q
What is the difference between Cushing’s Syndrome and Cushing’s Disease?
A
Syndrome: excess cortisol action
Disease: ACTH producing pituitary tumor -> excess cortisol production
11
Q
What is the most common form of Cushing’s syndrome?
A
Exogenous
ex: Iatrogenic (prednisone)
- > negative feedback: decreased ACTH secretion
12
Q
Major symptoms of Cushing’s
A
Impaired glucose tolerance Central obesity Purpura, ecchymoses, striae Proximal muscle atrophy Hirsutism HTN
13
Q
How does ectopic ACTH syndrome typically manifest? What tumors is it associated with?
A
Hypokalemic Alkalosis w/ Diabetes Associated with: -Bronchogenic carcinoma (SCLC) -Carcinoid of Thymus, Pancreas, Ovary -Medullary carcinoma of thyroid -Bronchial adenoma
14
Q
What is ectopic ACTH syndrome?
A
Non pituitary tumor releasing ACTH or CRH -> hyperplasia of adrenal cortex
15
Q
What is Dexamethasone and how is it used in Cushing’s?
A
Dexamethasone: high potency glucocorticoid. used to test feedback regulation Give at night - low morning cortisol. If high - feedback regulation dysfunction Low dose (2mg/d x 2d) or High dose (8mg/d x 2d): ability to eventually suppress cortisol highly suggestive of pituitary dysfunction as cause
16
Q
Diagnostic Strategy for Cushing’s Syndrome
A
- Screening and confirm: 1) late cortisol level 2) Dexamethasone suppression test 3) 24 hr urine free cortisol 4) confirm non-suppression w/ low dose Dex test.
- Differentials: 1) ACTH level 2) high dose Dex test 3) CRH test 4) Metyrapone test (no longer used)
17
Q
What is the Metyrapone test?
A
Used in Cushing’s diagnsosis - no longer used clinically
Metyrapone inhibits 11B-hydroxylase (11-DOcortisol -> cortisol)
-> increased ACTH in Cushing’s Disease, no response otherwise
-> increased 11-DOcortisol in Cushing’s Disease (also 17-OHCS in urie)
18
Q
How does plasma ACTH help differentiate between causes of Cushing’s syndrome?
A
Plasma ACTH levels in:
Cushing’s Disease: normal to high
Ectopic ACTH: very high
Adrenal tumor: low
19
Q
2 main forms of adrenal insufficiency
A
- Primary (Addison’s Disease)
2. Secondary: pituitary failure
20
Q
What tests are available to verify adrenal insufficiency?
A
- Morning cortisol and ACTH (20mcg/dL is N, <5 abnormal, 5-20 req. ACTH stim test)
- Cosynotropin (ACTH) test: admin 250 mcg IV/IM, draw for cortisol at 0, 30, 60 mins. Peak of 20+ is N.
- Metyrapone overnight test
- Insulin tolerance test - Gold Std for HPA axis
21
Q
How does insulin tolerance testing work?
A
Make patient hypoglycemic via insulin admin
Insulin: 0.1 U/kg IV
Measure Blood glucose at 0 and 30 min (s highly suspected or CAD
22
Q
What is congenital Adrenal Hyperplasia?
A
AR impairment of Cortisol production due to enzymatic dysfunction
21 hydroxylase: >90%
11 B-hydroxylase: 5%
17 a-hydroxylase: 1%
23
Q
Symptoms of 21-Hydroxylase defect
A
Depends on severity of enzyme defect
Virilized female infant
w/ Na+ wasting (severe defect) -> hypotension
Precocious male puberty
Adult onset may -> female hirsutism at puberty
24
What symptoms are seen with 11B hydroxylase deficiency?
CYP11B1 (ZF): virilized females w/ hypokalemic HTN
| CYP11B2 (ZG): non-virilizing, salt-wasting: hyperkalemic hypotension
25
What are symptoms of 17a Hydroxylase deficiency?
HTN, hypokalemia, hypogonadism
Male: varying degree of ambiguous genitalia at birth
Male and Female: pubertal failure
26
What is the anatomic location of the pituitary gland?
Beneath 3rd ventricle, posterior to optic chiasm, anterior to mamillary bodies, w/ internal carotid aa. on either side
27
What are Herring Bodies?
Seen in Neurohypophysis: Dilated nerve endings containing secretory granules (terminating on blood vessels)
28
What are ways of classifying pituitary adenoma?
Size: Microadenoma (10mm)
Spread: Can also consider confined to sella or invasive
Hormone producing: Functional vs. non
Non-hormone producing: Null-cell
29
What are different manifestations of GH producing pituitary adenoma (age determined)?
Gigantism: if before epiphyses
Acromegaly: if after (overgrowth of soft tissues and organomegaly
30
What defines pituitary carcinoma?
Distant metastases
| Very rare
31
What is an atypical pituitary adenoma?
Increased proliferative activity
High rate of recurrence
May express p53 protein
32
What can cause pituitary inflammatory "Pseudotumors"?
autoimmune inflammation: hypophysitis
| sarcoidosis
33
What is Pituitary Apoplexy?
"Pituitary stroke"
| Infarction of adenoma or hyperplastic gland -> necrosis and/or hemorrhage and acute pituitary insufficiency
34
What is Primary vs. Secondary Empty Sella Syndrome and who is at risk?
Primary: increased CSF compresses pituitary -> insufficiency. sella appears empty in imaging
-Middle aged women w/ hypertension, obesity, and headache
Secondary: Pituitary adenoma infarcts, necrosis -> empty space
35
What is Craniopharyngioma?
Most common sellar tumor in children.
Benign neoplasm derived from Rathke's Pouch (squamous) epithelium.
Occurs in 2 peaks: 1st 2 decades of life, then again at 45-60.
May form cysts: filled w/ cholesterol rich brownish thick fluid.
36
What is the description of the microscopic appearance of Craniopharyngioma tissue?
Adamantinomatous epithelium
"wet keratin" appearance
37
What is a Chordoma?
Neoplasm derived from vestigial remnants of notochord.
Men > Women, usually >30y.
Parasellar or involving Clivus
Looks like cartilage w/ abundant myxoid stroma
38
What are primary, secondary and tertiary hypothyroidism?
Primary: issue w/ Thyroid itself. High circulating TSH
Secondary: issue w/ Pituitary -> low TSH
Tertiary: issue w/ hypothalamus -> low TRH reaching pituitary and resulting low TSH
39
2 syndromes of hypothyroidism
1. Cretinism: if hypothyroidism develops in utero or early in childhood
- mental retardation, short stature, protruding tongue (GAGs), coarse features
2. Myxedema: development in adulthood
- slow physical and mental activity, cold intolerance, constipation, coarsening of facial features, enlarged tongue, swelling of arms and legs.
40
Name 2 long acting insulins and duration of action
Glargine (24 hrs) peakless
Detemir (12-20 hrs) relatively peakless
used to maintain basal insulin levels
41
What infectious agents can produce acute vs. chronic infective thyroiditis?
Acute: bacterial
Chronic: mycobacteria or fungi
42
What is the most common form of adult hypothyroidism?
Hashimoto - autoimmune destruction of follicular cells
43
What is the HLA association with Hashimoto's Thyroiditis? Other genetic connections?
HLA-DR5
| Also assoc. w/ Turner and Down's syndromes
44
3 mechanisms of cell destruction in Hashimoto's Thyroiditis?
Sensitization of CD4+ helper cells ->
1) CD8+ and cytotoxic Tcell activation and induction of apoptosis (Fas/FasL)
2) cytokine injury (IFN-y -> mac activation)
3) anti-thyroid antibodies (anti-thyroglobulin, anti-thyroid peroxidase)
45
What are Hurthle cels?
Eosinophilic epithelial cels seen in Hashimoto's at site of thyroid follicle remnants
46
What diseases are Hashimoto's patients at risk of developing?
Other autoimmune diseases
| B-cell Non-Hodgkin's Lymphoma: MALT
47
What occurs in deQuervain Thyroiditis?
Subacute Granulomatous Thyroiditis
viral infection -> Ag induced cytotoxic cell injury to thyroid follicles -> foreign body reaction to colloid -> granuloma formation
*Self-limited, painful w/ initial transient hyperthyroidism*
48
What is Riedel Thyroiditis?
Least common thyroiditis - probably autoimmune -> marked fibrosis
thyroid hard and painless
49
What variant of thyroiditis is found in young women postpartum?
```
Subacute Lymphocytic (Painless) Thyroiditis
probably autoimmune
produces hypothyroid state
extensive lymphocytic infiltrate, patchy destruction
```
50
What is the underlying cause of goiter formation (diffuse or multinodular)?
Impaired thyroid hormone synthesis -> increased TSH -> hyperplasia and hypertrophy
Iodine deficiency, enzymatic defect, goitrogen ingestion (brussel's sprouts, cabbage, cauliflower, cassava)
51
What is Plummer syndrome?
Autonomous nodule in goiter -> hyperthyroidism
| Rare. most goiters are euthyroid.
52
What is the most common thyroid neoplasm?
Benign Adenoma
usually non-functional
Requires excision for evaluation
53
2 types of thyroid carcinoma
From follicular epithelial cells: papillary, follicular and anaplastic carcinomas
From C-cells: medullary carcinoma
54
What is the distinguishing feature of papillary carcinoma of the thyroid?
"Little Orphan Annie" eye nuclei - large, clear, ground-glass appearance
55
Major risk factor for papillary carcinoma of the thyroid
Previous exposure to ionizing radiation
56
How does follicular carcinoma of the thyroid tend to spread?
Hematogenously (vs. lymphatics seen in papillary)
57
Who is at risk of developing follicular thyroid carcinoma?
Usually seen in areas w/ endemic iodine deficiency
58
What is the survival rate for anaplastic thyroid carcinoma and who is at greatest risk?
Survival <1 yr.
| Older patients, usually w/ concurrent or previous well-differentiated thyroid carcinoma
59
What is the usual genetic association of Medullary Thyroid Carcinoma?
RET proto-oncogene (MEN-2A and 2B)
60
Wolff-Chaikoff vs. Jod-Basedow
Wolff Chaikoff: Increased iodine load -> decreased thyroid hormone excretion
Jod-Basedow: increased iodine load -> hyperthyroidism (usually in iodine deficient person w/ endemic goiter)
61
Effect of thyroid hormone on: Heart, vascular, skin, GI, skeletal, neuromuscular
Heart: increased rate and contractility (increase B1 response)
Vascular: vasodilation -> widened pulse pressure
Skin: warm, smooth, moist
GI: increased motility
Skeletal: increased bone turnover
Neuromuscular: hyperactivity, increased muscle contraction, muscle weakness
62
What is the T3 Resin Uptake test?
Labeled T3 is added to serum, then a T3 binding resin is added.
Assume normal TBG level
Hypothyroid: more labeled T3 binds TBG, low resin uptake
Hyperthyroid: less labeled T3 binds TBG, high resin uptake
63
What can result from prolonged untreated hypothyroid condition? Characteristics and treatment?
Myxedema coma
Decreased mental status, hypothermia, hypotension, bradycardia, high TSH
Treat w/ thyroid hormone
64
What are reproductive symptoms of hyperthyroidism?
Oligo or amenorrhea in women
65
What can occur in untreated hyperthyroidism? Symptoms? Treatments?
Thyroid Storm - life threatening
AMS, Fever, Palpatations, weight loss, diarrhea, heat intolerance, irregular heart beat
Iodine - reduce thyroid hormone
B-blocker - adrenergic effects
Cooling blanket
66
What is the most common non-thryoidal illness w/ thyroid related manifestation?
Decreased activity of Type I deiodinase enzyme (T4 -> T3) -> clinical hypothyroid state
Associated with other severe illness (lung disease in ICU)
67
2 drugs that inhibit thyroid hormone synthesis / release
Iodine
| Lithium
68
How does Amiodarone effect the thryoid?
Reduces conversion of T4 -> T3
Blocks T3 binding at nuclear receptor
Direct toxic effect at follicular cells -> destructive thyroiditis
69
4 synthetic thyroid hormone replacements
1. L-thyronin: T3
2. Liothyroxine: T3
3. Liotrix: T3+T4
4. Levothyroxine: T4: Drug of choice
70
What is the dose limiting effect of Levothyroxine?
CV effects
71
How should patients receiving Levothyroxine be monitored?
Steady state after 6-8 weeks of treatment, then check TSH level.
Once euthyroid monitor every 6-12 mos.
Note: older patients have decreased clearance, so decrease dosage w/ age.
72
What types of drugs can impact levothyroxine therapy?
1. Resin Binders (cholestyramine, colestipol)
2. Aluminum containing preps. (hydroxide, sucralfate)
3. Enzyme inducers (Pheyntoin, Phenobarbitol, Rifampin, Carbamazepine)
4. Drugs that increase TBG (estrogen, Raloxifene)
73
What is treatment for Myxedema Coma?
1) IV bolus thyroxine: 300-500mcg, then 75-100 daily IV or PO until stable
2) IV hydrocortisone: 100mg q8h (r/o adrenal suppression)
3) supportive therapy: Vent, maintain euglycemia, BP, Temp,
74
What are the thiourea drugs? Action?
Anti-thyroid drugs: Propylthiouracil, Methimazole
- Inhibit Thyroid Peroxidase
- Inhibit coupling of Iodotyrosines
- PTU: inhibits peripheral conversion of T4->T3
75
In what cases is Propylthiouracil preferred over Methimazole for treatment of hyperthyroid?
Thyroid storm
| Pregnancy - esp 1st trimester. both cat. D, but PTU has more documented teratogenicity
76
What medications are given along with I-131 in Radioactive Iodine Treatment?
Beta blocker - symptomatic relief - all patients
Thionamide - select patients w/ severe or long standing hyperthyroid, elderly, cardiac disease, withdraw 4-6 days before iodine therapy
77
What are features and treatment of Thyroid Storm?
Thyroid storm: untreated hypertension, fever >103 F (39.4 C), tachycardia, tachypnea, N/V/D, dehydration, delerium, coma
May last 72 hours or up to 8 days w/ inadequate treatment
Treatment: Support vital functions, thionamide/iodide, B-Blocker, correct underlying factors, remove circulating hormones if severe (plasmapheresis / dialysis)
78
Hyperparathyroidism mnemonic
Bones, stones, abdominal groans, psychic moans
mostly due to Ca++
Bones: decreased Ca -> fragility and fractures
Stones: increased circulating Ca -> stones
Abd: hypercalcemia -> constipation
Psy: hypercalcemia -> psych manifestations
79
Genes assosicated with sporadic and familial hyperparathyroidism
Sporadic: PRAD-1 -> increased cyclin D1
inactivation of MEN1
Familial: inactivation of MEN1
RET mutation -> TK activation -> MEN2 syndrome
CASR: Ca++ sensing receptor mutation
80
What is ostitis fobrosis cystica?
End-stage bone disease associated with hyperparathyroidism
| Cystic bone spaces filled with brown fibrous tissue (hemorrhage -> hemosiderin filled macrophages)
81
With what condition is secondary hyperparathyroidism usually associated?
Chronic Renal Failure -> low vit D -> persistently low serum Ca++ -> longstanding stimulation of parathyroids
82
What is the major hormonal contributor to osteoporosis?
decreased estrogen (menopause) -> increased osteoblast activity w/ insufficient osteoblast response
83
3 sites of action of Vitamin D and respective action
Bone: Low Ca++: stimulates Ca and PO4 mobilizatoin
Normal Ca and PO4: mineralization of osteoid and epiphyseal
cartilage
Intestine: Increases abs. of Ca++ (upreg. of Ca binding prot. D-28K)
Kidney: Stimulates PTH dependent Ca++ reabs.
84
Stages of Paget's disease
1) Osteolytic: excessive bone resorption, numerous abnormally large osteoclasts
2) Mixed osteoclast / osteoblast: new bone deposition, marrow replaced by fibrous and granulation tissue
3) Sclerotic stage: Disorganized, excessive bone formation
85
Complications of Paget's disease
1) pain / fractures / osteoarthritis
2) skeletal deformity
3) high output HF due to increased vascularity of affected bone
4) sarcomas, esp. osteosarcoma
86
What cellular change is seen in the pituitary with Cushing's Syndrome?
Crooke's Hyaline change: ACTH producing cells damaged by elevated cortisol levels -> increased cytoplasmic keratin filaments
87
What is Conn syndrome?
Aldosterone producing adrenal cortical adenoma
88
What happens to renin levels in hyperaldosteronism?
Decreased renin due to neg. feedback on RAAS
89
What is Waterhouse-Friderichsen syndrome?
N. meningitidis associated hemorrhage of adrenal glands
| Bacteremia -> hypotension and shock -> DIC -> massive hemorrhage of adrenals
90
What is the most common cause of Addison's disease?
Autoimmune destruction of adrenals
- Autoimmune polyendocrine syndrome type I (APS1): ARIE gene mutation, chronic mucocutaneous candidiasis, ectodermal dystrophy
- APS2
91
What infections are associated w/ Addison's?
TB, Histoplasma capsulatum, CMV, mycobacterium avium intracellulare
92
Symptoms of Addison's
Weakness, fatigue, hyperpigmentation (MSH), N/V
Hypotension: hyponatremic, hyperkalemic
Hypoglycemia
93
What is pheochromocytoma?
Tumor of adrenal medulla - chromaffin cells
| Produces catecholamines
94
What is found in a 24 hr. urine collection or serum sampling of a patient w/ pheochromocytoma?
Increased catecholamines and metabolites such as metanepherine and vanillymandelic acid
95
What is neuroblastoma?
Childhood malignancy of neural crest origin
| cells are neuroblasts- intermediate stage of differentiation of sympathetic ganglion cells
96
What are genetic indicators of prognosis in neuroblastoma?
```
N-myc amplification: poor prognosis
1p deletion: poor prognosis
11q deletion: poor prognosis
17q gain: poor prognosis
hyperdiploidy: favorable!
```
97
What is a stage IV-S nuroblastoma?
Grade II or III tumor w/ metastasis restricted to liver, skin, and bone marrow
Favorable prognosis - often spontaneous regression of tumor
98
What is found in urine of patients w/ neuroblastoma?
Increased catecholamines and metabolites: vanillymandelic acid, homovanillic acid
99
what is the effect of lithium on PTH?
Lithium antagonizes the CaSR of the parathyroid -> increased hormone productoin.
100
What factors activate and inhibit 1a hydroxylase?
Activators: low serum phosphate, PTH
Inhibitors: Ca++ and FGF23
101
What percent of Ca++ is free in the blood vs. bound? What is the effect of pH on this?
Usually 50% bound w/ 80% of that to albumin and 20% to globulin
Lowered pH -> decreases binding
102
What is corrected Ca++?
corrected Ca++ = serum [Ca] + ((4.0- [albumin]) *0.8)
103
Normal level of vitamin D 25OHD
30-70 ng/mL
104
What is the most common presentation of hypercalcemia? Other symptoms?
Asymptomatic
| Other symptoms: weakness, fatigue, aches and pains, depression, thirst + polyuria, constipation
105
How could one have hypercalcemia with Low PTH?
1. Excessive release of Ca++ from bone due to
- PTHrP (lung / kidney ca)
- Metastatic destruction (breast ca., leukemia, lymphoma, mm)
- high bone turnover: hyperthyroid, immobilization, vit A tox
2. Excessive absorption of Ca++ from gut
- Vit D intox, sarcoidosis / granulomatous (1a-hydroxylase)
- Excessive Ca++ intake (milk alkalai syndrome)
106
Treatments for primary hyperparathyroidism
1. surgical removal of adenoma
2. hydration
3. bisphosphonates: reduce osteoclast activity
4. cinacalcet: calcimimetic: activates CaSR -> decreased PTH
107
What is the effect of hypocalcemia on the nervous system?
Excites
108
What are Chvostek and Trousseau's signs associated w/?
Indicators of Hypocalcemia
Chvostek: tap cheek - flinch toward same side (non-specific)
Troussear: inflate cuff above SBP -> PAINFUL spasm of hand
109
Most common cause of hypoparathyroidism
Autoimmune destruction
110
What are some genetic causes of hypoparathyroidism?
activating mutation of CaSR
| DiGeorge (failure of descent of 3rd and 4th pharyngeal pouch)
111
What occurs in pseudohypoparathyroidism?
Autosomal Dominant Gs-alpha mutation
1) from mother: PTH resistance + AHO phenotype
2) from father: AHO phenotype only
Tissue resistance to PTH -> elevated PTH w/ symptoms of hypo-PTH
Low Ca++, high PO4
112
What is Albrights Hereditary Osteodystrophy?
Associated with pseudohypoparathyroidism
| Results in short stature, mild mtard, short 4th and 5th metacarpals,
113
What is the effect of a PHEX gene mutation?
PHEX codes for FGF23 degradation enzyme -> excess FGF 23
| FGF23: inhibits 1a-hydroxylase -> low levels of active vitamin D -> decreased phosphate absorption and osteomalacia
114
What do Z and T scores of a DEXA scan refer to?
DEXA: bone density scan
Z-score: compares patient result to mean and STD of same sex and age control group
T-score: compared patient result to mean and STD of young adult control group of same sex
115
How is T-score on DEXA used?
DEXA: bone density scan
| T-score: -1.0: normal
116
3 types of primary osteoporosis
1) idiopathic in children and young adults
2) post menopausal: low E -> increased osteoclast act. + decreased osteoblast act.
3) senile: decreased ability of osteoblast to divide and produce osteoid
117
Drugs useful in treating osteoporosis
1) bisphosphonate : inhibit reabsorption
2) teriparatide / fluoride: stimulates bone deposition
3) strontium ranelate: inhibit reab / stim dep.
118
2 genetic conditions of Rickets
1) X-linked hypophosphatemic rickets: PHEX inactivating mutation -> increased FGF 23
2) AD hypophosphatemic rickets: FGF23 mutation -> resistant to inactivation
119
Osteogenesis Imperfecta treatment
bisphosphonate
120
What are the most common forms of endocrine HTN?
1) renal artery stenosis
2) Primary aldosteronism
3) pheochromocytoma
121
2 primary causes of Renal Vascular HTN
1) atherosclerosis (2/3)
2) fibromuscular dysplasia (1/3: young females)
* *hormonal influence implicated: affects women of childbearing age**
122
When are screening tests for Renal Artery Hypertension appropriate?
When corrective procedures are an option for treatment
123
What is the preferred treatment for Renal Vascular HTN due to atherosclerotic disease?
Medical management: ACEi / ARB, + thiazide if needed
124
Is percutaneous angioplasty more effective in treating Renal Vascular HTN due to atherosclerosis or FMD?
FMD.
| Atherosclerosis is more progressive and diffuse - low cure rate w/ stenting.
125
Indication for surgical treatment of Renal Vascular HTN?
1. Recent onset of HTN
2. Young pt.
3. HTN <5yrs
4. Inability to tolerate / non-compliant w/ meds
5. Recurrent flash pulmonary edema or refractory HF
126
What is the recommended screening test for primary aldosteronism?
Plasma Aldosterone / Plasma Renin Activity (100% sensitive, 60% spec)
>20 is positive test
Follow w/ suppression test (high Na+ test)
127
How is an aldosterone suppression test performed?
Salt tabs or high salt diet for 3 days followed by 24 hr. urine catch.
Adequate salt loading: >200mEq / L
Urine aldosterone >12 mcg / 24 hrs is positive.
Follow w/ imaging and renal vein sampling if needed to determine laterality of lesion
128
What are common locations for extra-adrenal pheochromocytomas to arise?
Tissues derived from neural crest: carotid body, aortic chemoreceptors, sympathetic ganglia
129
HTN + sweating, headache, palpitations suggests what?
Pheochromocytoma
| sensitivity 90% +
130
How and under what circumstances are plasma catecholamines drawn?
Patient supine w/ indwelling catheter for 30 mins in a quiet environment to prevent catecholamine spike.
131
What is the incidence of germ line mutations in pheochromocytoma? What gene is usually involved?
20% of cases, AD inheritence
Mitochondria Succinate Dehydrogenase
High recurrence rate (15%) - long term follow up
132
What substances inhibit insulin secretion?
Serotonin, PGE, a-agonists, thiazides, phenytoin, diazoxide
133
How is an oral glucose tolerance test performed?
Oral solution of 75g glucose
Serum glucose measured every 30 mins for 2 hrs.
No value should exceed 200 mg/dL
Value should be <140 at 2 hrs.
134
What are diagnostic criteria for diabetes?
```
Ant of these:
Random glucose >200 mg/dL + signs / symptoms
Fasting glucose >126 on 2 occasions
HbA1c >6.5%
OGTC results >200 at 2 hrs.
```
135
What are criteria for Impaired Glucose Tolerance?
HbA1c: 5.7-6.4%
Fasting glucose: 100-125
OGTT @2hrs of 140-200
136
Criteria for Gestational Diabetes Diagnosis
```
Made by OGTT after overnight fast of at least 8hrs.
Any of the following:
Fasting: >92
1hr: >180
2hr: >153
```
137
What % of Bcells must be destroyed in T1DM for symptoms to manifest?
90%
138
3 antibodies found in T1DM
Anti-islet cell
Anti-insulin
Anti-glutamic acid decarboxylase
139
Genetic links in Maturity Onset Diabetes of the Young?
AD with mutations in glucokinase and mitochondrial genes
140
What is the correlation between adiponectin and insulin sensitivity?
Only adipocytokine w/ positive correlation
141
Cholymicron apoproteins
Apo-E
| Apo-48
142
What apoproteins are on VLDL
Apo-B100
| Apo E
143
What is the underlying defect found in Familial hypercholesterolemia? What are the levels in Hetero and Homozygous forms?
LDL Receptor defect
Autosomal Dominant condition - complete penetrance
Hetero: TC and LDL: 250-600 mg/dL
Homo: TC and LDL: 500-1000 mg/dL w/ early CAD / death
144
What is the underlying defect in Type III hyperlipoproteinemia?
apo-E mutation (AR)-> VLDL, IDL, LDL remnants accumulate - can't bind to LDL receptor effectively
TG and TC elevation: 300-400 mg/dL
145
What is are the symptoms of LDL deficiency?
```
cholymicron accumulations and very high TG (AR)
early onset (homozygous)
Turbid serum
Eruptive xanthomas
Recurrent pancreatitis
Lipidemia retinalis
Hepatomegaly, splenomegaly
```
146
When does the process of breast tissue involution begin?
Before menopause, age 35-40
Progressive TDLU atrophy and replacement w/ fatty stroma
Failure to involute -> increased risk of br. carcinoma
147
What is the most common breast disorder?
Fibrocystic change
| >50% of all surgical procedures
148
Presentation of Intraductal Papilloma
serous or bloody nipple discharge
sub-areolar tumor
Typically pts. are >60 yrs
149
Does In Situ Carcinoma of the breast usually present as a palpable mass?
In 50-75% of cases NO.
| Detected as microcalcifications on mammogram
150
What is Paget's disease of the nipple? Incidence of underlying cancers?
Erosion / inflammation of the nipple/areola due to extension of neoplastic cells to the epidermis.
50% have underlying intraductal tumor (CIS)
50% have underlying invasive carcinoma
151
What is the most common breast cancer?
Invasive Ductal Carcinoma
| cells arranged in nests, cords, tubules, w/ fibrous stroma
152
What is the appearance of invasive lobular carcinoma?
Cells invade stroma individually - seen aligned in single file chains
No desmoplastic stroma
more common spread to CSF and elsewhere
153
What is phyllodes tumor?
```
Low-grade Malignancy that develops w/in a fibroadenoma
Arises from breast stroma
Pts. usually >60
leaf-like projections into cystic space
highly cellular stroma
```
154
What is the incidence of cancer development in women w/ BRCA-1 mutation?
85% chance in carriers
pre-menopausal breast / ovarian cancer
Triple negative cancers: Estrogen, Progesterone, HER-2 receptor negative
155
In what case is breast cancer chemoprevention appropriate? Agents?
```
Gail index >1.66% risk for 5 yrs
Tamoxifen (ER antagonist)
Raloxifene (SERM) if postmenopausal
- (+) estrogen in bone
- (-) estrogen in breast / uterus
```
156
What is close surveillance for patients at high risk for breast cancer?
Mammograms begin 10yrs before onset of youngest affected family member
MRI if 20-25% lifetime risk
Monthly self-exams in late teens
Clinical breast exams q6 mos starting @20 yoa
157
What does HER-2/neu code for? Specific drug?
EGFR-2, which dimerizes -> TK activity
158
5 subtypes of epithelial breast cancer and relative survial
```
Luminal A and B: ER (+)
Basal: ER (-)
ERBB2: HER2/neu, EGFR2 (+)
Normal Tissue: expresses adipose and non-epithelial genes
Survival: A>B >> Basal and ERBB2
```
159
What are the BIRADS categories of breast imaging results?
5: Highly suspicious (95% likely malignancy)
4: Suspicious (3-94% likely malignancy)
3: Probably benign (2% likelihood of malignancy)
2: Benign
1: Negative
0: Needs more workup
6: Known malignancy
160
In what cases is "neo-endocrine" adjuvant therapy appropriate?
```
ER (+) cancer in postmenopausal patients
Agent: Anastrozole (Amiridex)
Aromatase inhibitor
Plateau in 6-9mos
Continue up to 5 yrs. post-op
```
161
What are indications for Partial vs. Complete Mastectomy?
Partial: Tumor excision w/ clean margins and 30%, active conn. tiss. disease (SLE, systemic sclerosis) (may/ may not req. rad)
162
Is there an increased risk of cancer associated with Lichen Sclerosis?
Yes. 1-4% increase in lifetime risk for Sq. Cell Carcinoma
| Lesion itself is not pre-cancerous
163
Characteristics of Lichen Sclerosis
Flattening of Rete Pegs
Acanthosis
Hydropic degeneration of basal layer
Dermal fibrosis and perivascular lymphocytic infiltrate
164
How is vulvar intraepithelial neoplasia (VIN/CIN) graded?
VIN I: Mild dysplasia, involves lower 1/3 of epidermis (LSIL)
VIN II: Moderate dysplasia: involves lower 2/3 of epidermis (HSIL)
VIN III: Severe: full thickness (HSIL)
165
What % of vulvar squamous cell carcinomas are associated with lichen sclerosis?
15%
| p53 mutation in these
166
What is the gross and microscopic appearance of Paget's disease of Vulvar (extramammary) Paget's Disease?
Gross: Erythmatous, crusted, limited to epidermis and adnexa
Microscopic: Paget's cells (large mucinous cells w/ prominent nuclei + nucleoli, clear cytoplasm). Blue staining w/ PAS, Alcian blue, Mucicarmine
Note: no underlying tumor
167
How is Melanoma In Situ differentiated from Extramammary Paget's?
MIS: S-100 (+), Mucin stain (-)
168
What is condyloma acuminatum associated with (infection)?
HPV 1 and 6 (low-risk viruses)
| Benign lesions
169
Histologic tropisms for HPV viruses
HPV-6: always squamous lesion
HPV-16: squamous or glandular
HPV-18: most common in glandular lesions
170
Causes of chronic endometritis
Gonorrhea
Miliary TB
IUD
Spontaneous
171
What is the most common cause of dysfunctional uterine bleeding?
Anovulatory cycle
| Ovulatory failure and no progestational effect -> unopposed estrogen effect
172
What drug has been connected to incidence of endometrial polyps?
Tamoxifen - has weak estrogenic effects on endometrium
173
Most common invasive tumor of female genital tract
Endometrial carcinoma
174
Type I vs II Endometrial carcinoma
Type I: younger women, estrogen related, peri-menopausal, low grade, good prog, PTEN and micro-satellite instability
Type II: older women, no estrogen link, post-menopausal, high grade, poor prog, aggressive, p53 mutation
175
What are the grades of Type I endometrial cancer?
FIGO grades
| I: well differentiated, glandular architecture, 50% solid w/ increased atypia
176
What is carcinosarcoma of the endometrium?
Composed of a mix of malignant glands and malignant stroma
Sarcoma component may mimic other tissues: cartilage, bone, etc.
Not two tumors, but one tumor showing two differentiations
177
Most common uterine tumor?
Leiomyoma
| benign smooth muscle tumor
178
3 examples of abnormal placentation
1. Placenta accreta: attacment to and invasion of myometrium
3 types: accreta, increta, percreta
2. Placenta Previa: abnormal location of attachment - near cervix
3. Abruptio Placentae: premature separation of placenta from uterus
-> bleeding and possible fetal death.
179
Causes of complete and partial hyatidiform mole
Complete: fertilization of egg that lost chromosomes -> angrogenesis (doubling of paternal chromosomes) -> normal karyogype, usually 46XX. No fetal tissues found.
Partial: fertilization of egg w/ 2 sperm -> triploid / tetraploid karyotype. Fetal tissue present.
180
Risks w/ estrogen meds
```
Endometrial cancer
Breast cancer: uncertain - long term use
Cardiovascular outcomes (DVT (50%), stroke / TIA, primary CHD event)
```
181
What is the oral effectiveness of natural estrogens?
Poor - rapid, extensive 1st pass metabolism
| Estrogen derivatives: C17 modification: improved bioavailability
182
3 Progestin medications
Progesterone
Norethindrone
Medroxyprogesterone
183
What are the effects of Progesterone?
Development of secretory endometrium
Maintenance of pregnancy
Suppress menstruation and uterine contractions
184
When can hormone replacement be used to treat osteoporosis?
When also treating menopausal symptoms
185
What is POCD treatment?
Treat symptoms, modify according to patient goals
- Lifestyle modification: aerobic exercise, controlled eating, orlistat, tobacco avoidance
- Eflornithine cream: inhibit ornithing decarboxylase -> reduce hair growth
- Oral Contraceptives (reduce LH)
- Spironolactone (anti-androgen)
186
What drugs can be used to induce ovulation in patients with PCOS?
Metformin: +/- clompiphene. Incosistent result
Thiazolidinediones (reduce insulin levels)
Clomiphene: Increase FSH / LH (80% ovulate, 50% conceive)
Gonadotropin therapy
187
When is Clomiphene administered for fertility treatment?
5 day course on days 3-7 or 5-9 of follicular phase
| early admin increases likelihood of multiple follicle recruitment for maturation
188
When does ovulation occur following gonadotropin administration? what is it?
24-36 hours
Gonadotropin is injectable FSH or FSH + LH
admin daily throughout follicular phase, then hCG -> ovulation 34-36 hours later
189
What is balanoposthitis?
Penile inflammatory condition
Infection of glans and prepuce due to poor hygiene + smegma
Candida, anaerobes, gardnerella, pyogenic bacteria
190
Chancroid agent
Hemophilus ducreyi
| Painful chancre - rare in US
191
Granuloma inguinale agent
Klebsiella granulomatis
192
Virus most assoc. w/ penile carcinoma in situ
HPV 16
193
What are Bowen disease and Bowenoid papulosis?
Both penile carcinoma in situ usually associated w/ HPV 16
Microscopically indistinguishable, but morphologically distinct.
Bowen: over 35yoa, gray-white opaque plaque. 10% progress to infiltrating squamous carcinoma
Bowenoid: <35 yoa. papules. Never progresses to cancer
194
What are the major causes if epididymitis and orchitis by age?
Peds: gram (-) rods, assoc w/ genitourinary malformation
<35: chlamydia, neisseria
Older: E.coli, Pseudomonas
195
What can result from ascendin gonorrheal infection of the male GU tract?
Abscesses of epididymis and extensive damage / destruction
196
Where are Leydig cells found?
Testicular interstitium - between seminiferous tubules
197
Cells of seminiferous tubule and roles
Spermatogenic cells - mature to spermatocytes
| Sertoli cells- maintain maturing spermatozoa, secrete Mullerian Inhibiting Factor (MIF)
198
What are risk factors for male germ cell tumors? Common genetic marker?
```
Cryptorchidism - 10% of cases. Higher risk w/ higher level of undescended testicle
Genetic - family hx
Testicular dysgenesis (Kleinfelter's)
```
i(12p) found in 90% of cases
199
Most common male germ cell tumor and marker
Seminoma
| Shows elevated placental alkaline phosphatase
200
What is spermatocytic seminoma?
Develops in older patients (>65 yoa)
Slow growing, does not metastasize, excellent prognosis
No lymphocytic infiltrate
3 cells: medium (most numerous), small, scattered giant cells
201
What is Embryonal carcinoma?
```
Form of testicular cancer
Rare
20-30 yr age range
epithelial cells, primitive papillary architecture, bizarre cytology w/ syncytial cels
Markers: hCG, AFP
```
202
What are the most common testicular tumors by age group?
Pre-pubescent: yolk sac tumor
20-30: Embryonal seminoma
30s: Seminoma
>65: Spermatocytic seminoma
203
What is the microscopic feature most frequently associated with yolk sac tumors of the testes?
Schiller-Duval bodies : primitive glomerular cell formations
204
Identifying features of testicular choriocarcinoma
```
Resembles chorionic vili and contains 2 cell types:
-syncytiotrophoblast
-cytotrophoblast
Prominent hemorrhage and necrosis
expression of hCG -> gynecomastia
```
205
Are teratomas in men benign?
In children: yes
| Adult: always treated as malignant
206
What is the presentation of Leydig Cell tumors?
Usually sexual precocity due to androgen production
May present w/ gynecomastia
Testicular swelling
207
What is seen pathologically in Leydig cell tumors
Cicrumscribed nodule, golden color on cut surface
| Well differentiated cytology, Rienke crystals
208
How do Sertoli tumors present?
Usually hormonally silent (may produce androgen, but low level)
Cells (tall, columnar) arragnged in cordlike structures and tubules
209
What is the most common testicular cancer in older men?
Testicular lymphoma
| Poor prognosis
210
What is the most common cause of granulomatous prostatitis?
BCG (TB vaccine) treatment of bladder cancer
211
Pharm treatments for BHP
a-blocker, DHT inhibitor
212
Precursor to prostate cancer
High grade intraepithelial neoplasia
213
What is the best tool for determining prognosis of prostate cancer?
Gleason grading + stage
Gleason: 1-5 based on differentiation / pattern
1: well differentiated, glandular pattern
5: No differentiation
214
Targets of Testosterone vs. Dihidrotestosterone
T: hair, muscle, libido, brain, Wolffian duct
DHT: external genitalia, male pattern body hair, prostate
215
In males what are the respective target cells of FSH and LH?
FSH: Sertoli -> spermatogenesis (Inhibin decreases FSH)
LH: Leydig -> testosterone (neg feedback to decrease LH)
216
What can Inhibin B levels be used to estimate?
Number of active Sertoli cells
217
In a young male w/ hypgonadism when should testosterone levels be checked?
Evening - low levels.
| Diurnal variation of Testosterone: high in morning, low in evening
218
What is Klinefelter's Syndrome?
Male w/ XXY genotype -> hypogonadism
Damage to seminiferous tubules and Leydig cells
High gonadotropins, low T
219
What occurs in gonadal dysgenesis?
Mutation in sex determining region of Y chromosome -> streak gonads and female external genitalia
High risk of malignancy of gonads
Low GnRH -> low sex hormones
220
What is Kallman's syndrome?
X-linked (usually) hypogonadism
KALIG-1 defect -> failed migration of GnRH cells from olfactory placode -> hypothalmus
anosmia, mid-line defects, R-G colorblindness, neurosensory hearing loss
221
What lab finding constitute male infertility (semen analysis)?
3 abnormal samples over a 3 month period
222
What is 17a-alkylated Testosterone?
Daily dosing testosterone replacement
May be used for post-putertal hypogonadism
HEPATOTOXIC: not routinely used or recommended
223
What effect can testosterone supplementation have on male fertility?
T -> fedback inhibition on LH and FSH -> decreased sperm production and reduced fertility
224
3 GnRH Agonists
Leuprolide
Goserelin
Triptorelin
Agonism -> downreg of GnRH receptor -> decreased Testosterone
225
4 GnRH Antagonists
```
-elix drugs
Cetrorelix: IVF
Ganirelix: IVF
Degarelix: prostate ca
Abarelix: not in US - paliative prostate ca. care
```
226
3 non-steroidal AR antagonists used in Prostate Ca
Flutamide
Bicalutamide
Nilutamide
Often used w/ GnRH antagonist
227
5a-reductase inhibitors
Finasteride
Dutasteride
Bicalutamide
228
How does genetic imprinting occur?
Methylation of cytosines on CpG islands in regulatory sequences of DNA
229
What is MEN1?
Autosomal Dominant INACTIVATION of tumor suppressor MENIN
Results in multiple endocrine neoplasias of 3Ps:
Parathyroid, Pancreas, Pituitary and others
hypoparathyroidism in >90% of cases
55% of deaths due to reasons other than MEN1
230
What is MEN2?
AD ACTIVATING mutation of c-RET proto-oncogene
MEN2A: Pheochromocytoma, hyperparathyroidism, medullary thyroid carcinoma, hirschprung, cutaneous lichen amyloidosis
MEN2B: Marfanoid body, neuromas on tongue and GIT, thick lips and eyelids, NO HYPERPARATHYROIDISM
231
How does psuedohypoparathyroidism type 1a differ from 1b?
1a: presents with albright hereditary osteodystrophy due to tissue resistance to hormones other than PTH (inc. LH, FSH, GRF, CRF)
1b: PTH resistance only, no AHO
232
What are the hypothalamic nuclei involved w/ hunger /satiety?
Lateral: hunger: lesion -> anorexia
Ventromedial: satiety: lesion -> overeating
233
What is the neurocircuit model of hunger / satiety?
Arcuate nucleus is center of hunger / satiety
Neuronal expression of:
NPY / AgRP: increase hunger
aMSH / CART: decrease hunger
234
What is AgRP's role in obesity?
AgRP is specific inhibitor of aMSH at MC4 in hypothalamus -> obesity
Human mutations of AgRP -> increased BMR and obesity resistance
235
What are MC3 and MC4?
Melanocortin receptors in hypothalamus that decrease appetite and increase BMR.
Agonized by MSH
Antagonized by AgRP
Agonist drugs: experimental anti-obesity drugs
236
What is the role of Leptin in obesity?
produced by adipocytes (increased mass -> increased leptin)
Increases activity of aMSH neurons -> decreased hunger / increased MR
Many obese: resistant to leptin
237
What is orlistat and MOA?
drug for treatment of obesity
| Inhibits gastric and pancreatic lipase w/in intestine -> reduced TG absorption
238
What is Lorcaserin and MOA?
Lorcaserin: obesity drug
| 5HT2C agonist -> increased POMC production -> increased MSH -> increased activity of MC3 and MC4 -> decrease in hunger
239
Most common type of primary ovarian neoplasm?
Surface epithelial tumor
240
What organisms are associated with Pelvic Inflammatory Disease?
N. gonorrheae, Chlamydia, anaerobes (bacteroides, peptostrepto), aerobes (E.coli), mycoplasma
