First Pass Miss Flashcards
1
Q
What type of receptors do TGFbeta, activin, and inhibin use?
A
They all use serine/threonine kinase receptors which traverse the transmembrane domain
2
Q
What hormones stimulate and inhibit prolactin secretion in the posterior pituitary?
A
Prolactin is continuously secreted on a basal level unless it is inhibited. There is no dedicated releasing hormone, but are things which loosely stimulate it.
Stimulate: Estrogen, thyroid releasing hormone (TRH)
-> galactorrhea and infertility in primary and secondary hypothyroidism
Inhibit: Dopamine (PHIH)
Remember, many symptoms of prolactinoma are due to PRL decreasing GnRH
3
Q
What structures are most likely to be directly affected by pituitary tumors?
A
Structures directly adjacent to the sella turcica
- Cavernous sinus - directly adjacent, includes distal portions of internal carotid arteries, cranial nerves 3, 4, V1/V2, and 6, with 6 most likely to be damaged.
- Optic chiasm -> sits directly above sella
- Sphenoid sinus
- Diaphragma sellae, sits above and prevents CSF access into the sellae -> damage = empty sellae
4
Q
What hormones are produced more in the lateral vs medial portions of the anterior pituitary and why does this make sense?
A
Lateral - GH / PRL
Medial - TSH / ACTH
-> makes sense because stress hormones and metabolic hormones are more critical to life
5
Q
What cell lines are derived from somatotroph stem cells?
A
Thyrotrophs, mammosomatrophs, and somatrophs
6
Q
What is a functional vs nonfunctional pituitary adenoma? What nomenclature is used with the latter?
A
Functional - can secrete hormone and produces symptoms based on this
Nonfunctional - may or may not be producing hormone, but will have no symptoms caused by hormones. This could also be due to a loss in end-organ response.
These are described as “silent”. I.e. silent corticotroph adenoma.
7
Q
What is Cushing’s syndrome vs Cushing’s disease?
A
Cushing’s syndrome - syndrome of features associated with prolonged exposure to cortisol
Cushing’s disease - Cushing’s syndrome due to ACTH oversecretion by anterior pituitary (may be due to pituitary or hypothalamic dysfunction)
8
Q
What is an invasive adenoma? Why does this matter?
A
Tumors showing gross tumor invasion into the dura or bone
Increased likelihood of recurrence. But remember, these cannot metastasize (these are benign adenomas).
Atypical -> increased proliferation
Pituitary carcinoma -> very rare, characterized by presence of local or systemic metastasis.
9
Q
What is lymphocytic hypophysitis and what causes it?
A
Autoimmune inflammation of adenohypophysis caused by infiltration of lymphocytes, leading to destruction of anterior pituitary with fibrosis.
Usually occurs in women during late pregnancy or shortly after delivery
10
Q
What is primary vs secondary empty sella syndrome and who does it occur in? How does it present?
A
Primary - protrusion of a diverticulum of arachnoid membrane into sella. Occurs in middle-aged women, often with obesity and hypertension (same demographic as pseudotumor cerebri) -> presents as headache.
Secondary - pituitary fails to take up entire space of sella which allows CSF to seep in, follows surgical resection, apoplexy, or radiation treatment of sellar tumor
11
Q
What is the most common sellar tumor in children and what might is be confused with?
A
Craniopharyngioma - a tumor derived from Rathke’s epithelium
May be confused with pituitary adenoma -> both present with headache, hypopituitarism, and bitemporal hemianopsia
12
Q
What does the pathology of craniopharyngioma look like?
A
“Adamantinomatous” - squamous epithelium which appears cystic due to fluid accumulation between squamous epithelial cells.
Calcification is extremely common (remember pathoma’s mnemonic about this being derived from mouth and teeth have calcium).
“Wet keratin” - keratin pearls appear overly plump.
13
Q
What is a chordoma? Where does it occur? Who tends to get it?
A
A moderately malignant tumor derived from embryonic notochord - type of sarcoma.
Arises in sacrum (nucleus pulposus) or spheno-occipital bones (typically around the clivus of the occipital bone) typically in middle-aged men.
Physaliphorous cells - prominent vacuolization of cells as they produce extracellular matrix resembling cartilage + myxoid stroma
Pituitary dysfunction, CN3 involvement, or headaches
14
Q
How do men and women present differently with prolactinoma?
A
Women - present early when it is still a microadenoma (<1cm) with galactorrhea (not pathognomonic), amenorrhea, or oligomenorrhea (if you have irregular periods, should always check). Often presents with decreased bone density due to decreased estrogen.
Men - Present with macroadenoma (>1 cm), present very late because they do not seek medical attention for gonadal dysfunction. Typically present with visual field defects / headaches.
15
Q
What are some causes of hyperprolactinemia which are not prolactinoma?
A
- Estrogens - i.e. pregnancy or birth control pills -> number one cause of lactotroph hyperplasia
- Primary hypothyroidism - Increased TRH levels stimulate PRL
- D2 antagonist antipsychotics
- Cocaine use -> depletion of central dopamine stores
16
Q
What are the common causes of death in acromegaly / what important conditions are they at greater risk for?
A
Congestive heart failure -> most common cause of death
Patients also have increased relative risk of colon and breast cancer
-> IGF-1 has a permissive effect in tumorigenesis
Other symptoms you might not remember: arthritic joint complaints, hyperhidrosis
-> may present early as obstructive sleep apnea (large tongue) or carpal tunnel syndrome
17
Q
What is the most common cause of congenital hypopituitarism? What hormones will be low?
A
Mutation in Pit-1, which causes failure of differentiation of somatotroph stem cells, and subsequent failure to deevelop lactotrophs, somatotrophs, and thyrotrophs (see Kupsky lecture)
-> PRL, GH, and TSH will be low, with relative preservation of ACTH and LH/FSH
18
Q
What are the symptoms of pituitary apoplexy?
A
- Sudden onset severe headache
- Visual disturbance -> bitemporal hemianopia
- Diplopia due to CN3 palsy
- Features of hypopituitarism -> i.e. emergent cortisol insufficiency leading to hypotension
It is a medical emergency.
-> usually occurs in the setting of pre-existing pituitary adenoma
19
Q
What are the presenting symptoms of Sheehan syndrome?
A
Failure to lactate -> loss of prolactin secretion
Absent menstruation / loss of pubic hair -> failure of LH / FSH secretion
Cold intolerance -> loss of TSH
20
Q
What role does testosterone have in epiphyseal closure?
A
It leads to the closure of epiphyseal plates in puberty because estrogen is made from testosterone (requires aromatase).
Formation of estrogen closes epiphyseal plates. The estrogen is also what accounts for the bone-forming / massforming effect of testosterone.
21
Q
How is testosterone transported and what form is readily bioavailable? How does this differ from males and females?
A
98% is transported via sex hormone binding globulin (SHBG) and albumin in both males and females
Only free and albumin-bound testosterone are bioavailable. Males have less SHBG binding and more albumin-binding relative to females -> higher circulating levels of bioavailable testosterone.
(Note: estrogen stimulates synthesis of SHBG to make this happen)
22
Q
What are the physical features of Klinefelter syndrome and what is it?
A
Syndrome of extra X chromosome
Testicular atrophy / fibrosis -> small testes (pre-pubertal size) with seminiferous tubular sclerosis and rare Sertoli cell / sperm. -> infertility
Eunuchoid body shape + gynectomastia -> feminization of features (increased estrogen to testosterone ratio, leads to decreased testosterone availability)
Disproportionately long arms / legs.
Increased FSH and LH due to lack of feedback from inhibin B (sertoli) and testosterone (leydig). Estrogen magically increased due to increased relative sertoli cell function with aromatase.
23
Q
What are some acquired causes of primary hypogonadism?
A
- Mump orchitis in adulthood
- Radiation / chemotherapy - germ cells are very sensitive
- Ketoconazole
- Testicular torsion
- Hemochromatosis - (secondary)
- Autoimmune damage
- Chronic systemic diseases i.e. cirrhosis, renal failure, aids
- Aging - decline in Leydig cell number / volume, blood supply, decreased testosterone and number of Sertoli cells
24
Q
What is male gonadal dysgenesis and what causes it? What is the associated risk increase?
A
Mutation in SRY
Patient will have streak gonads and female type external genitalia, with Mullerian duct development
-> associated with high risk of malignant transformation of the gonads
25
Other than Kallman syndrome, what other congenital conditions are associated with lack of GnRH?
Prader-Willi
-> both are more associated with obesity
Laurence-Moon-Bardet-Biedl
-> associated with retinitis pigmentosa and polydactyly as well
26
What are the differential effects of primary vs secondary hypogonadism in the first trimester?
Primary - can lead to a spectrum of pathology, from development of female external genital to partial virilization with hypospadias (depend on degree of T deficiency)
Secondary (problem not at the level of the testes) - Differentiation of external genitalia will be completely normal because testosterone production is driven by placental HCG in the first trimester (HCG is homologous to LH)
27
What happens if androgen deficiency onsets prior to puberty?
Lack of virilization and Tanner development (lack of puberty), as well as development of Eunuchoid habitus (long arms / legs), poor muscle mass development / reduced peak bone mass
28
What are the side effects of using testosterone to treat hypogonadism? What is the contraindication?
1. Acne
2. Gynecomastia (increased estrogens)
3. Testicular atrophy (from suppression of FSH/LH)
4. Polycythemia / hyperviscosity syndrome -> testosterone increased RBC mass
Contraindicated in men with KNOWN prostate cancer
29
What will the lab values be for 5alpha reductase deficiency?
Normal estrogen/testosterone levels, LH may be normal or elevated.
-> testosterone is responsible for negative feedback in the pituitary
Main thing: Increased testosterone to DHT ratio. Testosterone levels are not high enough until puberty to stimulate the development of external genitalia (DHT has much higher affinity than T for same receptor which allows it to do dis early on)
30
What is balanoposthitis and how can it be prevented?
Infection of glans penis + prepuce
-> can be prevented with circumcision, since it is generally due to poor local hygiene in uncircumcised penis getting infected
31
What is Bowen disease vs erythroplasia of Queyrat?
Both are forms of squamous cell carcinoma in situ
Bowen disease - occurs on penile shaft or scrotum and appears as leukoplakia
erythroplasia of Queyrat - occurs on glands penis as shiny red or velvety plaques
32
What is Bowenoid papulosis and how is it different from Bowen disease?
Bowenoid papulosis is SqCC in situ which occurs in younger patients (<40 years) and presents as multiple pigmented reddish papules.
-> will NOT progress to invasive carcinoma
Bowen disease - happens in older patients, more frequently progresses to invasion
33
What controls the descent of the testes / what are the two phases? What happens if this fails and where does this usually occur?
1. Transabdominal phase - controlled by Mullerian-inhibiting factor of Sertoli cells
2. Inguinoscrotal phase - through inguinal canal, controlled by androgens
If this fails -> Cryptorchidism. Usually the testes are found in the inguinal canal.
34
What are the two age groups which get testicular torsions and why do they occur (defect?)?
1. Neonates - in utero or shortly after birth, not associated with any developmental abnormality
2. Adolescents - occur due to bell-clapper abnormality -> tunica vaginalis does not stop posteriorly but entirely wraps around testes, allowing for increase mobility of testicle.
**Abnormality is often bilateral and needs to be fixed surgical when one presents**
Acute severe pain and absent cremasteric reflex without inciting trauma
35
What tends to cause orchitis is young adults vs older adults?
Young adults - Chlamydia trachomatis, Neisseria gonorrhoeae
-> STDs
Older adults - E. coli and Pseudomonas -> as a result of ascending UTIs
These are the same as the causes for acute prostatitis
36
What is the most common category of all testicular tumors and how does this relate to how we tend to treat testicular tumors? Who tends to get them?
Germ cell tumors -> represent 95% of all testicular tumors. These are usually malignant and as a result we tend to resort to radical orchiectomy as empiric treatment
These commonly occur in young men (15-40)
37
What are the two subgroups of germ cell tumors and what does this mean?
1. Germ cell neoplasia in situ (GCNIS)-derived
and
2. non-GCNIS
These are seminoma-like cells (germ cells) with large nuclei, clumped chromatin, and prominent nucleioli along the basememnt membrane of seminiferous tubules. These cells are positive for embryonic stem cell marker OCT3/4
38
What tumors fall into non-GCNIS derived?
1. Spermatocytic tumor - >65 years, 3 distinct cell populations, looks like seminoma, rarely metastasizes
2. Prepubertal Yolk sac tumor -> most common testicular tumor in boys <3 years
3. Prepubertal teratoma -> will be mature, only type of benign teratoma in men
39
How does seminoma appear grossly? Who tends to get it?
Homogenous, lobulated gray-white mass with no hemorrhage or necrosis. Lobules are made via delicate fibrous stroma infiltrated by T cells.
Gotten by young men in their 30s. NEVER in infancy.
40
How does embryonal carcinoma differ from seminoma grossly and prognostically?
It is grossly much more poorly demarcated and punctuated by foci of hemorrhage and/or necrosis, more painful than seminoma.
It is composed of primitive epithelial cells forming glands and papillary structures
It has a much worse prognosis than seminoma because it can rapidly hematogenously disseminate
41
What marker do embryonal carcinoma stain positive for, and what are they commonly mixed with / how does this affect their markers which are elevated in serum?
EC is positive for CD30
Commonly mixed with yolk sac tumors, so can also cause elevated alpha-fetoprotein (AFP levels)
Also, like seminomas they can have syncytiotrophoblasts and have elevated hCG.
42
What are yolk sac tumors also called and who tends to get them? What is the prognosis in this group?
Also called endodermal sinus tumors
Tends to occur in children. It is the most common testicular tumor in children <3 years. In this age group, it is a pre-pubertal YST which is non-GCNIS derived and has an excellent prognosis (pure form of yolk sac tumor).
Schiller-Duval bodies - glomeruloid
Yellow, mucinous grossly
43
Are pure choriocarcinomas common? And what is their pattern of infiltration? What cell types make them up?
Made of syncytiotrophoblasts and cytotrophoblasts which produce beta-HCG.
Pattern of infiltration is formation of small tumors with rapid hematogenous spread around the body (since trophoblast cells have a tropism towards blood cells)
They are rare in their pure form, tend to be expressed in another form of germ cell tumor (i.e. seminoma, embryonal carcinoma)
44
What symptoms do patients with choriocarcinoma often have and why?
Often have symptoms of hyperthyroidism or gynecomastia
| -> alpha subunit of hCG is structurally similar to LH, FSH, and TSH
45
How do testicular cancers tend to spread?
Seminomas tend to spread via para-aortic lymph nodes before hematogenous.
Non-seminoma GCNIS derived tend to present at a later stage via metastasis with hematogenous routes very early.
46
How does a Leydig cell tumor present?
Produces androgens so:
Prepubertal boys -> presents as precocious puberty
Adults -> Presents as gynecomastia (excess testosterone gets converted to estrogen)
Reinke crystals - rod-shaped eosinophilic cytoplasmic inclusions with unknown function
Appears very yellow with clear, vacuolated cytoplasm
47
What is a Sertoli cell tumor also called? What does it look like microscopically and what is its clinical behavior?
Androblastoma
- > looks like tall columnar cells forming cords -> immature seminiferous tubules
- > Usually benign and clinically silent (does not produce enough androgen to be significant)
48
What is the most common form of testicular tumor in men over the age of 60 and what is its behavior? Is it a primary tumor?
Testicular lymphoma - usually a diffuse B cell lymphoma
- > very aggressive with a poor prognosis
- > It is a secondary tumor arising elsewhere
49
What causes chronic prostatitis and how will the symptoms differ?
May or may not be UTI related, but often cultures of prostatic secretions are negative despite showing lymphocytic inflammatory infiltrate.
More likely to present with lower back pain.
50
What are the secondary complications which may occur due to BPH? What can be done to surgically correct this problem?
Distention and hypertrophy of bladder (Due to increased resistance), hydronephrosis (due to backflow of urine), recurrent UTIs
Surgically correct with TURP - transurethral resection of the prostate
BPH is caused by increased age-related conversion of testosterone to DHT
51
What is the growth pattern of prostate adenocarcinoma?
Small, invasive glands with prominent nucleoli. Basal cell layer is lost.
Tends to show perineural invasion
52
What is the most common site of metastasis for prostate cancer and how does this show up on labs?
Lumbar spine or pelvis -> osteoblastic metastasis which presents as lower back pain.
Serum alkaline phosphatase will go up (osteoblastic activity marker) as well as prostatic acid phosphatase (PAP)
53
What are Gleason groups and what are they used for? What is the most useful prognosticator?
Groups of Gleason scores to indicate prognosis. There are groups 1-5 (probs don't memorize):
```
Group 1: Score 6
Group 2: Score 7 (3+4)
Group 3: Score 7 (4+3)
Group 4: Score 8
Group 5: Scores 9-10
```
Most useful prognosticator is the Gleason score associated with the stage
54
What are some anti-androgens used in prostate cancer?
Leuprolide - continuous GnRH analog
Flutamide - competitive inhibitor at the androgen receptor
-> Flutes are anti-manly
55
Place the following in the correct order, and define them:
Growth spurt, adrenarche, pubarche, thelarche, menarche
What is the definition of precocious vs delayed puberty in females?
```
Thelarche - breast bud / breast growth
Pubarche - pubic hair growth
Adrenarche - axillary hair growth (A = axillary)
Growth spurt - follow hair growth
Menarche - first menstrual bleed
```
Precocious - Tanner Stage 2 at <8 years
Delay - Tanner Stage 1 at age 13, or no menses by age 16.
56
What are the most common causes of precocious pseudopuberty in boys and girls? What is this also called?
GnRH-independent puberty (peripheral puberty)
this is opposed to "true precocity" which is due to central GnRH overaction
Boys - Testicular tumor (either Leydig cell or choriocarcinoma secreting hCG)
Girls - Ovarian tumor (i.e. granulosa cell making estrogen)
57
What marker do primary follicles express, and what stage of Meiosis are they found in? When do they move on?
They express **anti-Mullerian hormone **-> can be used to track the development of the primary follicles
They are stuck in Prophase I of Meiosis I, they will move on when the corona radiata (inner layer of granulosa cells) stops delivering cAMP thru the zona pellucida (distinct mucopolysaccharide band) during the Graafian follicle stage -> secondary oocyte will arrest at Metaphase II until fertilization.
Metaphase til they "met" a sperm
58
What is going wrong hormonally in PCOS which accounts for the symptoms?
Hyperinsulinemia / insulin resistance alter the hypothalamic hormonal balance and cause:
1. Increased LH:FSH ratio, which stimulates increased androgen production from theca interna cells --> hirsutism.
2. High circulating androgen levels are converted to estrone via adipose tissue (these women are obese with insulin resistance) -> feedback by estrone decreases FSH levels secreted by anterior pituitary.
3. Since FSH is low, androgens are not rapidly turned into estrogen via granulosa cells -> slowed rate of follicular maturation. This leads to small follicular cysts and anovulation -> infertility.
59
What are the pharmacologic treatments for PCOS?
1. Weight reduction
2. OCPs -> prevent endometrial hyperplasia due to unopposed estrogen (provide hormones exogenously)
3. Clomiphene - infertility treatment which blocks estrogen receptor negative feedback in hypothalamus
4. Metformin - to combat insulin resistance
5. Spironolactone / ketoconazole -> block androgen receptor as well as production
6. Statins - for treatment of metabolic syndrome.
60
What is the approximate age of onset of normal menopause, and what marker is specific for it?
Approximately 51 years (can be earlier in smokers)
Increased FSH levels are specific (loss of negative feedback on FSH due to decreased estrogen levels. This is due to decreased granulosa cells responding to FSH)
61
What is the source of estrogen in menopause, and what are the general symptoms to remember?
Peripheral conversion of androgen to estrogen. (LH stimulates the theca cells). These increased androgens can lead to hirsutism.
Remember HAVOCS:
Hot Flashes
Atrophy of ->
Vagina
Osteoporosis (first three from decreased estrogen)
Coronary Artery Disease
Sleep Disturbances (from hot flashes and night sweats)
62
What is the question you have to ask yourself when evaluating primary amenorrhea?
Is there normal development of female secondary sexual characteristics.
If NO -> hypogonadism, hyper or hypogonadotropic (as explained before)
If YES -> Mullerian anomalies, outflow obstruction, androgen insensitivity, or weight/exercise issue
63
Why do patients with Mullerian agenesis have primary amenorrhea? How will their gonads look?
Mullerian ducts give rise to fallopian tubes, uterus, and upper vagina.
- > uterus and upper vagina + fallopian tubes will be hypoplastic
- > usually variable uterus development and blind / short upper vagina
- > lower 1/3 of vagina formed via urogenital sinus and develops normally
64
What genitalia will those with androgen insensitivity have?
They have normal female external genitalia, but blind vagina / absent uterus / upper vagina (MIF secreted by Sertoli cells to inhibit Mullerian duct).
Wolffian / mesonephric duct not formed properly due to lack of testosterone response.
-> testes will be present with normal high circulating levels of testosterone for a male, the only difference is end-organ response
65
What is the first step in the algorithm for secondary amenorrhea (amenorrhea which has started after menarche)? What does a positive test mean?
Progesterone / progestin challenge test
- > Withdrawal bleeding 2-7 days after giving progesterone (and levels have dropped) indicates that there is a presence of estrogen, but ovulation and thus formation of corpus luteum has not been occurring
- > endometrium stuck in proliferative phase, never reaches secretory phase to turn over
Basically, withdrawal bleed = ANOVULATION, where estrogen is present
66
What do you do if there is no withdrawal bleed after the progestin challenge? What are the possible results?
Estrogen + Progesterone challenge
If bleeding -> reason for amenorrhea is low estrogen. Check FSH levels to see if gonadal failure or CNS failure.
If no bleeding -> uterus / anatomical outflow tract problem
67
How is the diagnosis of functional hypothalamic amenorrhea made, and is it common?
Low estrogen levels, with no withdrawal bleed from progestin challenge
It is one of the most common causes of amenorrhea
1. Low weight (eating disorders like anorexia / bulimia) -> we said these are causes of anovulation as well
2. Endocrine conditions (hypothyroid, hyperprolactinemia, diabetes)
Stress and exercise also contribute
-> results in ultimately low GnRH
68
What are the symptoms of trichomoniasis and how is it transmitted? How is it visualized?
It is an anerobic, flagellated protozoan which does NOT form cysts so it is sexually transmitted
Symptoms:
Pruritis with foul-smelling greenish discharge
Inflamed cervix: "Strawberry cervix"
Visualize as MOTILE via wet mounts.
69
What is chronic atrophic dermatitis also called and who tends to get it?
```
Lichen sclerosis (et atrophicus)
-> commonly seen in postmenopausal women, with possible autoimmune etiology
```
atrophy of epidermis with sclerosis and thickening of underlying dermis
Primary cause of non-HPV related squamous cell carcinoma of the vulva
70
What is the hallmark of invasive cervical carcinoma and a feared complication?
Invasion of the stroma.
Often, it can invade anteriorly into the bladder wall, leading to ureteral obstruction
-> post-renal azotemia is a common cause of death in advanced carcinoma
71
What is "inadequate luteal phase" and how does it present?
Inadequate corpus luteal progesterone output
- > presents as infertility (many miscarriages due to underdeveloped decidua) with early dysfunctional uterine bleeding
- > underdeveloped glands relative to where they should be in the cycle
72
What is the hallmark of chronic endometritis and what are some common causes?
Plasma cells in the stroma as part of chronic inflammation, as lympocytes and macrophages are often present in endmetrial stroma
```
Causes:
Pelvic inflammatory disease
Retained gestational products
IUDs
TB -> will show granulomatous inflammation
```
73
What is the most common cause of dysfunctional uterine bleeding? Who tends to get it?
Anovulatory cycle
-> lack of ovulation occurs, so there is excessive estrogen stimulation of proliferative phase, leading to unscheduled breakdown of stroma
Common at menarche and in perimenopausal women (ovulation never occurred, so no secretory phase)
74
What is an endometrial polyp?
Masses of endometrial tissue which protrude into the endometrial cavity
-> overgrowth of endometrium with crowded glands and multiple proliferating cells
Causes painless abnormal uterine bleeding, associated with tamoxifen use
75
What discharge will be seen in acute endometritis and how is the situation remedied?
Purulent BLOODY discharge with many PMNs
- > removal of retained product removes nidus for infection
- > this is an organic cause of uterine bleeding
76
What proliferates in endometrial hyperplasia and what is the general underlying cause? How does it present?
Caused by a hyperplasia of endometrial GLANDS relative to stroma
Excess estrogen stimulation, i.e. obesity, estrogen replacement, anovulatory cycles, or polycystic ovarian syndrome (increased circulating estrone)
Presents as postmenopausal uterine bleeding
77
What does endometrial hyperplasia increased your risk for and what gene is associated with it?
Associated with inactivation of PTEN tumor suppressor gene (increased risk with Lynch syndrome)
-> increased risk for endometrial carcinoma (endometroid type) -> which is the most common gynecologic malignancy
78
What are the two ways in which endometrial hyperplasia is histologically characterized based on its growth? Which is more important?
1. Simple vs complex
- > simple = glands look nice
- > complex = glands look complicated with many outpouchings and loss of stroma
2. Presence of absence of cellular atypia
- > nuclear atypia is more important
79
What is the other type of endometrial cancer and who tends to get it?
Sporadic endometrial cancer -> Type 2, occurs in older (POST-menopausal women, i.e. 70s/80s), no associatd with estrogen
- > Occurs in the setting of atrophic endometrium with no precursor lesion
- > early p53 mutations and very aggressive behavior
80
What is the most common form of sporadic endometrial carcinoma (Type 2) and what is seen on histology?
Serous carcinoma. Forms papillary structures which can necrose around fibrovascular cores, leading to psammoma body formation.
To remember it forms psammoma bodies, alot of people remember it as "papillary-serous carcinoma"
81
What causes fibroids and how will they change with age?
They are estrogen sensitive: tumor increases in size with pregnancy and decreases in size with menopause.
Peak occurrence is in 20-40 years.
82
What are classic symptoms for leiomyoma?
Usually asymptomatic, but may present with abnormal uterine bleeding (stretch lining of uterus) with iron deficiency anemia, infertility, and a pelvic mass
83
Who tends to get leiomyosarcoma?
Usually in older (postmenopausal) women, since they are not related to estrogen exposure.
84
When does separation occur for a monochorionic diamnionic twin vs monochorionic monoamnionic twin? Which is more common?
Monochorionic diamnionic - separation occurs 4-8 days -> occurs after morula (compacted 8 cell embryo) has formed but before blastocyst has been made and implanted
-> most common twinning overall (even more than dichorionic)
Monochorionic monoamnionic -> very rare, occurs when cleavage happens in blastocyst stage, two embryos arise from same inner cell mass
(conjoined twins would be even later, but still monochorionic/amnionic)
85
What is vasa previa? What should be done?
When fetal vessels run over / close to cervical os
- > can lead to vessel rupture and fetal death if the membrane ruptures
- > Should do an Emergency C-section
Associated with velamentous (membrane) insertion of umbilical cord
86
What is the clinical presentation of placental abruption for the mother?
Abdominal pain / tenderness in the third trimester marked by:
1. Painful vaginal bleeding
2. Uterine contractions
3. Disseminated intravascular coagulation and hypovolemic shock -> placenta releases procoagulant factors (tissue factor)
87
What are the two major routes of placental infections and what usually causes them? What areas of the placenta get infected (I'm sorry mate you probs won't remember this)?
1. Acute chorioamnionitis - usually due to ASCENDING infections from vagina / cervix, associated with early membrane rupture. Almost always bacterial.
- > will cause funisitis of fetal umbilical cord
2. Chronic villitis - (inflammation of chorionic villi) usually hematogenous dissemination in a TRANSPLACENTAL mechanism of TORCH pathogens. Almost always viruses and parasites
88
What is the definition of pre-eclampsia? Consequences?
Development of hypertension, edema, and proteinuria during pregnancy, which may cause end-organ dysfunction
Headaches and visual disturbances secondary to hypertension, with hypercoagulability and acute kidney injury (due to fluid loss and malignant hypertensive damage).
Pulmonary edema may result from proteinuria.
89
What are eclampsia and HELLP syndrome?
Eclampsia - Preeclampsia + seizures
HELLP - Severe pre-eclampsia leading to
- > Hemolysis, Elevated Liver Enzymes, Low Platelets
- > microangiopathic hemolytic anemia involving liver damage
90
What are the placental factors released into circulation causing maternal endothelial dysfunction and hypercoagulability?
Placental ischemia -> induces release of angiogenesis modulating factors like endoglin
-> systemic endothelial dysfunction
Hypercoagulability -> caused by endothelial damage causing decreased prostacyclin production and increased prothrombotic factors -> systemic thrombi formation
91
How does molar pregnancy usually present / what is the usual way you know it's happening?
Usually presents as spontaneous miscarriage or with increased uterine size and hCG levels which are TOO HIGH for gestational age (trophoblastic proliferation)
-> increased hCG may lead to theca cell cysts, hyperthyroidism, and early pre-eclampsia
92
What is gynecomastia and who is it physiologic in?
Breast enlargement in males due to increased estrogen relative to testosterone
Physiologic in:
1. Newborns
2. Puberty - usually resolves in 6-12 months
3. Elderly - secondary to decreased testosterone
93
What are some pathologic non-drug-related causes for gynecomastia and what should be done?
1. Klinefelter syndrome
2. Cirrhosis (increased estrogen)
3. Renal failure -> uremia-associated hypogonadism
Should give mammogram to rule out cancer
94
What is the utility of mammography, breast ultrasound, and breast MRI in diagnosis of breast lumps?
Mammography - best screening and diagnostic tool
Breast ultrasound - not used for screening, but determines if cyst or solid lump
Breast MRI - adjunctive, should NOT be used instead of mammography / ultrasound
95
What is periductal mastitis, what is the pathogenesis, and who tends to get it?
Painful subareolar mass which occurs as keratinizing squamous metaplasia occurs in the ducts, which causes duct blockage and inflammation. There will be a granulomatous response to spilled keratin, and chronic inflammatory infiltrate.
Occurs in smokers -> have a relative vitamin A deficiency, causing squamous metaplasia
96
What benign entity is most likely to mimic breast cancer both clinically and on mammography? What is its pathogenesis?
Fat necrosis
- > trauma leads to formation of a hard mass which is necrotic
- > dystrophic calcification (due to saponification) allows it to be seen on mammography
- > necrotic fat cells and giant cells (macrophaged-derived foam cells) seen on histology
- > treat with NSAIDs
97
What is the single most common change in the premenopausal breast and what is the cause? What age group is susceptible?
Fibrocystic changes -> older premenopausal women (>35 years). (Because <35 gets fibroadenoma)
Thought to be due to abnormal hormonal response / sensitivity
-> multifocal and bilateral breast lumps which may be painful
98
How does a fibrocystic change generally appear grossly? Are the lesions benign or malignant?
Appears to have a blue-dome appearance on gross exam.
Represents a fluid-filled ductal proliferation which forms scarring and fibrosis around an obstructed duct. The duct then erodes into a blood vessel -> bleeding into cyst = BLUE DOME.
They are benign, but may be associated with increased risk of developing breast cancer in BOTH breasts
99
What two lesions are associated with roughly 2x risk of breast cancer as fibrocystic changes? How will the lumens look on the ductal one?
1. Usual ductal hyperplasia - excess benign cells lining ducts-> lumens will appear irregular (indicates benign), a type of proliferative change
2. Sclerosing adenosis - adenosis = glands, sclerosing = fibroblasts, this is a normal looking hyperplasia of acini with intermixed fibrosis. Often becomes calcified (confusable on mammogram)
100
What fibrocystic lesions are at greater risk (4-5x) of progressing to breast cancer? How will the lumens of the ductal one appear?
1. Atypical ductal hyperplasia - lumens within the proliferated ducts appear more round than usual ductal hyperplasia, and cells are monomorphic / atypical
2. Lobular hyperplasia - increased number of cells lining each lobule, look like "marbles in a petri dish" acini
101
What is the growth pattern of fibroadenoma and does it increase your risk for cancer?
Small, well-circumscribed mass, usually solitary. Includes fibrous component with proliferative intralobular duct connective tissue, and a gland component.
It is estrogen-sensitive, so it grows during pregnancy and prior to menstruation.
No increased risk of cancer.
-> somewhat similar to uterine fibromas, except in the breast with glands / fibrous connective tissue
102
What is the most common cause of serous or bloody nipple discharge? How can you tell if it's benign or malignant?
Intraductal papilloma
-> papillary growth into a large duct, typically under the areola.
Can see two layers of cells to know it's not malignant.
103
What neoplasm should be suspected if what was presumed to be a fibroadenoma does not regress after menopause? What is its growth pattern?
Phyllodes tumor
- > fibroadenoma-like (both proliferations of glands and stroma) but has an overgrowth of the "fibrous" mesenchymal component of the tumor
- > They have a very cellular stroma -> sarcomatous type tumor (stroma can be very ugly, much less benign looking than fibroadenoma).
- > characteristic "leaf-life" projections of fibrous tissue on biopsy
104
What is comedocarcinoma? Will both layers of epithelial cells be present?
High grade DCIS -> necrosis and dystrophic calcification seen in the center of the ducts. Cells are atypical but still in situ because bounded by basement membrane.
-> picked up easily via mammography due to calcifications
Yes, both layers of epithelial cells will be present until tissue invasion occurs
105
Is LCIS usually solitary? How is it treated?
It is often multifocal and bilateral
Treated as a super risk factor, as risk of cancer is usually for invasive DUCTAL carcinoma.
Observe closely and give tamoxifen hormonal therapy. (ER antagonist as breast, agonist at bone/uterus)
106
What are the four main subtypes of invasive ductal carcinoma?
1. Tubular carcinoma -> forms tubules, most common, good prognosis
2. Mucinous carcinoma -> stuck in myxoid stroma, good prognosis
3. Medullary carcinoma
Invasive ductal carcinoma with large, high-grade cells associated with lymphocytes / plasma cells, BRCA1, good prognosis. Looks like adrenal medulla / neuroendocrine
4. Inflammatory carcinoma
-> peau d'orange, neoplastic cells clog lymph vessels
107
How does invasive lobular carcinoma appear histologically?
Appears as an orderly row of cells "single file" pattern due to being discohesive.
- > will not form glands (lack E cadherin)
- > minimal desmoplasia -> rarely presents with mass
108
What are the risk factors for male breast cancer?
Hyperestrogenic states: Klinefelter syndrome.
BRCA2
Typically a ductal breast cancer presenting as a subareolar mass
109
What causes streak or absent gonads?
When the germ cells do not migrate to the gonadal ridges properly -> as in Turner syndrome
-> ovaries are replaced by useless connective tissue with no follicles
110
What is the order of areas in the Fallopian tube from the ovary to the uterus in females? Where does fertilization occur?
Fimbrae -> infundibulum -> ampulla -> isthmus -> ostium of uterus
Fertilization typically occursin the ampulla
111
How can endometriosis appear grossly in the ovaries, serosa of pelvis / abdomen, and intestines?
Ovaries - "chocolate cysts" - blood-filled endometrioma
Serosa - "powder burns" - black spots on serosa
Intestines - induce fibrosis leading to adhesions and even mural-thickening of smooth muscle (Crohn's like presentation)
112
Where does ectopic pregnancy usually occur and what are the risk factors?
Usually occurs in ampulla of Fallopian tube -> where fertilization occurs
Risk factors:
Previous tubal surgery
History of PID
Peritubal adhesions due to endometriosis or appendicitis
113
What is the most common cause of ovarian enlargement and what are three types?
Ovarian cysts
Paraovarian cysts are also very common.
1. Epithelial inclusion cysts - small cysts formed by invagination of ovarian surface epithelium (single layer)
2. Follicle cysts
- > unrupture Graafian follicles lined by granulosa / theca cells -> functional and produce estrogen
3. Corpus luteum cysts
- >
114
What are follicle cysts and are they functional?
"Follicular cysts"
- > upruptured Graafian follicles
- > lined by granulosa and theca cells
- > are functional -> can be lined by granulosa cells and produce estrogen
115
What is the most common malignant ovarian neoplasm overall? What is the differentiation towards? What does it look like histologically?
Papillary serous cystadenocarcinoma -> papillary pattern means it's differentiated towards Fallopian tube
Columnar epithelial cells, and since it is papillary carcinoma -> psammoma bodies are frequently seen
116
What type of ovarian cancer arises in the setting of endometrial cancer and are they related?
Ovarian endometrioid carcinoma
| -> often arises in the setting of endometriosis, but the uterine endometrial cancer is independent (not the same tumor)
117
What are the three forms in which each subtype of ovarian neoplasm can be found?
1. Adenoma - benign -> minimal epithelial proliferation
2. Borderline - inbetween benign and malignant (malignant, but much better prognosis)
3. Adenocarcinoma - marked epithelial proliferation and STROMAL INVASION
118
What are the three major histologic subclassifications of surface epithelial tumors of the ovary? Which is most common?
1. Serous neoplasms - most common -> Fallopian tubes -like
2. Mucinous neoplasms -> endocervix (to keep sperm out) or intestines-like
3. Endometrioid neoplasms
- uterine endometrium
119
What is a Brenner tumor and why is it unique?
It is a Benign tumor that is actually solid (rather than cystic) and is composed of Bladder epithelium (urothelial / transitional type)
120
If sexcord-stromal tumors are functioning, who tends to get estrogenic vs androgenic versions?
Estrogenic - older women
Androgenic - younger women
But obviously there are exceptions to rules
121
What is the most common malignant sex cord-stromal tumor? Who tends to get it gets it? What is their presentation?
Granulosa cell tumors
- > estrogen-secreting, thus adult-type (women in their 50s, postmenopausal)
- > presents as abnormal uterine bleeding due to endometrial hyperplasia
122
What is a fibroma-thecoma and who tends to get it? What hormone is secreted?
Benign tumor of varying amounts of fibroblasts and theca cells (epithelial derived) -> actually produce estrogen (rather than testosterone, they go the next step)
Thus, like granulosa cell tumors, presents as abnormal uterine bleeding in postmenopausal women
123
What is Meigs syndrome? What might you confuse it for?
Triad of ovarian fibroma, ascites, and hydrothorax
| -> might confuse for ovarian carcinoma ascites, but actually fibromas / thecomas are benign
124
Who is the androgenic sex cord-stromal neoplasm which usually occurs in younger women? What does it look like histologically?
Sertoli-Leydig cell tumor (yes! this can occur in the ovaries!)
Sertoli cells will form tubes, and the Leydig cells will be the stroma between the tubules.
Reinke crystals can be seen on histology in Leydig cells (as in male Leydig cell tumors)
125
What are the contraindications to estrogen therapy?
1. Estrogen dependent neoplasma
2. Undiagnosed genital bleeding
3. Hepatic disease (decrease the metabolism)
4. Pregnancy
5. History of thromboembolic disorder (increased cardiovascular risk)
126
How does estrogen affect your warfarin levels?
It decreases your warfarin levels (probably by CYP induction to some extent, idk)
127
What are the three main synthetic progestins?
1. Medroxyprogesterone
2. Norethindrone
3. Norgesterel
- >look for a "-gest" and its probaly gucci
128
What is clomiphene used for and why?
Treatment of infertility
- > tends to block estrogen receptor in hypothalamus, which makes hypothalamus see low estrogen -> increasing GnRH release
- > leads to increased FSH levels, and subsequent follicle stimulation
129
What other class of medications can induce ovulation by reducing circulating estrogen levels?
Aromatase inhibitors - i.e. Anastrozole, Letrozole, exemestane
- > similar mechanism to clomiphene, increase FSH levels by causing hypoestrogen environment.
- > Use at same time in follicular phase
130
How can FSH / LH be directly used to induce ovulation? Describe the regimen.
FSH - give once daily during follicular phase
LH - normal surge will be inhibited due to negative feedback from FSH inducing estrogen. Thus, give hCG (mimics LH) roughly 36 hours before you want to ovulation.
complications include ovarian hyperstimulation syndrome: ascites and increased capillary permeability
131
What are the three primary androgen drugs? Adverse effect of concern and how can it be avoided
1. Testosterone salts - long IM release
2. Methyltestosterone
3. Fluoxymesterone
Adverse effect: hepatotoxicity if given orally -> recommend using patch, gel, on buccal mucosa, or subcutaneous pellet
132
What is Danazol and what is it used for?
An ethinyl derivative of testosterone -> Weak androgen agonist and inhibitor of midcycle surge of FSH / LH.
Used in treatment of ENDOMETRIOSIS
Dana smith constantly on her period and bitchy, bleeding from her vagina
can cause pseudotumor cerebri + hepatotoxicity
133
Give two non-steroidal androgen receptor antagonists used in the treatment of prostate cancer. Which one has the better side effect profile? What are they given in combination with?
Flutamide (playing a flute is anti-manly)
Bicalutamide (less hepatotoxic than flutamide)
Give in combination with GnRH agonist (i.e. leuprolide)
134
What is the mechanism of action of abiraterone and what is it used for? What should it be given in combination with?
Inhibits testosterone synthesis by inhibiting CYP17A1 (17alpha hydroxylase), an enzyme needed to make androgens from progestins
Used for treatment of castration-resistant prostate cancer
Give in combination with prednisone
135
Describe the mechanism of the symptoms seen in severe insulin insensitivity (Type 2) or insulin deficiency (Type 1)?
Unopposed glucagon -> hyperglycemia, proteolysis for gluconeogenesis
Hyperglycemia -> increased plasma osmolality -> polydipsia
Hyperglycemia -> osmotic diuresis (exceed tubular maximum) -> polyuria and hypovolemia -> dehydration
Proteolysis and weight loss -> polyphagia
136
What are the consequences of the large vessel non-enzymatic glycation in diabetes? What is the most common cause of death in diabetes?
Atherosclerosis - most important, increases strokes and MIs
Coronary artery disease
Peripheral vascular occlusive disease with gangrene -> common cause of limb amputations
Most common cause of death in diabetes is MI
137
What is the glucose tolerance test and what is diagnostic for diabetes?
Give the patient 75g of glucose in water
If glucose is >200 mg/dL 2 hours after consumption, patient has diabetes
Same as random plasma glucose
138
What are the signs and symptoms of DKA?
DKA is Deadly
D - delirium / psychosis (from decreased brain perfusion due to hypovolemia)
K - Kussmaul respirations - deep / rapid breathing
A - abdominal pain, nausea / vomiting
D - Dehydration
Fruity odor can be smelled on breath due to exhaled acetone
139
How does maternal diabetes occur? When does it occur?
Human placental lactogen normally also stimulates an increase in insulin levels in the mother, to prevent diabetes. If the pancreatic beta cells cannot produce sufficient levels of insulin, maternal diabetes mellitus occurs
Occurs during 2nd or 3rd trimester, usually during the first pregnancy
140
What are the possible fetal consequences of uncontrolled maternal diabetes?
Fetal anomalies due to hyperglycemia-induced oxidative stress.
1. Heart - transposition of the great arteries, ASD / VSD
2. CNS - neural tube defects
3. Large for gestational age (macrosomia)
4. Intrauterine growth retardation (if there is placental insufficiency due to vascular disease)
5. Caudal regression syndrome
141
What are the two pathways through which insulin signals? Which one is impeded vs not in Type 2 diabetes and what does this explain?
1. MAPK pathway - cell growth and proliferation pathway - not affected in Type 2 diabetes -> explains why Type 2 diabetes is associated with higher cancer risks
2. PI3K signalling - glucose import and glycogen / protein / lipid synthesis pathway - affected in Type 2 diabetes
142
What antibodies are often positive in Type 1 diabetes?
1. Anti-islet cell antibodies
2. Anti-insulin antibodies
3. Anti-glutamic acid decarboxylase antibodies
143
When do risk of macrovascular vs microvascular complications onset in diabetes?
Macrovascular - with impaired glucose tolerance, as in prediabetes (reason for increased cardiovascular effects)
Microvascular - when glucose levels start rising (postprandial spikes first) -> reason why diabetes brings out microvascular changes
144
What are the meglitinides? What is their claim to fame?
Repaglinide
Nateglinide
"Nate be Rapping cuz he so fly"
- > non-sulfa drug sulfonylureas, but more short-acting.
- > think of the goose "gliding" / flying in the air
145
What are the adverse effects of metformin use and who is it contraindicated in?
GI disturbances -> dose-related, especially at start of therapy -> girl about to puke
Lactic acidosis (from decreased usage of lactate in gluconeogenesis)
-> avoid in renal insufficiency (Decreased clearance of metformin, not metabolized hepatically)
Spilled milk in broken kidney tray
Also avoid in liver disease, or alcoholics
146
What drug is a DPP-4 inhibitor, and what is its primary benefit over the GLP-1 homologs? What is its main side effect?
Sitagliptin (Januvia)
- think of the gliptin clips (4 clips for DPP-4)
Can be taken orally, does not show GI disturbances.
However, no associated weight loss :/
Side effect: upper respiratory tract infections (think of the clothespin on the lady's nose)
147
What are the clinical uses / benefits of SGLT2 inhibitors?
Taken orally, modest HbA1c reduction in combination with metformin.
Also reduces CVD outcomes and may promote weight loss due to excretion of glucose
148
```
Tell me if the following classes of drugs have demonstrable cardiovascular benefits or harms?
Metformin:
GLP1:
SGLT2:
DPP4:
TZDs:
```
```
Metformin: Definite benefit
GLP1: Definite benefit (weight loss)
SGLT2: Benefit
DPP4 (gliptins): Neutral (possible increase in HF exacerbations)
TZDs (glitazones): Harm (heart failure)
```
149
What will happen to the bones and the reproductive system in women in thyrotoxicosis? Muscle mass?
Bones - osteoporosis due to excessive bone turnover
Reproductive - oligomenorrhea (light periods, irregular)
Muscle mass is decreased due to need for gluconeogenesis -> can lead to proximal myopathy
150
What is the pathogenesis of Hashimoto's thyroiditis? What antibodies are present and are they the cause of disease?
Sensitization of autoreactive CD4+ cells to thyroid antigens, causing activation of immune system.
CD8 T cells -> perforin/granzymes / Fas pathways.
Cytokine-mediated -> macrophage activation via IFNy
Antibody-dependent cell-mediated cytotoxicity via NK cells -> probable minor role of antibodies, more of a marker.
1. Antithyroglobulin antibodies
2. Anti-thyroperoxidase antibodies
151
How does someone with Hashimoto's initially present / what does it devolve into? Is it tender or painless?
Present with transient thyrotoxicosis due to inflammatory cell lysis, but eventually hypothyroidism will occur
The gland will be PAINLESS since the enlargement / inflammation isn't that acute
Remember Hurthle cell change and lymphoid aggregates
152
What is the pathogenesis of Subacute Granulomatous Thyroiditis and what is it also called?
Also called De Quervain thyroiditis
```
Pathogenesis: Viral infection -> antigen-induced, CD8 T-cell mediated injury to thyroid follicular cells
-> It is a type of infectious thyroiditis, but we put it in its own class because of its unique histology
```
de QuerVAIN = PAIN
granulomas forming around colloid
153
What can you confuse Riedel thyroiditis with and why? How does it present?
Simulates an invasive neoplasm such as anaplastic carcinoma since it invades surrounding structures with fibrosis
Presents as a "hard as wood" / rock hard PAINLESS goiter, some may be hypothyroid. But patients are generally too young to have anaplastic carcinoma and there are no malignant cells on biopsy.
154
Who tends to get Graves' disease and what HLA markers make you more susceptible to it?
Tends to occur in women of childbearing age (younger than Hashimoto's)
Associated with HLA-DR3 and HLA-B8. Think of a mnemonic you fker. (3-88?)
Also associated with CTLA4 gene variants (loss of lymphocytic immune tolerance)
155
What is the true definition of a goiter?
A goiter is a process by which impaired thyroid hormone synthesis leads to increased TSH secretion and thus thyroid follicular hyperplasia. It does not refer to Hashimoto's or graves' which is a "goitrous enlargement" where the thyroid is enlarging due to a pathologic process (i.e. inflammatory infiltrate, or nonstop stimulation of thyroid release)
156
What is the spectrum in which true goiter which it exists in? What is meant by "toxic"?
Starts as a Diffuse, nontoxic goiter (i.e. patient remains euthyroid), but may progress overtime to a multinodular goiter with multiple hypertrophied nodules producing thyroid hormone.
Thyroid nodules become "toxic" when they become TSH-independent and start secreting T3/T4 without TSH stimulation
157
What is hot nodule vs a cold nodule? Which one is more likely malignant?
Based on the amount of radioactive iodine uptake. Hot = lots of uptake.
As just explained, hot nodules as in a goiter or Graves disease (more diffuse) are usually benign.
"Cold" nodules, or low uptake, are usually benign as well, but warrant biopsy. These ones can be malignant.
158
What two types of thyroid carcinoma are associated with RET mutations. Which one is associated with an MEN, and what cell is it derived from?
1. Papillary carcinoma - associatied with RET fusion protein
2. Medullary carcinoma of thyroid (Parafollicular / C cell derivation) - associated with RET mutation, in MEN2A and MEN2B syndromes.
159
What are the three types of thyroid carcinoma derived from follicular cells, which one is most common, and what mutations are associated with them?
1. Papillary carcinoma - most common, associated with RET mutation
- > ionizing radiation in childhood, psamMOMA bodies
- > Papi and Moma with those Orphan annie eyes
2. Follicular carcinoma - associated with RAS mutations. Similar to follicular adenoma.
- > iodine deficiency
3. Anaplastic carcinoma - no mutation in particular
160
Other than salt and pepper chromatin, what else can be seen histologically on examination of a medullary thyroid carcinoma?
Amyloidosis -> due to accumulated AE amyloid derived from calcitonin.
Usually happens as a single mass (sporadic), may be multiple in MEN2
161
What things can increase and decresae the amount of TBG?
Increase - pregnancy and oral contraceptives (estrogen increases TBG)
Decrease - hepatic failure, androgens (decreased synthesis with testosterones or decreased protein synthesis. Think men getting super hyped up)
162
What are two common causes of iodine excess, and what physiologic effect do they cause?
1. Amiodarone (lots of iodine in structure)
2. Iodine in contrast agents
High levels of iodine temporarily inhibit thyroperoxidase, decreasing organification of iodine and thus its production
-> this is called the Wolff-Chaikoff effect
163
What is it called if an iodine load induces hyperthyroidism and who can this happen in?
Jod-Basedow effect, can be viewed as the opposite of Wolff-Chaikoff effect.
This cannot happen to individuals with normal thyroids
-> usually occurs in patients who have had longterm iodine deficiency
or
-> can be seen in individuals with partially autonomous thyroid tissue (i.e. toxic goiter or Graves' disease)
164
Give two situations in which measuring serum thyroglobulin might be useful.
1. Thyroiditis - indicates escape of thyroglobulin from damaged gland
2. Thyroid cancer - when gland is surgically removed, and rise in serum thyroglobulin will be a since of cancer recurrence.
165
What test is useful in differentiating between Graves' disease causing hyperthyroidism vs subacute thyroiditis causing hyperthyroidism?
24 hour radioiodine uptake test
- > uptake will be increased in Graves' disease and TSH producing tumors
- > uptake will be decreased in thyroiditis causes of hyperthyroidism since TSH levels will be low.
166
What is acropachy and what condition is it associated with?
Finger clubbing - perostitis of the fingers
Soft tissue swelling of the hands
Acropachy = "distal thickness" like pachymeninges = dura,
Associated with Graves disease -> one of the distinctive findings due to overstimulation of TSH receptors by TSI antibodies
167
What are the usual causes of Thyroid storm?
1. Untreated / undertreated hyperthyroidism
+
2. Infection (lowers transthyretin levels), trauma (breaks cells open), or surgery (breaks cells open)
168
What is Sick Euthyroid Syndrome also called and what is the pathogenesis?
"Nonthyroidal illness"
During a serious illness, there is decreased peripheral conversion of T4 to t3, and rT3 is favored.
Body does this to conserve energy during illness -> no true underlying thyroid issue which needs to be treated
169
When should you take levothyroxine and what should you avoid taking at the same time?
Take at least 30-60 minutes before breakfast, or 4 hours after the last meal
- > need to not interfere with its absorption
- > avoid iron-containing products, calcium-containing products which avidly bind thyroxine and reduce absorption
170
What drugs interact with levothyroxine concentrations overall?
Estrogens -> increase TBG
CYP Enzyme inducers -> increase clearance
Resin binders -> i.e. cholestyramine
Aluminum-containing compounds -> Aluminum hydroxide, sucralfate
171
What should one do if PTU or MMI causes hepatotoxicity, agranulocytosis, or benign transient leukopenia (WBC<4000)?
Hepatotoxicity - don't switch to the other agent! they are cross-reactive
Agranulocytosis - don't switch to the other agent! they are cross-reactive
Benign transient leukopenia - no one cares, continue onward
172
What is the mechanism of action of Radioactive iodine and what are the contraindications?
Mechanism: Disrupts hormone synthesis, causes cellular necrosis and follicular breakdown
-> generally only need one treatment, can repeat at 6 months
Contraindications: pregnancy (hypothyroid of fetus), breastfeeding, children
173
How does ionized calcium concentration change with pH?
Alkalosis -> albumin is deprotonated, exposing negative charges -> calcium binds albumin more avidly -> hypocalcemia
Acidosis -> opposite -> hypercalcemia
174
How do you tell if a patient is hypercalcemic or hypocalcemic depending on albumin changes?
Use this formula:
"Corrected" Total Calcium = Measured Total Ca + 0.8 (4 - measured albumin)
Calcium in mg/dL
Albumin in g/dL
-> basically it's giving you the total calcium equivalent @ normal albumin which would generate the free calcium the patient is seeing based on their albumin levels.
175
What are primary, secondary, and tertiary hyper-PTH usually caused by? (not all of these will be associated with elevated serum calcium levels)
Primary - Usually parathyroid adenoma or hyperplasia, less commonly parathyroidism carcinoma.
Secondary - due to hypocalcemia, i.e. renal failure
Tertiary - autonomous hyperparathyroidism from renal disease (nodule becomes autonomous from longstanding secondary)
176
Why does hypercalcemia tend to make hypercalcemia worse? What medication can make this worse?
Polyuria leads to ECF volume depletion -> more Na+ and hence Ca+2 resorption in the proximal tubule
Made even worse by thiazide diuretics -> decrease renal calcium excretion
177
What are the causes of primary hyperparathyroidism and what will the glands look like in the two most common cases?
Parathyroid adenoma - 80% of cases. Single enlarged nodule / one gland enlarged gland, with other three atrophied due to lack of activity
Parathyroid hyperplasia - all four glands are enlarged -> 20% of cases
Parathyroid carcinoma
178
What are causes of hypoparathyroidism?
1. Surgical - most common, after total thyroidectomy
2. Autoimmune
3. Idiopathic / genetic -> activating mutation of CaSR, or DiGeorge (lack of pouch 3/4)
4. Infiltration of gland -> iron overload, malignancy
5. Hypomagnesemia - known cause of low PTH
6. Pseudohypoparathyroidism
179
What is the cause of pseudohypoparathyroidism type 1A and what is the name of the phenotype?
Autosomal dominant defect in Gs protein alpha-subunit -> end-organ resistance to PTH.
Defect must be inherited by MOTHER due to imprinting
Phenotype: Albright hereditary osteodystrophy
PTH levels high in pseudohypoPT 1A, normal in pseudopseudohypoparathyroidism
180
What lab values characterize secondary hyperparathyroidism and what are some causes?
Low serum calcium with high PTH
1. Chronic Kidney Disease - most common
2. Vitamin D deficiency
3. Malabsorption of calcium
4. PTH resistance - pseudohypoparathyroidism
181
How is FGF23 degraded and why is this clinically relevant? What is the inheritance pattern?
PHEX protein, inherited via X-chromosome.
Dominant mutation that causes resistance of FGF23 to degration -> increased phosphate wasting -> X-linked hypophosphatemic rickets
pg. 55 of first aid
Autosomal dominant hypophosphatemic rickets is a mutation in FGF23 which makes it resistant to degradation by PHEX
182
What are the symptoms of hypophosphatemia?
Severe muscle weakness due to decreased ATP synthesis -> may cause paralysis and rhabdomyolysis
Hemolysis -> RBCs require ATP to maintain membrane integrity
Bone pain and osteomalacia (hypophosphatemic rickets)
183
What are the causes of hypophosphatemia?
1. Vitamin D deficiency or resistance
2. Primary hyperparathyroidism or hypercalcemia of malignancy -> increased phosphate wasting
3. Alkalosis -> activates PFK-1 to increase lactic acid production thru glycolysis
4. Excess FGF23
5. Insulin therapy of DKA
6. Refeeding syndrome
184
What is the general underlying pathophys of Paget disease of bone and does it happen everywhere or is it focal? Include the phases of disease.
Imbalance between osteoclast and osteoblast function -> a localized rather than systemic disease.
1. Lytic phase - osteoclasts overwork without the permission of osteoblasts
2. Mixed phase - osteoblasts begin working to rebuild bone ASAP
3. Sclerotic - osteoclasts stop, but blasts keep building and cause bone overgrowth of poor quality
worst in skull, pelvis, and long bones
185
What pattern can be seen in lamellar bone in Paget disease, histologically and on X-ray?
Histology: Mosiac or puzzle piece pattern of bone with cement lines not having been sealed properly
X-ray: Thick, sclerotic bone which fractures easily
high output cardiac failure (AV malformations in bone) and increased risk of sarcoma
186
What are common presenting symptoms of Paget disease? One of these is a lab value.
1. Increasing hat size with lion-like faces -> craniofacial involvement
2. Hearing loss -> impingement on cranial nerve + auditory foramen narrowing + damage to ossicles themselves sometimes
3. Bone pain due to microfractures
4. Isolated elevated alkaline phosphatase (no other labs abnormal).
treat w/ bisphosphonates and calcitonin early in dz course
187
What is the cause of tumor induced osteomalacia?
FGF23 secreting tumor -> paraneoplastic syndrome of renal phosphate wasting and decreased vitamin D levels.
188
What are the clinical features associated with osteogenesis imperfecta? What might it be confused with?
BITE
B = Bones - multiple fractures
I = Eye -> blue sclera from choroidal veins showing (translucent connective tissue)
T = Teeth, - abnormal dentin
E = Ears- hearing loss, due to abnormal ossicles
Confused with child abuse -> look for ITE signs
189
What are the clinical features of osteopetrosis?
Petrosis = hardening, loss of osteoclasts
1. Easy fractures
2. Bone fills the marrow space -> pancytopenia, extramedullary hematopoesis "myelophthisic process"
3. Vision / hearing impairment -> impingement of cranial nerves from thickening of skull
4. Hydrocephalus - foramen magnum narrowing
5. Poor teeth eruption
190
What is the most common enzyme deficiency underlying osteopetrosis and what other symptom is associated with this variant?
Carbonic anhydrase II deficiency (also used in proximal tubule)
-> needed for acid environment of Howship's lacunae
Associated with a Type II (Proximal) renal tubular acidosis
191
What enzyme is deficient in hypophosphatasia? Why does this matter?
Tissue nonspecific alkaline phosphatase (TNSALP)
TNSALP is required to cleave inorganic pyrophosphate and PLP (B6) outside of cells.
If inorganic pyrophosphate is not cleaved -> accumulation inhibits hydroxyapatite -> osteomalacia
If PLP is not cleaved -> B6 cannot enter cells -> severe CNS neurotransmitter deficits
192
What is the cause of autosomal dominant osteopetrosis type 1 (ADO1)? I'll give you a hint: he's obsessed with this pathway from earlier in the lecture.
LRP5 activating mutation -> activates the Wnt pathway, makes it immune to inactivation by interaction with sclerostin.
Dense skull base
Wide jaw
Torus palatinus -> bone growth of palate
193
What is the insulin-induced hypoglycemia test used for? How does it work?
Used for testing for secondary adrenal insufficiency
-> insulin dropping your blood sugar to below 40 mg/dL should naturally trigger release of growth hormone and ACTH (so cortisol can raise your blood sugar)
194
What is the definition of adrenal insufficiency? How do you differentiate primary from secondary clinically?
Deficiency in cortisol secretion (no other hormones matter, though they may be deficient)
Primary - ACTH levels will be high, and will not respond to cosyntropin or insulin-induced hypoglycemia
Secondary - ACTH levels will be low, cortex will respond to cosyntropin so long as the gland has not atrophied yet
195
What symptoms are specific to Addison's disease vs secondary adrenal insufficiency?
1. Hyperpigmentation- Overproduction ACTH due to lack of negative feedback from primary issue
2. Salt craving and hyperkalemia - Addison's disease only, as zona glomerulosa will also not be working. In secondary, zona glomerulosa is intact and functioning normal (does not require ACTH)
196
What are the top two causes of Addison's disease?
1. Autoimmune destruction (of adrenal gland)-> most common in Western world
2. Tuberculosis -> most common in developing world
197
What is the metyrapone stimulation test? What is normal / abnormal.
Test blocking the last step of cortisol synthesis -> 11-deoxycortisol to cortisol.
It's basically a test to see if decreased cortisol will stimulate a response from pituitary and whether it's transmitted into increased products via HPA axis.
198
What is the most common cause of congenital adrenal hyperplasia? What accumulates / what is decreased in it?
21-hydroxylase deficiency, enzyme which catalyzes the conversion of 17-OH-progesterone and progesterone to aldosterone and cortisol precursors.
Accumulates: DHEA / androstenedione (androgens) + 17-OH progesterone
Decreased: Cortisol / aldosterone
Appears like Addison's disease + virilization
199
What is the second most common cause of CAH, and what accumulates / is underproduced?
11-beta-hydroxylase deficiency
-> similar to metyrapone testing
11-deoxycortisol accumulates -> decreased cortisol synthesis
11-deoxycorticosterone accumulates (precursor to aldosterone), but is actually a mineralocorticoid
Some level of excess androgen is also present due to shunting away from cortisol pathway
200
What accumulates or is decreased in 17a-hydroxylase deficiency? Will aldosterone be increased?
Inability to make 17-OH-progesterones, so all is shunted into mineralocorticoid pathway
Accumulates: 11-deoxycorticosterone, mineralocorticoid. Aldosterone not increased because aldosterone synthase under control of angiotensin II
Decreased: cortisol / androgens
Males ambiguous genitalia, females normal at birth but lack puberty
201
What test is run at newborn screening to check for congenital adrenal hyperplasia? How will they be changed in the three major conditions?
17-hydroxyprogesterone levels
21-hydroxylase: increased
11beta-hydroxylase: increased
17alpha-hydroxylase: decreased
