Endocrinology (Clinical Review Q's) Flashcards
What would hyponatremia with an absence of edema indicate?
SIADH
low plasma sodium w no edema
What might darkening skin/ hyperpigmentation indicate?
High levels of ACTH
How can one shut down hormone production rapidly in hyperthyroid patients?
Clinically: very high iodide doses are used to rapidly shut down thyroid hormone production in hyperthyroid patients
If you see a rise in hormones that are secreted by the pituitary what could this mean?
lung cell carcinoma- secretes hormones that would normally be secreted by pituitary and causes all sorts of endocrine problems
or pituitary tumor?
Match disease to symptom…
postpartum hemorrhage/shock; results in massive pituitary cell death.
Trauma/Stress (endocrine pathology)
Sheehan’s Syndrome – postpartum hemorrhage/shock; results in massive pituitary cell death
What is Kallman Syndrome?
Rare genetic disease (1:8000 men/1:40,000 women)
GnRH neurons fail to enter CNS
Characterized by reproductive failure and anosmia
Heritable: X-linked = Kal1, autosomal = Kal2
What could a patient being treated with Lithium for bipolar disease experience? How/why?
DIABETES INSIPIDUS
Decreased renal responsiveness to AVP
Acquired: lithium treatment
also can have decreased renal responsiveness- most common reason in adults is acquired (lithium treatment prescribed for bipolar disease, enters through epithelial sodium channels but cant get out so accumulates inside cell and interferes w AVP abiity to traffic AQP2 channels) accumulation inside cell may either decrease AQP2 synthesis or increase lysosomal degradation of these channels
(Lithium can also inhibit NIS symporter in follicular epithelial cell)
What will AVP levels be in a case of acquired diabetes insipidus?
Describe differential diagnosis.
-AVP levels typically normal bc thirst mech. can compenstate for changes in plasma osmolality
(differential diagnosis- alter plasma osmolality and see what happens through water restriction)
What is the effect of treating someone with carbenoxolone?
What does carbimazole do?
Certain drugs (carbenoxolone) will inhibit 11B-HSD2 resulting in excess MR activation.
Carbenoxolone used to treat esophogeal inflammation – increases local cortisol
Carbimazole – inhibits thyroid peroxidase (TPO) -treatment for thyroid storm!
What might happen if someone eats too much licorice? (real licorice/glycyrrhetinic acid)
Licorice (glycyrrhetinic acid) also inhibits 11B-HSD2 – excessive consumption can lead to increased sodium and water retention.
Why might you target 11B-HSD1 for drug therapy for DM T2?
Local production of Cortisol by 11B-HSD1 potential pathogenic role in DM T2 – novel drug target
target enzyme bc idea is local prod. of cortisol esp in abdomen can contribute to obesity and type II Diabetes. so potential drug target
What will a 21alpha hydroxylase deficiency lead to? Why?
What are some clinical indications?
Congenital Adrenal Hyperplasia (CAH)
21 alpha hydroxylase deficiency - results in excess DHEA, no mineralocorticoids or glucocorticoids
Most common cause of CAH
Clinical indications: virilization (masculinization) ambiguous genitalia at birth, sodium loss
No cortisol
No aldosterone/MR activity
Increased androgens
Clinical presentation: Hypotension Hyperkalemia High plasma renin Masculinization High ACTH
What are pheochromocytes?
What are pheochromocytomas?
chromaffin cells of adrenal medulla
Pheochromocytomas – tumors originating from chromaffin cells.
Pheochromocytomas: the 10% tumor
What can vanillylmandelic acid levels be used to indicate clinically?
can be used to clinically detect tumors prod. excess EPI or NE.
What could hypertension (no response to medication), headaches, and tachycardia indicate?
Diagnosis? What tests?
Treatment?
Pheochromocytomas – tumors originating from chromaffin cells.
Diagnosis: measurements of urinary metanephrines
Treatment: surgery, pre-surgery: alpha/beta blockers.
What could opthalmopathy- edema behind eyes, and tachycardia indicate?
Graves disease -
Autoimmune – antibodies (Long-acting thyroid stimulator - LATS)
stimulate TSH receptor
- Elevated T4/T3
- Diffuse symmetrical goiters with hyperthyroid symptoms: tachycardia,
opthalmopathy, irritability, hyperactivity, heat intolerance, weight loss,
nervousness, muscle wasting
Histology of thyroid gland from patient with Graves Disease. Note:
scant colloid, tall columnar activated follicular cells, and infiltration of
lymphocytes.
tachycardia- effects of thyroid hormone on heart med. those catecholamine effects
get opthalmopathy- edema behind eyes (defects in carbohydrate metabolism..buildup of polysaccharides in interstitial space which retains water… so these individual easy to spot bc looks like eyes bulging out of heads)
Diffuse goiter with hypothyroid symptoms: lethargy, fatigue, hair loss, cold intolerance, brittle nails decreased appetite, weight gain.
Hashimotos Thyroiditis
Autoimmune destruction of thyroid follicles
Antibodies against TPO, TG
Symptoms:
High fever Tachycardia Altered mental status Severe nausea, vomiting, diarrhea Severe circulatory collapse
What is diagnosis? How to treat?
CLINICAL DISORDERS – THYROID STORM
Emergency life threatening situation
Hyperthyroid coupled with severe acute illness
-normal hyperthyroid response … coupled w that massive up regulation of stress response, catecholamines v high…
can result in severe circulatory collapse bc all vessels dilate and body tries to perfuse all tissues at once, we don’t have enough blood to perfuse all tissues at once and circulatory system will eventually collapse
Treatment:
Propylthiouracil (PTU – only acute treatment)
Carbimazole (methimazole)
Beta blockers to restore normal heart function
PTU-treatment …will block thyroid peroxidase (TPO)…stop making thyroid hormone (some liver toxicity issues so not given long term)
carbimazole- given to inhibit TPO in hyperthyroid patients and give beta blockers.
What is Kussmaul breathing?
What might this indicate in a patient? What type of diabetes?
Would labs show high or low PCO2?
deep rapid breathing
respiratory compenstaion in response to decreased bicarb and increased CO2
Low PCO2
Why is the blood pressure low and the pulse rate high (T1DM)?
Dehydration – vomiting, osmotic diuresis results in low BP
Decreased baroreceptor firing (less stretch due to low blood flow) induces tachycardia.
What is Sheehan’s Syndrome?
Sheehan’s Syndrome – postpartum hemorrhage/shock; results in massive pituitary cell death
Usually affects other pituitary cell types – loss of axillary and pubic hair
(progesterone will increase blood volume in preg. to anticipate possible hemorrhage… )
What type of therapy for Crohn’s disease?
Glucocorticoid therapy
Describe Euthyroid sick syndrome.
Hypothyroid symptoms with low T4/T3
Normal TSH and thyroid
What is Laron Syndrome?
GH Deficiency
Dwarfism (children): related to GH
Laron Syndrome –
genetic defect in GH receptor – no production of IGF-I. Treatment with IGF-I can prevent dwarfism
Plasma GH levels are normal to high (lack of feedback).
What is African Pygmy?
African Pygmy
Partial defect in GH receptor – some IGF-I response.
Plasma levels of GH normal – no pubertal increase in IGF-I.
What would you see in adult GH deficiency?
What would this person be at risk for?
Caused by pituitary tumor/surgery or treatment (76%)
Increased fat deposition, muscle wasting
Reduced bone density, risk of fractures
Higher LDL, Triglicerides
What is Addison’s disease?
Failure of adrenal to secrete glucocorticoids, mineralocorticoids, or both.
Primary – failure at adrenal
Addison’s Disease = autoimmune destruction of adrenals
70% of primary AI cases
What is the Wolf-Chaikoff Effect?
WOLF-CHAIKOFF EFFECT: An intrathyroidal response that assures constancy of iodide storage in the face of changes in dietary iodide
Increases in iodide intake decrease gland transport (solid line) and hormone synthesis (dashed line), and vice-versa
Clinically: very high iodide doses are used to rapidly shut down thyroid hormone production in hyperthyroid patients
this can be clinically useful in person w crisis… can shut down thyroid gland temporarily by overdosing w a lot of iodide.
What is pertechnate? What is its significance?
What is perchlorate? What is it used for?
Radioactive iodide (131I, 123I) and anions like pertechnetate (TcO4) can be transported by NIS
Used to determine function of thyroid gland
Organification defect - iodine cannot be incorporated into tyrosine. Test by blocking NIS with inhibitor (i.e. perchlorate)
How will the following affect TBG levels?
Hepatitis
Steroids
Estrogen
Nephrotic syndrome
Estrogen, hepatitis increase TBG; nephrotic syndrome, steroids decrease TBG = no net change in “free” T4/T3.
What is Grave’s Disease?
Autoimmune – antibodies stimulate TSH receptor (Long Acting-Thyroid Stimulator – LATS)
Elevated T4/T3
Diffuse symmetrical goiters with hyperthyroid symptoms: tachycardia, opthalmopathy, irritability, hyperactivity, heat intolerance, weight loss, nervousness, muscle wasting
What is Hashimotos Thyroiditis?
Autoimmune destruction of thyroid follicles
Antibodies against TPO, TG
Diffuse goiter with hypothyroid symptoms: lethargy, fatigue, hair loss, cold intolerance, brittle nails decreased appetite, weight gain
now these antibodies are against TPO
if you don’t have TPO now you have organification defect, conjugation doesn’t happen, cant convert iodide to iodine (TPO does all those things)
If you found a bladder tumor and the patient also had hypercalemia, what conclusion might be appropriate?
Many tumors produce PTHrP (renal, bladder, lymphoma, head/neck) resulting in hypercalcemia
more importantly than binding, this activates the same intracellular signaling pathways as PTH. so if you have a tumor secreting PTHrP you will have all same effects as if you had high levels of PTH.
Deficiency linked to: Multiple Sclerosis Asthma Cardiovascular disease Type II Diabetes mellitus Colorectal/breast cancer Major Depressive Disorder (MDD)
What is deficient?
Vitamin D
Reduced bone density – mainly trabecular bone
Causes: genetic, menopause (low estrogen), glucocorticoid therapy/chronic stress, low dietary Ca2+
What is diagnosis and how is it treated?
Osteoporosis
Treatment: estrogens, calcitonin, bisphosphonates (inhibit bone resorption), Vitamin D
What could chronic renal failure lead to?
Patient has hypercalcemia and kindey stones.
(Primary and secondary causes)
Hyperparathyroidism
Primary: hyperplasia, carcinoma of parathyroid gland
Hypercalcemia, kidney stones
Secondary: due to chronic renal failure
Reduced Vitamin D leads to excess PTH synthesis
What would the following indicate?
Chvostek sign: twitching of facial muscles in response to tapping of facial nerve
Hypoparathyroidism
Hypocalcemic tetany
What would a Vitamin D deficiency in children and adults lead to?
Rickets (children)/Osteomalacia (adults)
Unmineralized bone due to Vitamin D deficiency
“bowing” of long bones (children)
Decreased bone strength
What is the following? Describe.
Clinical signs: low Ca++, high phosphate, elevated PTH, short stature
Pseudohypoparathyroidism
Congenital defect in G protein that associates with PTHR1
Clinical signs: low Ca++, high phosphate, elevated PTH, short stature
Generalized resistance to PTH, TSH, LH, and FSH
What would urinary hydroxyproline indicate?
Urinary hydroxyproline = enhanced bone resorption
Name the following disease. How is it treated?
Excessive localized regions of bone resorption and reactive sclerosis.
Very high bone turnover
Cause is unknown.
Paget disease
CALCITONIN
Therapeutic use: inhibits osteoclast reabsorption of and slows bone turnover (net effect = hypocalcemic action).
“Escape” phenomenon – rapid downregulation of calcitonin receptors cause the antiosteoclastic actions of calcitonin to diminish within a few hours making this a less effective treatment option.
What can PCBs (Polychlorinated biphenyl) cause? Why?
PCBs compete with thyroid hormone binding to its transport protein in the blood (TTR; TBG)
Result:
Increased breakdown of thyroid hormone
Compensatory excessive production by thyroid gland
Goiter (enlarged thyroid gland)
Also causes cancer, immune function suppression (atrophied thymus), reduced sperm count, neurological deficits
What chemical was later found to cause a 40% increase in cervical/vaginal cancers of daughters whose mothers were treated?
Diethylstilbestrol (DES)
Non-steroidal synthetic estrogen
Used in cattle feed
Given to pregnant women from 1940-1970 to reduce complications
Also used for prostate cancer treatment
“DES daughters” = 40% increase in cervical/vaginal cancers
Which chemical is an agonist for thyroid hormone receptor?
BPA
Physiological Consequences:
Estrogenic
Obesogenic and diabetogenic (alters lipid homeostasis and pancreatic beta cell function)
Neurological effects
Antagonist for thyroid hormone receptor
Reproductive and developmental effects (male and female)
Cardiovascular disease – evidence for arrhythmias and atherosclerosis
Change in body fat distribution – moon face, buffalo hump, abdominal obesity, thin skin, bruising
Other symptoms? Disease?
Inhibition of intestinal calcium absorption – osteoporosis
Hypertension – excess glucocorticoids activate MR
Glucose intolerant – antagonism of insulin action
Purple Striae – Fragile thin skin stretches over increased abdominal fat, vessels hemorrhage into striae
**Also occurs with long-term glucocorticoid therapy
“Cushing disease” – excessive cortisol secretion due to pituitary adenoma
“Cushing syndrome” – all others
How might you treat an insulin-producing tumor?
Somatostatin (SS14) –
Inhibited by insulin
Suppresses insulin release - used in clinic for management of insulin-producing tumors
What is POMC a gene for?
ACTH – ADRENOCORTICOTROPIN HORMONE
Precursor = POMC (pro-opiomelanocortin)
(CRH prod. in PVN stimulates POMC in ant. pituitary to releas ACTH)
also alphaMSH is cleaved from POMC which is an inhibotr of appetite and is stimulated by leptin
Describe the factors Leptin stimulates and inhibits.
Stimulators
Neuropeptide Y (both are neurons in hypothalamus)
Agouti-Related Peptide (AGRP)
**Leptin inhibits these causing decreased food intake
Inhibitors
αMSH – cleaved from POMC
Cocaine-amphetamine regulated transcript (CART)
**Leptin stimulates these decreasing food intak
What would Elevated HbA1C: greater or equal to 48mMol/l (6.5%) indicate?
T2DM
How does metformin treat T2DM?
Sulonyureas? “Glyburide”, “Glipizide”
Alpha-glucosidase inhibitors “Precose” “Glyset”
metformin- Inhibits hepatic gluconeogenesis
Increases insulin receptor activity making cells more sensitive to insulin, increased glucose uptake
Sulfonylureas – “Glyburide”, “Glipizide”
Close ATP-dependent K+ channels in beta cells causing insulin release
Alpha-glucosidase inhibitors “Precose” “Glyset”
Delays intestinal absorption of carbohydrates- in T2DM is first phase secretion dampened, these alpha slow things down to allow for beta cells to catch up
What does amylin do?
Amylin –
Released with insulin from vesicles in beta cells
Synergistic with insulin in regulation of blood glucose
Circulating amylin increased in obesity, hypertension
Possibly contributes to beta cell destruction by forming amyloid
What are PDX-1 and TCF72 and Neurogenin 3?
PDX-1 important for both islet neogenesis and beta cell proliferation
TCF72 downstream targets regulate beta cell proliferation
Neurogenin 3 = key for endocrine cell development
ISLET CELL DEVELOPMENT
What is hirutism?
What is gynecomastia?
hiruitism- male patterned hair growth
gynecomastia- enlarged breast tissue
Are there oogonia present at birth?
What is the diplone stage part of?
No oogonia are present at birth – all converted to primary oocytes or subject to atresia
Arrest due to oocyte maturation inhibitor (OMI) = small peptide secreted by follicular cells
diplotene stage is part of prophase
(arrest in diplotene phase as a primary oocyte)
Patient has very short stature,
“shield” chest, webbed neck, and upper torso deformities. Does not go through puberty or have menstrual cycles.
Name disease and karyotype.
45, XO KARYOTYPE “gonadal dysgenesis”
Turner’s syndrome.
Both X chromosomes are required during development for oogonia. Ovary becomes a “streak” = fibrous tissue
Systemic phenotypic issues due to aneuploidy
Karyotype for Kleinfelters?
Klinefelter Syndrome 47, XXY
Y chromosome: testes present (small, hyalinated); infertile
Testosterone is low (due to testicular dysfunction), micropenis
Eunuchoid body: lower segment > upper segment by more than 2”; short arms
Gynecomastia – elevated estradiol
Systemic phenotypic issues due to aneuploidy
often testis not descended… small development of external genitalia (due to lack of DHT) DHT low bc testosterone is low
testosterone tends to be converted to estradiol so get breast development and lots of systemic problems bc of anepleudy
Describe hormones and phenotype.
Complete Androgen Resistance 46, XY
Male Pseudohermaprhoditism
Complete: loss of X-linked AR gene
Phenotype: female with blind vaginal pouch
Y chromosome – induces mullerian duct regression, testes (undescended); lack of androgen effects (no Wolffian duct development, no external genitalia)
High estrogens induce development of female body characteristics
but no response to androgens so also no Wolf development. no internal male or female structures
look female but no internal structures of any kind. infertile
high estrogens bc androgens at high levels shunted into pathway to be converted into estrogens.
Describe Androgen Resistance 46, XY (partial).
Partial: AR mutation – partially functional
Hormones: Androgen levels are high (lack of feedback, estrogen levels high (for male). Gonadotropins?
Phenotype: ambiguous with blind vaginal pouch (under masculinized)
Y chromosome – induces Mullerian duct regression, testes (undescended); Wolffian duct develops, gynecomastia
enough testosterone prod. locally to allow structures to develop but not enough systemically.. Wolf develops so there is still lack of neg. feedback and still gynecomastia bc androgens pref. converted to estrogens.
46,XX PRENATAL ANDROGEN EXPOSURE (not chromosomal abnormality)
What is the most common cause?
FEMALE PSEUDOHERMAPHRODITISM
Fetal congenital adrenal hyperplasia ** most common
Maternal androgen excess
Adrenal or ovarian tumors
Progestational drugs
What does the following describe? Virilization by androgens- advanced skeletal “age”, clitoromegaly and other ambiguities of genital anatomy.
46,XX PRENATAL ANDROGEN EXPOSURE (not chromosomal abnormality)
FEMALE PSEUDOHERMAPHRODITISM
child age 5 but bone age, excessive androgen prod. that increases bone age, so acceleration of bone age in child (bones of 9 year old) short… height of 11 year old but is 23… happens w contraceptives during preg. 8-12th week of development, fusion of labia, retention of urogenital sinus
Differentiation of external genitalia is highly variable – ambiguous
Cryptorchidism and hypospadias
What would this be?
XX hermaphrodites generally raised as females. Possible SRY translocation or loss of RSPO1 gene (testes repressor).
No spermatogenesis because other Y genes not present.
Describe a true hermaphrodite.
What is kisspeptin? What would a mutation is KISS1 receptor cause?
Kisspeptin – required to initiate increased GnRH release at the time of puberty. Presumed signal for pubertal onset.
Mutations in KISS1 receptor cause hypogonadotropic hypogonadism
What is the primary determinant for testis size at puberty?
FSH
FSH –
Stimulates spermatogenesis
Increases sperm motility
Stimulates growth of seminiferous tubules – primary determinant of testes size
Stimulates androgen binding protein (ABP) – maintains high local T
Stimulates aromatase
Stimulates inhibin
Stimulates growth factors
Why might excess T cause CV problems in men?
increase LDL in liver prod. and decrease HDL- could put men at risk for CV problems
