Endocrine Flashcards
1
Q
Describe the development of the thyroid.
A
- thyroid tissue is primarily derived from endoderm, specifically the third pharyngeal pouch; however, parafollicular cells (C cells) are derived from neural crest
- the thyroid diverticulum arises from the floor of the primitive pharynx and descends into the neck via the thyroglossal duct, which at its cranial end, is connect to the tongue
2
Q
What is the foramen cecum?
A
- the cranial portion of the thyroglossal duct through which the thyroid descends
- a normal remnant of that duct, which is seen at the apex of the terminal sulcus of the tongue
3
Q
What is the most common site for ectopic thyroid tissue?
A
the tongue (called lingual thyroid)
4
Q
Under what circumstances will removal of lingual thyroid tissue cause hypothyroidism?
A
if it is the only thyroid tissue present
5
Q
Thyroglossal Duct Cyst
A
- an anterior midline neck mass that moves with swallowing or protrusion of the tongue
- a remnant of the thyroglossal duct through which the thyroid gland descends
6
Q
Describe the structure of the adrenal glands as well as it’s embryonic tissue of origin.
A
- the cortex is derived from mesoderm and can be divided into three layers: the zone glomerulosa, fasciculate, and reticularis, which each respond to and secrete different chemicals
- the medulla within is derived from neural crest cells and composed of chromaffin cells, which respond to preganglionic sympathetic fibers and release catecholamines
7
Q
What are chromaffin cells?
A
endocrine cells in the adrenal medulla, which are derived from neural crest tissue, respond to preganglionic sympathetic fibers, and release catecholamines
8
Q
List the levels of the adrenal cortex, their primary regulator, and their secretory products.
A
“GFR corresponds with salt, sugar, and sex; the deeper you go the sweeter it gets”
- glomerulosa: responds to angiotensin II by secreting aldosterone
- fasciculata: responds to ACTH and CRH by secreting cortisol
- reticularis: responds to ACTH and CRH by secreting sex hormones
9
Q
Into what two divisions is the pituitary separated?
A
- anterior: adenohypophysis
- posterior: neurohypophysis
10
Q
How does the anterior pituitary compare to the posterior pituitary in structure, function, and embryologic derivative?
A
- anterior: secretes various hormones in response to signals from the hypothalamus; derived from oral ectoderm, specifically Rathke pouch
- posterior: the hypothalamus secrete vasopressin and oxytocin from projections that terminate in the posterior pituitary
11
Q
What are neurophysins?
A
carrier proteins that deliver ADH and oxytocin from neurons in the hypothalamus out to their terminal projections in the posterior pituitary
12
Q
Which hypothalamic nuclei project to the posterior pituitary?
A
the supraoptic and paraventricular nuclei
13
Q
The endocrine cells of the anterior pituitary are divided into two major groups. What are these groups, and how do they differ?
A
- basophils: secrete FSH, LH, ACTH, and TSH
- acidophils: secrete GH and prolactin
14
Q
Describe the structure of most hormones in the anterior pituitary? What are the exceptions to this?
A
- TSH, LH, FSH, and hCG all share a common alpha subunit and the beta subunit determines hormone specificity
- ACTH and MSH on the other hand are derivatives of POMC
15
Q
What is proopiomelanocortin?
A
- abbreviated POMC
- it is the precursor molecule for MSH and ACTH
16
Q
Describe the structure of a Islet of Langerhans.
A
- it is a collection of endocrine cells in the pancreas
- it is structured such that alpha cells surround a cluster of beta cells in which delta cells are interspersed
- alpha cells secrete glucagon, beta cells secrete insulin, and delta cells secrete somatostatin
17
Q
What are the roles of alpha, beta, and delta cells in the Islets of Langerhans?
A
- alpha cells secrete glucagon
- beta secrete insulin
- delta secrete somatostatin
18
Q
Describe the synthesis of endogenous insulin.
A
- the presignal is cleaved from preproinsulin to yield proinsulin
- the C peptide from proinsulin is then cleaved out to yield the C peptide and an alpha chain linked to a beta chain by sulfur bonds
- the C-peptide and insulin molecules are then both exocytosed
19
Q
Describe the function, mechanism of action, and effects of insulin.
A
- it binds tyrosine kinase receptors
- these receptors stimulate cell growth; synthesis of glycogen, proteins, and lipids; and the expression of GLUT4 receptors
- the net effect is an anabolic one
- it increases glucose transport into skeletal muscle and adipose tissue, initiates glycogen synthesis and storage, increase sodium retention, increases protein synthesis, increases the cellular uptake of potassium and amino acids, it inhibits glucagon release, and inhibits lipolysis in adipose tissue while induce triglyceride synthesis
20
Q
Name the insulin-dependent glucose transporter.
A
GLUT4
21
Q
How does GLUT2 compare to GLUT4? What purpose does these differences serve?
A
- GLUT2 has low affinity and high Vmax and is expressed by beta-islet cells, hepatocytes, kidney cells, and cells in the small intestine
- GLUT4 has a high affinity and low Vmax and is expressed in most tissues including adipose and skeletal muscle
- GLUT4’s high affinity means that when glucose levels in the blood are low, most of it will be uptaken by cells that need it for functioning and it’s low Vmax means that it will be saturated quickly (as in when cells are being provided plenty of glucose and don’t need more; instead it can be shunted towards glyconeogenesis)
- GLUT2’s low affinity and high Vmax make it an excellent glucose “sensor” and will only take glucose up into cells with regulatory and glyconeogenic purposes when there is a surplus of circulating glucose)
22
Q
What two things can increase expression of GLUT4?
A
insulin and exercise
23
Q
Describe the distribution of GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5.
A
- GLUT1: RBCs, brain, cornea, and placenta
- GLUT2: hepatocytes, renal cells, small intestine, beta-islet cells
- GLUT3: brain and placenta
- GLUT4: adipose tissue and striated muscles in response to insulin
- GLUT5: spermatocytes, GI tract
24
Q
What is the purpose of GLUT5?
A
it is a fructose transporter expressed by spermatocytes and cells in the GI tract
25
Which cells exhibit insulin-independent glucose uptake?
```
BRICK L
- brain
- RBCs
- intestine
- cornea
- kidney
- liver
plus three which utilize GLUT transporters for absorption
- renal tubular cells
- enterocytes
- placenta
```
26
Glucose has what effect on beta-islet cells? What is the mechanism of action?
- glucose enters beta-islet cells via GLUT2 and drive glycolysis forward, increasing ATP formation
- as the ATP/ADP level rises, ATP-sensitive potassium channels close
- this causes a depolarization, which opens voltage-gated calcium channels
- the influx of calcium drives exocytosis of insulin
27
How does the bodies response to oral glucose compare to that in response to IV glucose?
- after meals (oral glucose), the body secretes additional factors like the incretin glucagon-like peptide 1 (GLP-1)
- these increase the sensitivity of beta-islet cells to glucose
- thus the insulin response to oral glucose exceeds that of IV glucose
28
What are the effects of glucagon? How is it's release regulated?
- it serves a catabolic function, inducing glycogenolysis, gluconeogenesis, lipolysis, and ketone production
- is is secreted in response to hypoglycemia
- it's release is inhibited by insulin, hyperglycemia, and somatostatin
29
What is the effect of CRH within the hypothalamus-pituitary axis?
- it is called corticotropin releasing hormone
| - it increases the release of ACTH, MSH, and beta-endorphin
30
What is the effect of dopamine within the hypothalamus-pituitary axis?
it inhibits the release of prolactin and TSH
31
What is the effect of GHRH within the hypothalamus-pituitary axis?
it stimulates the release of GH
32
What is the effect of GnRH within the hypothalamus-pituitary axis?
it stimulates the release of FSH and LH
33
What is the regulatory effect of prolactin within the hypothalamus-pituitary axis?
it inhibits the release of GnRH
34
What is the regulatory effect of somatostatin within the hypothalamus-pituitary axis?
it inhibits the release of GH and TSH
35
What is the regulatory effect of TRH within the hypothalamus-pituitary axis?
it increases TSH and prolactin release
36
Draw the "hypothalamus-pituitary-prolactin" axis.
See page 310 of FA
37
What are the primary effects of prolactin.
- stimulate milk production
- inhibit ovulation and spermatogenesis (by suppressing GnRH and the subsequent release of FSH and LH)
- excessive amounts are associated with decreased libido
- it also inhibits it's own production by stimulating dopamine release from the hypothalamus
38
What two factors inhibit prolactin release?
- dopamine from the hypothalamus
| - elevated plasma T3/T4 (they inhibit TRH which normally serves to stimulate prolactin release)
39
Through what mechanism does nipple stimulation lead to milk production?
- nipple stimulation inhibits dopamine release from the hypothalamus to the anterior pituitary
- this disinhibits prolactin release, which then acts on the breast
40
What is somatotropin?
aka GH, secreted by the anterior pituitary to promote linear growth and muscle mass through IGF-1
41
Describe the hypothalamus-pituitary-GH axis.
- GH release is inhibited by somatostatin and stimulated by GHRH
- when it is released, it stimulates linear growth and an increase in muscle mass by inducing the release of IGF-1 from the liver
42
What is IGF-1?
a hormone released by the liver in response to GH, which works to keep blood glucose high while stimulating anabolic functions
43
What are the effects of GH and IGF-1?
- trigger insulin resistance, gluconeogenesis, lipid mobilization, and AA uptake
- promoting high serum glucose, increased organ size and functioning, and linear/lean growth
44
GHRH and GH levels rise during what events and in response to what changes within the body?
- increase during exercise and deep sleep
- levels rise during puberty
- release is stimulated by hypoglycemia
45
Excess secretion of GH will cause what change in adults? In children?
- adults: acromegaly
| - children: gigantism
46
How is excessive GH release treated?
with somatostatin analogs, which function to inhibit further GH release
47
What is ghrelin? Specifically, what triggers it's release and what are it's effects?
- a hormone produce in the stomach in response to fasting, sleep deprivation, and Prader-Willi syndrome
- stimulates hunger and the release of GH
48
What is leptin? Specifically, what triggers it's release and what are it's effects?
- a hormone produced by adipose tissue which promotes satiety
- production is inhibited by sleep deprivation and starvation
49
Where do endocannabinoids work to stimulate appetite?
in the hypothalamus and nucleus accumbens
50
Where is ADH secreted from?
the posterior pituitary
51
Central Diabetes Insipidous
- a disease caused by low levels of ADH production
- the result is frequent urination of dilute urine and the inability to concentrate urine even during periods of water restriction
- treat with desmopressin, an ADH analog
52
Nephrogenic Diabetes Insipidous
- a disease most frequently caused by a mutation in the V2 receptor for ADH
- the result is frequent urination of dilute urine and the inability to concentrate urine even during periods of water restriction
- ADH levels are high and desmopressin is not an effective treatment
53
Draw a diagram explaining synthesis of adrenal steroids.
See FA page 312
54
How does ACTH stimulate the release of hormones from the adrenal gland?
it stimulates cholesterol deesmolase, the initial enzyme required in steroid synthesis
55
Steroid synthesis in the adrenal glands begins with what step?
ACTH stimulation of cholesterol desmolase, which converts cholesterol to pregnenolone
56
What is 17a-hydroxylase?
an enzyme expressed in the zona fasciculata, which converts pregnenolone and progesterone to 17-hydroxypregnenolone and 17-hydroxyprogesterone, respectively
57
What is 21-hydroxylase?
an enzyme expressed in the zona glomerulosa and fasciculata which converts progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol, respectively
58
What is 11B-hydroxylase?
an enzyme expressed in the zona glomerular and fasciculata, which converts the products of 21-hydroxylase to corticosterone and cortisol, respectiviely
59
What is glycyrrhetic acid?
an molecule (found in licorice), which inhibits conversion of cortisol to cortisone in the zona fasciculata, leading to syndrome of apparent mineralocorticoid excess
60
17a-hydroxylase Deficiency
- an enzyme deficiency within the steroid synthesis pathway, inhibiting production within the fasciculata and reticularis
- excess aldosterone contributes to hypokalemia and hypertension
- lack of cortisol leads to adrenal hyperplasia
- XY individuals have ambiguous genitalia with undescended testes while XX lack sexual development and pubic hair and suffer from amenorrhea
61
21-hydroxylase Deficiency
- most common deficiency of steroid synthesis
- deficiency in the glomerulosa and fasciculata, inhibiting production of aldosterone and cortisol with excess sex hormones
- low aldosterone: hypotension and hyperkalemia with elevated renin activity in response
- low cortisol: adrenal hyperplasia
- classic form: XX individuals are virilized with ambiguous genitalia and enlarged clitoris
- non-classic: presents later with precocious puberty in males; hirsutism and menstrual irregularities in females
62
11B-hydroxylase Deficiency
- deficiency in the glomerulosa and fasciculata, inhibiting production of aldosterone and cortisol with excess sex hormones
- 11-deoxycorticosterone (weak mineralocorticoid) builds up, elevating BP and producing a hypokalemia
- low cortisol: adrenal hyperplasia
- XX individuals are virilized by elevated testosterone and present with ambiguous genitalia and enlarged clitoris
63
All congenital adrenal enzyme deficiencies are characterized by what feature?
enlarged adrenal glands due to increased, chronic ACTH stimulation
64
What are the effects of cortisol?
BIG FIB
- BP is elevated: up regulates a1 receptors on arterioles and can bind aldosterone receptors at high concentrations
- Insulin resistance
- Gluconeogenesis, lipolysis, and proteolysis
- Fibroblast activity is diminished
- Inflammatory and Immune responses are low: reduced NF-kB and impaired neutrophil migration
- Bone formation: reduced osteoclast activity
65
What percent of calcium is normally ionized? Bound to albumin? Bound to anions?
- 45% free
- 40% bound to albumin
- 15% bound to anions
66
How does pH affect serum calcium levels?
an increase in pH increases it's affinity for binding albumin, causing a hypocalcemia
67
What diseases in adults and kids are caused by VitD deficiency?
- rickets in children
| - osteomalacia in adults
68
What are four causes of VitD deficiency?
- malabsorption
- reduced sunlight
- poor diet
- chronic kidney failure
69
Describe the actions of calcitriol.
- stimulates absorption of calcium and phosphate from the intestinal lumen
- promotes absorption of calcium and phosphate form the renal tubules
- stimulates bone resorption
70
What stimulate production of 1,25(OH)2 vitamin D?
- elevated PTH levels
- low calcium levels
- low phosphate levels
71
Describe Vitamin D biosynthesis.
- D3 comes from exposure of the skin to sun and ingestion of fish and plants
- D2 comes from ingestion of plants, fungi, and yeast
- both are converted to 25-OH in the liver by 25-hydroxylase
- then to the active 1,25-(OH)2 form in the kidney when 1a-hydroxylase is stimulates by PTH
72
What is the role of chief cells in the parathyroid?
release of PTH
73
Describe PTH. Where is it released from? What are it's effects? How is it regulated?
- released from parathyroid chief cells
- in response to low calcitriol, low free calcium, high phosphate, and low magnesium (inhibited by really low Mg)
- stimulates bone resorption by promoting release of RANK-L from osteoblasts; inhibits phosphate reabsorption in the PCT; increases calcium reabsorption in the DCT; activates 1a-hydroxylase in the PCT to form calcitriol
- the effort is to increase serum calcium, reduce serum phosphate, and increase urine cAMP
74
What is 1a-hydroxylase?
an enzyme found in the PCT, which converts inactive vitamin D to the active dihydroxy form
75
What is PTHrP?
- PTH related peptide
- functions like PTH
- commonly increased in malignancies
76
What is calcitonin? Where is it produced? How does it function?
it is released by parafollicular cells (C cells) of the thyroid and works against PTH to decrease bone resorption
77
Which endocrine hormones utilize a cAMP signal cascade?
```
FLAT ChAMP
- FSH
- LH
- ACTH
- TSH
- CRH
- hCG
- ADH (V2 receptor)
- MSH
- PTH
and also calcitonin, GHRH, and glucagon
```
78
A cGMP signal cascade is classically utilized by which ligands?
vasodilators
- BNP
- ANP
- EDRF
79
An IP3 signal cascade is classically used by which endocrine hormones?
GOAT HAG
- GnRH
- Oxytocin
- ADH (V1 receptor)
- TRH
- Histamine
- Angiotensin II
- Gastrin
80
Which endocrine hormones use an intracellular receptor?
PET CAT on TV
- progesterone
- estrogen
- testosterone
- cortisol
- aldosterone
- T3/T4
- Vitamin D
81
Which endocrine hormones use a tyrosine kinase receptor?
growth factors
- insulin
- IGF-1
- FGF
- PDGF
- EGF
82
Which endocrine hormones use non receptor tyrosine kinase signaling pathways (JAK/STAT)?
- prolactin
- immunomodulators (cytokines)
- GH
- G-CSF
- EPO
- Thrombopoietin
83
What is sex-hormone-binding globulin? What changes the available levels in men and women? What are the effects?
- a hormone in circulation that carries steroid hormones, increasing their solubility since they are lipophilic
- in men, increased levels lower available free testosterone and contribute to gynecomastia
- in women, high levels, due to OCPs or pregnancy, reduce free testosterone and prevent hirsutism
84
Describe thyroid hormone synthesis.
- TSH from the anterior pituitary stimulates follicular cells
- iodine is shuttled into the follicular lumen from blood or recycled from unused MIT and DIT
- these iodine ions are oxidized by thryoperoxidase to I2 and attached to tyrosine residues on thyroglobulin, forming DIT and MIT, also by thyroperoxidase
- thyroglobulin with DIT and MIT bound is endocytosed in to the follicular C cell where thyroperoxidase couples DIT and MIT moieties
- specifically, T3 is made by the combination of DIT with MIT and T4 from the combination of two DIT moieties
- these are moved into circulation and in the periphery, T4 is converted to T3 by 5'-deiodinase
85
What is 5'-deiodinase?
an enzyme in the periphery responsible for generating T3 from T4
86
What are the primary functions of T3?
- brain maturation
- bone growth
- beta-adrenergic effects (increase CO, HR, SV, contractility)
- basal metabolic rate increase (via increase in Na/K-ATPase activity which increases O2 consumption, RR, and body temperature)
87
What is thyroxine-binding globulin? What causes a deficiency?
- a protein to which T3/T4 bind in circulation
- it thereby keeps circulating T3/T4 inactive
- hepatic failure or steroids can reduce levels while pregnancy or OCP will increase levels
88
What is the Wolf-Chaikoff effect?
says that excess iodine temporarily inhibits thyroid peroxidase, decreasing T3/T4 production
89
Pituitary Adenoma
- a benign tumor of anterior pituitary cells with hormone-producing potential
- present with a mass effect: bitemporal hemianopsia, hypopituitarism, and headache; along with symptoms related to the hormone that is over-produced
- prolactinomas most common followed GH- and ACTH-secreting tumors
90
Prolactinoma
- a pituitary adenoma that produces prolactin
- presents with galactorrhea, amenorrhea, and decreased libido in addition to mass effect
- treat with a dopamine agonists like bromocriptine or cabergoline; surgery reserved for larger lesions
91
Growth Hormone Cell Adenoma
- a pituitary adenoma that produces growth hormone
- presents as gigantism in children or acromegaly in adults (enlarged bones, coarse facies, cardiac failure, and enlarged tongue) and secondary diabetes mellitus
- diagnosis made by elevated GH and IGF-1 with lack of GH suppression by oral glucose
- treat with a somatostatin analog like ocreotide
92
At what point do symptoms arise in those with hypopituitarism?
not until more than 75% of the parenchyma is non-functional, compressed, etc.
93
Pituitary Apoplexy
- bleeding into or ischemia of the pituitary
- commonly follows growth of a pituitary adenoma or as a complication of pregnancy
- can present with a mass effect and/or the symptoms of hypopituitarism
94
Sheehan Syndrome
- a pregnancy-related infarction of the pituitary gland leading to hypopituitarism
- during pregnancy the gland grows without complementary growth of the vasculature; during labor and delivery, blood loss can precipitate ischemia and infarction of the pituitary
- presents with poor lactation, loss of pubic hair, and fatigue after delivery
95
Empty Sella Syndrome
- a congenital defect of the pituitary diaphragm that allows CSF to flow into and expand the subarachnoid space within the sella, compressing and destroying the pituitary
- the pituitary gland will be absent on imaging and the individual will suffer hypopituitarism
96
What two hormones are released from the posterior pituitary?
ADH and oxytocin
97
What is the physiologic role of oxytocin?
it mediates uterine contraction during labor and the release of breast milk in lactating mothers
98
Central Diabetes Insipidus
- an ADH deficiency that results from pathology of the hypothalamus or pituitary
- lack of ADH impairs reabsorption of water from the collecting tubules of the kidneys
- presents with symptoms related to the loss of free water: polyuria, polydipsia, life-threatening dehydration, hypernatremia, high serum osmolality, low urine osmolality, and specific gravity
- diagnosis is made based on a failure to increase urine osmolality during a water deprivation test until desmopressin is administered
99
Nephrogenic Diabetes Inspidus
- a disease defined by impaired renal response to ADH
- due to inherited mutations (particularly of the V2 receptor) or drugs (classically lithium and demeclocycline)
- clinical features are similar to central diabetes insidious, except that the individual doesn't respond to desmopressin
100
Syndrome of Inappropriate ADH Secretion
- a disease defined by excessive ADH secretion
- most often due to ectopic production by a small cell carcinoma of the lung as well as CNS trauma, pulmonary infection, or drugs
- symptoms are related to the retention of free water: hyponatremia, low serum osmolality, mental status changes, and seizures as hyponatremia leads to neuronal swelling and cerebral edema
- treatment is with free water restriction or demeclocycline, which inhibits the V2 intracellular cascade mediated by Gs
101
What are the signs and symptoms of hyperthyroidism? Through what mechanisms do these feature arise?
increased thyroid hormone increases synthesis of Na/K-ATPases, which increases basal metabolic rate, and increases sympathetic activity by increasing expression of B1 receptors
- weight loss despite increased appetite
- heat intolerance and sweating
- tachycardia, arrhythmia
- tremor, anxiety, insomnia, heightened emotions
- staring gaze with lid lag
- diarrhea with malabsorption
- oligomenorrhea
- bone resorption with hypercalcemia
- decreased muscle mass with weakness
- hypocholesterolemia
- hyperglycemia
102
Grave's Disease
- a type II hypersensitivity with IgG against TSH receptors
- presents with hyperthyroidism, exophthalmos, and pretibial myxedema
- thyroid storm is a potential fatal complication
- histology reveals a hypertrophic, hyper plastic thyroid with irregular follicles and scalloped colloid
- labs find elevated total and free T4, low TSH, hypocholesterolemia, and increased serum glucose
- treatment involves B-blockers and methiomazole/PTU
103
Thyroid Storm
- a potentially fatal complication of hyperthyroidism
- in response to stress, there are elevated levels of catecholamines and massive hormone excess
- presents with arrhythmia, hyperthermia, and vomiting with hypovolemic shock
- treat with PTU because it blocks peripheral conversion of T4 to T3, beta blockers, and steroids
104
What is propylthiouracil?
a drug that inhibits thyroperoxidase and 5'-deiodinase, which is used to treat the thyroid storm associated with Grave's disease and hyperthyroidism in pregnant women
105
What is pre-tibial myxedema?
- a symptom of Grave's disease caused by activation of TSH receptors expressed by pre-tibial fibroblasts
- results in glycosaminoglycan buildup, inflammation, fibrosis, and edema
- has a dough-like consistency
106
Multinodular Goiter
- iodine deficiency causes an increase in TSH, which promotes nodular enlargement of thyroid
- individuals are typically euthyroid (nontoxic), but regions can occasionally become TSH-independent and cause hyperthyroidism
107
Cretinism
- hypothyroidism in neonates and infants
- caused by maternal hypothyroidism, thyroid genesis, iodine deficiency, or dyshormonogenetic goiter (thyroid peroxidase deficiency)
- presents with mental retardation, short stature with skeletal abnormalities, coarse facial features, enlarged tongue, and umbilical hernia
108
Myxedema
- hypothyroidism in older children and adults
- clinical features are based on decreased basal metabolic rate, decreased sympathetic activity, and elevated TSH
- presents with weight gain, muscle weakness, bradycardia, oligomenorrhea, constipation and myxedema contributing to a deepened voice and large tongue
- most commonly due to iodine deficiency, Hashimoto thyroiditis, lithium, or thyroidectomy
109
Hashimoto Thyroiditis
- autoimmune destruction of the thyroid gland and most common cause of hypothyroidism worldwide
- strongly associated with HLA-DR5
- may initially present as a hyperthyroidism due to excess release, but there is actually under production
- labs find low T4 and elevated TSH
- antithyroglobulin and anti-thyroid peroxidase antibodies may be present but don't mediate disease
- histology reveals chronic inflammation with germinal centers and Hurthle cells
- increases risk for marginal B-cell lymphoma
110
What are Hurthle cells?
metaplastic thyroid epithelial cells that are eosinophilic and characteristic of Hashimoto thyroiditis
111
Subacute Granulomatous Thyroiditis
a self-limiting, granulomatous thyroiditis that follows viral infection and presents with a tender thyroid and transient hyperthyroidism
112
Riedel Fibrosing Thyroiditis
- chronic inflammation and fibrosis of the thyroid gland
- presents with hypothyroidism and hard as wood, nontender thyroid
- importantly, fibrosis may extend and involve the airway
- it mimics anaplastic carcinoma clinically except that patients are younger and malignant cells are absent on histology
113
How is radioactive iodine uptake used for clinical diagnosis?
helps characterized thyroid nodules
- increased uptake is seen in Graves disease and in those with a nodular goiter
- decreased uptake is a sign of adenoma or carcinoma
114
How is the thyroid biopsied? Why?
- via a fine need aspiration
| - the thyroid is too bloody to biopsy in other ways
115
Follicular Adenoma of the Thyroid
- a benign proliferation of follicles
- usually nonfunctional
- differentiated from a follicular carcinoma in that it is entirely surrounded by a capsule without invasion
116
Papillary Carcinoma of the Thyroid
- the most common type of thyroid carcinoma
- major risk factor is ionizing radiation as a child
- histology shows papillae lined by cells with clear "Orphan Annie eye" nuclei and nuclear grooves in addition to the presence of psammoma bodies
- tends to spread to the cervical lymph nodes, but has an excellent prognosis regardless
117
Follicular Carcinoma of the Thyroid
- a malignant proliferation of follicles surround by a fibrous capsule but with invasion through this capsule
- this invasion is how it is differentiated from an adenoma, thus the entire capsule must be examined microscopically to make a diagnosis; fine needle aspiration isn't sufficient
- it is one of four carcinomas that tends to spread hematogenously
118
Medullary Carcinoma of the Thyroid
- a malignant proliferation of parafollicular C cells, which secrete calcitonin
- may lead to hypocalcemia
- elevated calcitonin tends to deposit as amyloid in the tumor and histologically is described as "tumor cells on an amyloid background"
- familial cases are often due to multiple endocrine neoplasia (MEN), which is associated with a RET mutation
119
Anaplastic Carcinoma of the Thyroid
- an undifferentiated malignant tumor of the thyroid
- tends to invade local structures, leading to dysphagia or respiratory compromise
- symptoms resemble those of Riedel fibrosing thyroiditis, except that it presents in the elderly
- has a poor prognosis
120
Multiple Endocrine Neoplasia 2A and 2B
- a cluster of malignancies associated with an autosomal dominant RET oncogene mutation
- MEN 2A is associated with medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia
- MEN 2B is associated with medullary thyroid carcinoma, pheochromocytoma, ganglioneuromas of the oral mucosa, and marfanoid habitus
121
What is the role of parafollicular C cells in the thyroid?
produce calcitonin, a substance that in many ways counters PTH
122
What is the role of chief cells in the parathyroid glands?
produce PTH to regulate free calcium
123
What are the principal effects of PTH?
- increase bone osteoclast activity by inducing osteoblasts to release RANKL, thereby resorbing calcium and phosphate
- increase renal calcium absorption and decrease renal phosphate rabsorption
- trigger activation of D3, which increases absorption of calcium and phosphate from the gut
124
What are the symptoms and lab findings of someone with primary hyperparathyroidism
- symptoms come from hypercalcemia: nephrolithiasis, nephrocalcinosis, CNS disturbances, constipation, peptic ulcer disease, acute pancreatitis, osteitis fibroma cystic
- lab findings include increase serum calcium, low serum phosphate, elevated alkaline phosphatase, and elevated urine cAMP (PTH receptor is AC linked)
125
What is osteitis fibrosa cystica?
resorption of bone leading to fibrosis and cystic spaces, often seen in those with hyperparathyroidism
126
What is nephrocalcinosis?
metastatic calcification of renal tubules, potentially leading to renal insufficiency and polyuria
127
What is alkaline phosphatase?
a product secreted by osteoblasts which helps lay down bone by increasing the pH and precipitating calcium
128
Secondary Hyperparathyroidism
- a hyperparathyroidism most commonly caused by chronic renal failure
- renal insufficiency leads to decreased phosphate excretion, which lowers free calcium, and triggers excess PTH release
129
How can primary hyperparathyroidism be distinguished from secondary hyperparathyroidism?
- primary is associated with high serum calcium while secondary is associated with low serum calcium because it is bound to phosphate
- primary is associated with low serum phosphate while secondary is associated with elevated serum phosphate
130
Hypoparathyroidism
- any condition that results in low PTH
- typically caused by autoimmune damage, surgical excision, or DiGeorge syndrome
- presents with symptoms related to hypocalcemia: circumoral tingling and numbness, tetany (including Trousseau sign and Chvostek sign), low PTH and calcium
131
What is Trousseau sign?
- an indication of hypocalcemia
| - muscle spasm elicited by filling of a blood pressure cuff
132
What is Chvostek sign?
- an indication of hypocalcemia
| - muscle spasm elicited by tapping on the facial nerve
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Pseudohypoparathyroidism
- a hypoparathyroidism due to end-organ resistance to PTH
- labs will reveal hypocalcemia in the setting of elevated PTH
- most commonly due to an autosomal dominant Gs mutation and associated with short stature and short 4th and 5th digits
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Type I Diabetes Mellitus
- an insulin deficiency contributing to hyperglycemia
- a type IV hypersensitivity as the deficiency results from auto-immune destruction of beta cells by T-cells
- autoantibodies against insulin are often present but are only a marker of disease and do not mediate it
- associated with HLA-DR3 and HLA-DR4
- manifests in childhood with high serum glucose, weight loss, low muscle mass, polyphagia, polyuria, polydipsia, glycosuria
- highest risk is for diabetic ketoacidosis
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Diabetic Ketoacidosis
- a state of excessive serum ketones
- often arising with stress, fasting, or epinephrine, which all trigger a shift toward lipolysis and FFA production
- FFAs are converted to the ketone bodies B-hydroxybutyric acid and acetoacetic acid
- results in hyperglycemia and an anion gap metabolic acidosis with hyperkalemia (moved extracellular but total K is low as it is lost in the kidneys)
- presents with Kussmaul respirations (rapid and deep), dehydration, n/v, mental status change, and fruity smelling breath
- treat with fluids, insulin, and replacement of electrolytes
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What are the major ketone bodies produced in diabetic ketoacidosis?
- B-hydroxybutyric acid
| - acetoacetic acid
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What is the key mechanism for the onset of type II DM?
What leads to beta-cell exhaustion later in the disease?
How is a diagnosis made?
What is the major risk or feared complication?
- typically arises in middle-aged, obese adults as obesity decreases the number of insulin receptors key mechanism
- early in the disease course, insulin levels are high, but later, insulin deficiency develops due to beta cell exhaustion (amyloid deposition in the islets)
- diagnosis is made by measure random glucose > 200, fasting glucose > 126, glucose tolerance test > 200 after two hours, or A1C > 6.5
- risk for hyperosmolar non-ketotic coma
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Hyperosmolar Non-Ketotic Coma
- a risk associated with type 2 diabetes mellitus
- high glucose levels (>500) lead to life-threatening diuresis with hypotension and coma
- ketones are noticeably absent
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What are the effects of hyperglycemia and non-enzymatic glycosylation associated with diabetes?
- can lead to atherosclerosis of large- and medium-sized vessels, increasing the risk for CVD and non traumatic amputations
- can lead to hyaline arteriolosclerosis of small vessels, particularly the efferent arteriole of the kidney leading to hyper filtration injury and a nephrotic syndrome
- can cause osmotic damage to Schwann cells, pericytes of retinal blood vessels, and the lens, leading to peripheral neuropathy, impotence, blindness, and cataracts
140
Describe the pathogenesis of peripheral neuropathy and blindness in those with uncontrolled diabetes?
- glucose freely enters Schwann cells, pericytes of retinal blood vessels, and the lens
- inside these cells, aldose reductase converts glucose to sorbitol, which causes osmotic damage
- this leads to peripheral neuropathy, impotence, blindness, and cataracts
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Insulinomas
- the most common pancreatic endocrine tumor, typically benign
- most are asymptomatic and the only sign is elevated insulin-to-glucose ratio with mild hypoglycemia
- symptoms may be sweating, fainting, weakness, and confusion which are relieved by food
- infrequently arise in ectopic pancreatic tissue, most commonly in a Meckle's diverticulum
- histology reveals architecture that resembles giant islets without anaplasia; deposition of eosinophilic amyloid is common
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Gastrinoma
- a pancreatic endocrine neoplasia that secretes gastrin
- results in multiple, treatment-resistant peptic ulcers that can extend into the jejunum
- known as Zollinger-Ellison syndrome when it presents with abdominal pain and diarrhea
- commonly arise from the duodenum, peri-pancreatic soft tissue, or within the pancreas (gastrinoma triangle)
- diagnose with a secretin stimulation test since secretin should inhibit gastrin but won't in this instance
- PPIs and somatostatin analogs can help but treatment is surgical
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Somatostatinoma
- a pancreatic endocrine neoplasia capable of producing somatostatin, which reduces gastrin, causing achlorhydria
- it also inhibits cholecystokinin, preventing gall bladder contraction and causing cholelithiasis with steatorrhea
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What are the symptoms of a VIPoma?
watery diarrhea, hypokalemia, and achlorhydria
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Primary Hyperaldosteronism
- an excess of aldosterone
- most commonly due to bilateral adrenal hyperplasia or adrenal adenoma
- presenting with hypertension, hypokalemia, and metabolic alkalosis
- treatment is mineralocorticoid receptor antagonist like spironolactone or eplerenone for hyperplasia and surgical resection for adenoma or carcinoma
- distinguished from secondary hyperaldosteronism because primary has low renin and no edema
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Secondary Hyperaldosteronism
- an excess of aldosterone arising from activation of the renin-angiotensin system
- most commonly due renovascular hypotension (atherosclerosis in men and fibromuscular dysplasia of the renal artery in women) or CHF
- presenting with hypertension, hypokalemia, and metabolic alkalosis
- distinguished from primary aldosteronism because renin levels are high and edema is often present
- can be treated with modification of the renin-angiotensin system or a mineralocorticoid receptor antagonist like spironolactone or eplerenone
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Glucocorticoid-Remediable Aldosteronism
- an autosomal dominant hyperaldosteronism
- attributable to aberrant expression of aldosterone synthase in the fasciculata
- presents in childhood with hypertension, hypokalemia, and metabolic alkalosis
- responds well to dexamethasone, which suppresses ACTH stimulation of cells in the fasciculata
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How should Liddle Syndrome be treated?
with a potassium-sparing diuretic as spironolactone is not as effective
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Cushing Syndrome
- an excess of cortisol
- causes include exogenous glucocorticoids (most common), an ACTH-secreting pituitary adenoma, ectopic ACTH secretion, or a primary adrenal adenoma/hyperplasia/carcinoma
- presents with muscle weakness, thin extremities, moon facies, buffalo hump, truncal obesity, abdominal striae, osteoporosis, and immune suppression
- hypertension with hypokalemia and metabolic alkalosis are also common as cortisol increases the sensitivity of arterioles to sympathetic activity and directly activates aldosterone receptors
- diagnosed based on a 24-hour urine cortisol level, increased late nigh salivary cortisol level, and poor response to low-dose dexamethasone suppression test
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Through what mechanism does cortisol act as an immune suppressant?
- inhibits PLA2 to impair synthesis of arachidonic acid metabolites
- inhibits IL-2
- inhibits mast cell degranulation
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How are the various causes of Cushing's syndrome differentiated?
- exogenous glucocorticoids: low ACTH, no imaging abnormalities, and bilateral adrenal atrophy (secondary to low ACTH)
- ACTH-secreting pituitary adenoma: high ACTH, high-dose dexamethasone suppression, pituitary adenoma may be found on imaging, bilateral adrenal growth
- ectopic-ACTH secretion: high ACTH, no response to high-dose dexamethasone suppression, imaging likely to find a lung cancer, bilateral adrenal growth
- primary adrenal adenoma: low ACTH, atrophy of the contralateral adrenal gland
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What is Nelson syndrome?
- a syndrome of hyperpigmentation, headaches, and bitemporal hemianopsia
- often seen in response to bilateral adrenalectomy in refractory cases of Cushing syndrome
- adrenalectomy causes enlargement of a pituitary adenoma that wasn't seen on imaging as the negative feedback to the adenoma is removed
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What is the most common cause of Cushing's syndrome?
use of exogenous glucocorticoids
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What is the most likely place for ectopic ACTH secretion?
a small cell carcinoma of the lung
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How do we screen newborns for congenital adrenal hyperplasia? What is the downside to this?
measuring serum 17-hydroxyprogesterone is a routine screening but only catches 21- and 11-hydroxylase deficiencies
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Pheochromocytoma
- a tumor of chromatin cells leading to excess catecholamines
- associated with MEN2, VHL, and neurofibromatosis type 1
- presents as episodic release of catecholamines (hypertension, headaches, palpitations, tachycardia, and sweating)
- diagnosed by increased metanephrines and VPA (catecholamine metabolites) in urine
- gross exam reveals a brown tumor
- treatment is preparation with an irreversible alpha blocker called phenoxybezamine and then a beta blocker (prevents hypertensive crisis during surgery) before removal
- follow the rule of 10s: 10% bilateral, 10% familial, 10% malignant, 10% located outside the medulla
- most frequent ectopic location is in the bladder wall, in which case symptoms are tied to urination
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Acute Adrenal Insufficiency
- a sudden cortisol deficiency
- most often caused by abrupt withdrawal of glucocorticoids, treatment of Cushing syndrome, or Waterhouse-Friderichsen syndrome
- presents with weakness and shock
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Addison Disease
- chronic adrenal insufficiency
- common causes include autoimmune destruction (part of autoimmune polyendocrine syndrome), TB, or metastatic carcinoma from the lungs
- may also arise from a pituitary or hypothalamic issue
- presents with vague, progressive symptoms of hypotension, weakness, fatigue, n/v, and weight loss
- treatment is glucocorticoids and mineralocorticoids
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Waterhouse-Friderichsen Syndrome
- hemorrhagic necrosis of the adrenal glands contributing to acute renal insufficiency
- presents with weakness and shock
- classically in the setting of a young child with sepsis and DIC due to Neisseria meningitidis infection
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Why does adrenal insufficency present with hypotension?
- because the lack of cortisol reduces arteriole sensitivity to sympathetic activity
- and the loss of aldosterone cause a loss of water
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How are primary, secondary, and tertiary Addison disease differentiated from one another?
- primary: excess ACTH leads to hyper pigmentation and low aldosterone leads to a hyperkalemia
- secondary: there is no excess ACTH or lack of aldosterone so no hyperpigmentation or hyperkalemia; instead ACTH levels are low and don't respond to a metyrapone stimulation test
- tertiary: there is no excess ACTH or lack of aldosterone so no hyperpigmentation or hyperkalemia; instead, ACTH levels are low but respond to a CRH stimulation test
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Why does adrenal insufficency present with hyperpigmentation of body creases and sun-exposed areas?
- because ACTH is a derivative of POMC and when ACTH levels rise, so do levels of POMC
- POMC is also used to make MSH, which stimulates melanocytes, leading to hyperpigmentation
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Which thyroid goiters are smooth/diffuse and which are nodular?
- smooth: Graves, Hashimoto thyroiditis, iodine deficiency, TSH-secreting pituitary adenoma
- nodular: toxic multi nodular goiter, thyroid adenoma, thyroid cancer, thyroid cyst
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Neuroblastoma
- a neuroendocrine tumor that can occur anywhere along the sympathetic chain but is the most common adrenal medullary tumor in children
- originates from neural crest cells and associated with N-myco oncogene over expression
- presents in children under 4 with abdominal distension and a firm, irregular mass that can cross the midline
- this distinguishes it from a Wilms tumor which is smooth and unilateral
- less likely to develop hypertension that with a pheochromocytoma but may present with opsoclonus-myoclonus syndrome ("dancing eyes and dancing feet")
- histology reveals prominent rosettes
- the catecholamine metabolites HVA and VMA are elevated in urine, the tumor is bombesin and neuron-specific enclave positive in addition to containing amine precursor uptake decarboxylase
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Jod-Basedow Phenomenon
thyrotoxicosis in a patient with iodine deficiency and partially autonomous thyroid tissue who is suddenly made iodine replete (opposite the Wolff-Chaikoff effect)
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Familial Hypocalciuric Hypercalcemia
- a deficiency in the calcium-sensing receptor in multiple tissues
- as a result, higher than normal calcium levels are required to suppress PTH
- there is excessive renal calcium reuptake, mild hypercalcemia, and hypocalciuria with normal to elevated PTH
- similar to a change in calcium set point
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Laron Syndrome
- a form of dwarfism caused be defective growth hormone receptors
- less IGF-1 is released in response to GH and there is less linear growth
- presents with short height, small head circumference, characteristic facies with saddle nose and prominent forehead, delayed skeletal maturation, and small genitalia
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How does the histology of type 1 DM compare to that of type 2?
- type 1: leukocytic infiltrate in the islet cells
| - type 2: islet amyloid polypeptide deposits
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Glucagonoma
- a tumor of pancreatic alpha cells
- overproduction of glucagon presents with dermatitis (necrolytic migratory erythema), diabetes, DVT, declining weight, and depression
- treatment is with octreotide or surgery
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Multiple Endocrine Neoplasias 1
- a cluster of neoplasias associated with a mutation in MEN1, a tumor suppressor gene on chromosome 11
- autosomal dominant
- associated with pituitary tumors, pancreatic endocrine tumors, and parathyroid adenomas (3 Ps)
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What are the non-endocrine symptoms of carcinoid tumors and what is the associated rule of 1/3s?
- most are asymptomatic unless they cause angulation or obstruction of the small intestine
- may also cause respiratory obstruction and hemoptysis if found in the lungs
- follows the rule that 1/3 metastasize, present with 2nd malignancy, and are multiple
