Hormones released by the anterior pituitary gland:
- thyroid-stimulating hormone (TSH)
- prolactin (PRL)
- adrenocorticotropin hormone (ACTH)
- growth hormone (GH)
- follicle-stimulating hormone (FSH)
- luteinizing hormone (LH)
In pituitary histology, the pink staining acidophils (eosinophilic cytoplasm) release ______ and ______. The purple staining basophils secrete __________, ___________, __________, and ________.
Pink: * GH * PRL Purple: * FSH * LH * TSH * ACTH
Histologically, the posterior pituitary resembles _______ tissue.
Neural
- glial cells
- nerve fibers
- nerve endings
- intra-axonal neurosecretory granules
The 2 hormones secreted by the posterior pituitary, ______ and _______, are synthesized __________.
ADH and oxytocin
in the hypothalamus, stored in the post pit
__________ occurs as a result of excess secretion of trophic pituitary hormones.
Causes include:
Hyperpituitarism
- pituitary adenoma (MC)
- hyperplasia
- carcinomas of ant pit
- secretion or hormones by non-pit tumors
- certain hypothalamic d/o’s
Result of deficiency in one or more of the hormones produced by the pituitary gland:
Hypopituitarism
- ischemic injury
- surgery
- radiation
- inflammatory reactions
- non-functioning adenoma
Pituitary-related changes that may be referred to as mass effect:
- sellar expansion
- bony erosion
- disruption of the sella
Pituitary lesions of a sufficient size often compress:
leading to:
the optic nerve at the optic chiasm
visual field abnormalities, usu lateral visual field deficits
“bitemporal hemianopsia”
MC pituitary tumor:
Pituitary adenoma
Also MC brain tumor!
15% of all intracranial lesions
How do you differentiate a macro- and microadenoma?
Macro - >/=10mm
Micro -
How are pituitary adenomas classified?
By hormone secreted (MC - PRL)
formerly by staining, still use “chromophobic” for non-fxn tumors
Describe the typical pituitary adenoma (gross):
soft
well-circumscribed
mb confined to sella, or extend superiorly
larger:
erode sella
infiltrate neighboring tissues (cavernous/sphenoid sinuses, dura)
Histology of pituitary adenoma:
- small round cells
- uniformly round nuclei
- pink to blue cytoplasm
- nest or cords
- prominent vascularity
Mass effect sx:
- HA
- visual field deficit
- cranial nerve defect
- cavernous sinus syndrome (rare)
- sx specific to excess hormone (if fxn)
MC functioning pituitary adenoma:
prolactinoma (lactroph adenoma)
30%
underlies ~25% of cases of amenorrhea
Adenomas of the anterior pituitary are a (major/minor) clinical feature of ______, a form of inherited endocrine disorder.
major
multiple endocrine neoplasia type 1 (MEN 1 )
MEN causes various combos of benign or malignant tumors in endocrine glands or may cause glands to enlarge w/o forming tumors
MEN syndromes MC affect:
- parathyroid glands
- pancreatic islet cells
- anterior pituitary (25% of MEN1)
MEN1 may cause non-endocrine tumors likes:
- facial angiofibromas
- collagenomas
- lipomas
- meningiomas
- ependymomas
- leiomyomas
Acute hemorrhage into an adenoma or pituitary infarction:
pituitary apoplexy - rapid enlargement of the lesion
80% not previously dx - although usu pre-existing
MC initial sx of pituitary apoplexy:
sudden HA
- often w/rapidly worsening visual field defect
- double vision
Necrosis of the pituitary gland due to blood loss and hypovolemic shock during and after childbirth:
Sheehan’s syndrome (postpartum hypopituitarism)
Hypertrophy and hyperplasia of lactotrophs (PRL cells) during pregnancy results in:
enlargement of the anterior pituitary, without a corresponding increase in blood supply.
agalactorrhea - MC initial sx
may go undetected, mb found later upon hypothyroid or 2° adrenal insufficiency dx
An empty sella contains:
only CSF w/o visible pituitary tissue on MRI
pituitary stalk typically visible, extends to floor of sella
Hypothalamic suprasellar tumors may induce:
hypo- or hyperfunction of the anterior pituitary, diabetes insipidus, or combinations of these manifestations.
MC implicated hypothalamic suprasellar lesions:
gliomas and craniopharyngiomas
The craniopharyngioma is thought to be derived from vestigial remnants of _______________.
Rathke’s pouch
Craniopharyngiomas are (fast/slow) growing tumors with a (early/late/bimodal) onset.
slow
bimodal
* 5-15
* 65+
Diagnostic histopathology of craniopharyngiomas:
- compact lamellar keratin formation “wet keratin”
also see:
- peripheral palisading
- cords of squamous epithelium
less important:
- dystrophic calcification
- cyst formation
- fibrosis
- chronic inflammatory reactions
Malignant anterior pituitary tumors (1°) are defined by:
ability to metastasize
although many are widely invasive, destructive to adjacent tissues, and lethal, they are not classified as malignancy (H-ras and p53 have been noted in association, but not in tumor)
MC cancers that mets to the pituitary:
breast and lung
but mets to pituitary = rare
Newborn screening for congenital hypothyroidism, which can cause __________, is performed by __________ test. If tx is delayed by ___ (weeks/months), development is impaired and full function is not possible.
cretinism
heel-pad test
6 months
____ from the ant pituitary binds a specific receptor on the thyroid surface. This with ______________ increase formation of ______ in the thyroid, which initiates exocytosis and release of _________ hormone.
TSH
adenylate cyclase
cAMP
thyroid
A decrease in pituitary and circulating ____ stimulates production of TRH from the ___________. TRH serves to stimulate release of _____ and subsequent release of ___ and ___ until (negative/positive) feedback causes diminished release of TRH.
T3 hypothalamus TSH T3 and T4 negative
Metabolic functions increased by T3:
- protein synthesis/degradation
- drug metabolism
- catecholamine receptor sensitivity
- glucose absorption
- gluconeogenesis
- O2 consumption
- heat production
- metabolic rate
- lipid synthesis/oxidation
- cholesterol synthesis/degradation
Target tissue effects of excess T3:
- heart - inc HR
- vascular - vasodilation
- skin - warm, smooth, moist
- GI - inc motility
- bone - inc turnover
- neuromuscular - hyperactivity, inc contraction
At a cellular level, thyroid hormone action is initiated by binding to a (specific/non-specific) receptor from a family of _______ factors that regulate specific genes. These receptors preferentially bind ____, which is why it has a greater biologic effect than ____.
specific
transcription
T3
T4
Normal thyroid histology consists of:
follicles lined by epithelium, and filled with colloid.
The interstitium may contain “C” cells (parafollicular cells) and has a rich vascular supply, into which hormone is secreted.
C cells secrete:
calcitonin
The conditions most notable for causing a hypothyroid state:
- Hashimoto’s thyroiditis
- acute thyroiditis
- subacute thyroiditis (DeQuervain’s)
- infiltrative thyroid dz
- post-op hypothyroidism
- iatrogenic hypothyroidism
MC cause of autoimmune lymphocytic thyroiditis:
Hashimoto’s thyroiditis
_______ is essential for the production of thyroxine. When lacking from the diet, this can lead to thyroid gland (shrinking/enlargement), resulting in what is termed _______________.
Iodine
enlargement
endemic goiter
Adding iodine to ____ has eliminated __________ in most developed countries.
salt
endemic cretinism
Condition due to excess amount of free thyroid hormone:
mb the result of increased ________ and _______ of thyroid hormone by:
hyperthyroidism synthesis and secretion * serum stimulators * autonomous thyroid hyper function * over secretion of TSH w/o inc synthesis of T3/T4
Another major cause of hyperthyroidism is thyrotoxicosis factitia, which is:
conscious or accidental ingestion of excess quantities of thyroid hormone
The principle conditions responsible for causing a hyperthyroid state include:
- Graves dz
- toxic thyroid nodule
- toxic multinodular goiter (Plummer’s dz)
- iatrogenic hyperthyroidism
- thyroid storm (usu Graves + infx)
In relation to thyroid, “toxic” refers to:
producing excess hormone
taking up more iodine
Autoimmune dz where thyroid gland is attacked by a variety of cell- and antibody-mediated immune processes:
Hashimoto’s thyroiditis (chronic lymphocytic thyroiditis)
In Hashimoto’s, the thyroid gland becomes:
But dz develops w/o:
firm
large
lobulated
w/o visible or palpable change to thyroid gland
First dz recognized to be an autoimmune dz:
Hashimoto’s
in 1912
Thyroid enlargement in Hashimoto’s is due to:
A. tissue hypertrophy
B. lymphocytic infiltration and fibrosis
B. lyphocytic infiltration and fibrosis
In Hashimoto’s, antibodies against ______ and/or __________ cause gradual destruction of _________ in the thyroid gland.
TPO (thyroid peroxidase)
thyroglobulin
follicles
Cells that often appear in thyroid tissue of pts with Hashimoto’s or follicular thyroid cancer:
Hürthle cells
Histologically, Hürthle cells appear:
- enlarged epithelial cells
- generally stain pink
- abundant eosinophilic granular cytoplasm as a result of altered mitochondria.
Form of thyroiditis that can cause both hypo- and hyperthyroidism:
subacute thyroiditis
Subacute thyroiditis manifests as:
- sudden, painful enlargement of the thyroid gland
- fever
- malaise
- muscle aches
Types of subacute thyroiditis:
- DeQuervain’s (subacute granulomatous) thyroiditis
- subacute lymphocytic thyroiditis
- postpartum thyroiditis
- palpation thyroiditis
Features of DeQuervain’s thyroiditis:
- multi-nucleated giant cells
- ESR >100mm/hr
- painful enlarged thyroid gland
- fever, malaise, neck soreness
- low uptake of tracer on scan
Subacute thyroiditis can be distinguished from Graves’ disease by:
the low uptake of tracer on a thyroid uptake scan
- vs increased uptake in Graves’ disease
MC location for a thyroglossal cyst:
btw isthmus of the thyroid and hyoid bone
MC type of congenital neck malformation:
thyroglossal duct cyst = persistent duct becomes fluid filled, 2-4% of neck masses
The thyroglossal duct connects the _______ to the _______ during fetal development, and usu atrophies at ___ weeks gestation.
tongue
thyroid
9
About ___% of thyroid nodules are malignant.
5%
prevalence of nodules is 5% clinically, but much higher on US or autopsy
Most thyroid cancers are _________________________ with (poor/good/excellent) prognosis.
well-differentiated papillary or follicular tumors
excellent
Most cost-effective dx tool for thyroid nodules:
fine-needle aspiration biopsy
A thyroid gland that contains autonomously functioning thyroid nodules, resulting in hyperthyroidism:
toxic nodular goiter (TNG)
TNG represents a spectrum of dz, from single hyperfunctioning nodule (toxic adenoma) w/in a multinodular thyroid to a gland with multiple areas of hyperfunction.
What is Graves’ dz?
autoimmune dz caused by long acting thyroid autoantibodies (LATS-Ab) which activate TSH-receptors, stimulating thyroid hormone synthesis/secretion and thyroid growth - causing a diffusely enlarged goiter.
MC cause of hyperthyroidism:
Graves’ dz
60-90% of all cases
Graves’ dz usu presents during ________, has a powerful hereditary component, and is more prevalent in (men/women).
adolescence women (5-10:1)
The exophthalmos assoc w/Graves’ is caused by:
inflammation of the eye muscles by attacking autoantibodies and glycoprotein deposition.
Histopathology of Grave’s:
- hyperplastic epithelium
- prominent infoldings
- tall columnar thyroid epithelium lining
- clear vacuoles in the colloid
T/F: It is sometimes difficult to tell a follicular adenoma from a well-differentiated follicular carcinoma.
True
thus, pts with follicular neoplasms are usu treated with subtotal thyroidectomy.
Four main types of thyroid cancer:
- Papillary
- Follicular
- Medullary
- Undifferentiated / Anaplastic
The majority of thyroid cancers are (benign/malignant) and are (generally/not) responsive to treatment.
highly malignant
generally responsive to tx
Thyroid nodule findings that might suspect malignancy:
- feels hard
- solitary nodule
- cold nodule on scan
- Hx of radiation exposure to head/neck/chest, esp as youth
MC thyroid cancer:
Papillary carcinoma
60-70%
Papillary carcinoma is dx more frequently in the (young/elderly) but when dx in the other, it is more likely (benign/malignant) with a (better/worse) prognosis.
Young - more frequent
Elderly - malignant, worse prognosis
F:M 2 or 3:1
Papillary tumors develop in cells that produce:
Metastasis occurs via:
thyroid hormones
lymph
the cells grow slowly, and form tiny mushroom-shaped patterns in the tumor
Histopathology of papillary carcinoma:
- fronds of tissue in papillary (finger-like) pattern
- thin fibrovascular core
- clear nuclei
- psamomma bodies
T/F: Papillary adenomas are common and benign, but lead to carcinoma.
FALSE!!
There is NO such thing! ALL papillary neoplasms should be considered malignant.
Follicular carcinoma accounts for ___% of thyroid cancers, more frequent in __:__, and is more commonly noted in the (young/elderly).
15%
MC F:M
elderly
Follicular carcinoma is (more/less) malignant than papillary carcinoma with (lymph/hematogenous) spread causing (local/distant) metastases.
more
hematogenous
distant
Follicular tumors develop in cells that produce:
iodine-containing hormones
On gross exam, follicular carcinoma appears:
- encapsulated
- solitary
- found in necrotic/hemorrhagic areas
Histopathology of follicular carcinoma:
- mb encapsulated
- well-defined follicles
- colloid-containing
T/F: Follicular adenoma and carcinoma can be readily differentiated histologically.
False
Medullary carcinoma may occur as a ________ (usually unilateral) condition or as a _______ (frequently bilateral) condition that is transmitted as an autosomal (recessive/dominant) trait.
sporadic
familial
dominant
1 in 10 is hereditary
Medullary tumors develop in cells that produce:
calcitonin C cells (parafollicular)
T/F: The excess calcitonin produced by medullary tumors significantly lowers serum calcium and phosphate levels.
False
concentration is rarely high enough to alter serum levels
T/F: Although medullary tumors are slow growing, they mb harder to control than papillary and follicular d/t tendency to metastasize.
True
Familial medullary carcinomas are associated with:
syndrome
multiple endocrine neoplasia syndrome
The fastest growing thyroid tumors are:
anaplastic tumors
Anaplastic carcinoma tumors are characterized by:
rapid growth painful enlargement of the thyroid gland 80% die w/in 1 year of dx MC in elderly >F:M
4+ glands located on the posterior thyroid:
Typical weight:
parathyroid glands
25-40mg (each is the size of a grain of rice)
Microscopically, the parathyroid glands are (easy/hard) to differentiate. Surgically, they are (easy/hard).
easy microscopically - densely packed cells
hard surgically - visibly similar to thyroid and fat
The activity of the parathyroid glands is controlled by the level of free _________ in the bloodstream, rather than ___________ secreted by the hypothalamus and pituitary.
(ionized) calcium (neg feedback)
trophic hormones
decreased serum calcium stimulates synth/release of PTH
Summarize the metabolic functions of PTH in regulating serum calcium levels:
- Inc renal tubular reabsorption of Ca2+, conserving free Ca2+.
- Inc conversion of vit D to active dihydroxy form in Ki.
- Inc urinary phosphate excretion, lowering serum phos levels.
- Augments GI Ca2+ absorption.
(Similar/in contrast) to the mechanism that most secretory cells use, calcium (increases/inhibits) vesicle fusion and release of PTH.
In contrast
inhibits
In parathyroids, Mg plays role of stimulus-secretion coupling. Hypomagnesia may result in paralysis of PTH secretion, leads to a reversible form of hypoparathyroidism.
Parathyroid stimulators:
- dec serum Ca2+
- mild dec serum Mg2+.
- inc serum phosphate (inc phosphate causes complex w/ serum Ca2+, forming calcium phosphate -> reduces stimulation of Ca-sensitive receptors that dont sense Calcium phosphate. lack of stimulation triggers inc in PTH)
Parathyroid inhibitors:
- Inc serum Ca2+
* Severe dec in serum Mg2+ (mb produce sx of hypoparathyroidism, such as hypocalcemia)
PTH is secreted by the _____ cells in the glands, and acts to increase concentration of _____ in the bloodstream. This is in contrast to the effects of _______ which is produced by the _______________ cells that act to decrease concentrations.
chief
calcium
calcitonin
parafollicular C cells (of the thyroid)
PTH inc the concentration of Ca2+ in blood by acting upon ____ receptors which are found in high concentrations in the ____ and ______. It also works on _____ receptors found in __________________________.
PTH1
bone and kidney
PTH2
CNS, pancreas, testes, and placenta
Avg PTH levels in serum:
10-60pg/ml
PTH enhances the uptake of phosphate from the ______ and _______ into the blood.
intestine and bones
slightly more calcium than phosphate is released from the breakdown of bone.
Oxyphil cells are (larger/smaller) than the chief cells, (more numerous/fewer) in number and stain more (lightly/darkly). The function of Oxyphil cells is:
larger
fewer
lightly
not yet known
Histology of parathyroid chief cells:
- abundant
- stain light to dark pink
- polygonal
- eosinophilic staining cytoplasm
- centrally located, uniformly round nuclei
- secretory granules containing PTH
- sometimes appear clear d/t lg amt of stored glycogen
One of the MC endocrine d/o’s and an important cause of hypercalcemia:
primary hyperparathyroidism
Underlying condition in 85-95% of parathyroid hyperfunction:
adenoma
5-10% primary hyperplasia
1% parathyroid carcinoma
80% of pts w/1° hyperparathyroidism are dx:
incidentally on a serum electrolyte panel
- most 50+
- F:M 4:1
Parathyroid adenomas are almost always (solitary/multiple) lesions
solitary
T/F: Dx of parathyroid carcinoma based on cytologic detail is unreliable, and invasion of surrounding tissues and metastasis are the only reliable criteria.
True
What morphological changes to the skeletal system occur with hyperparathyroidism?
- skeletal - inc # of osteoclasts to mobilize Ca2+ salts, inc osteoblast activity w/widely spaced trabeculae, thinned cortex (late stage) w/fibrous marrow, hemorrhage foci, cyst formation.
2° hyperparathyroidism is caused by _____________, which leads to ___________________.
any condition that gives rise to chronic hypocalcemia
compensatory over activity of the parathyroid glands -> inc cell division, cell number -> eventual hyperplasia
MC cause of 2° hyperparathyroidism:
renal failure
other: inadequate dietary intake of calcium vitamin D deficiency steatorrhea malabsorption syndromes
In 2° hyperparathyroidism the parathyroid glands are:
hyperplastic
Do you see the same bone changes in 2° hyperparathyroidism?
yes. Mb also metastatic calcifications - lungs, heart, stomach, blood vessels.
Mechanisms - renal failure -> 2° hyperparathyroidism:
- dec phosphate excreted in urine -> hyperphosphatemia
- inc serum phosphate depresses serum Ca2+ -> stimulate parathyroid activity
- dec Vit D3 synthesis in affected kidneys -> dec GI absorption of Ca2+
Histopathology of parathyroid hyperplasia:
- little/no adipose
- all normal cell types
- pink oxyphil cells
T/F: The onset of hypercalcemic symptoms in parathyroid carcinoma is usu more abrupt and more severe than hyperparathyroidism from non-malignant causes.
True
esp severe bone and renal sxs!
Common clinical findings of parathyroid carcinoma:
- bone pain, pathologic fracture (90%)
- renal stones (80%)
- fatigue
- weakness
- confusion
- depression
- constipation
Parathyroid carcinoma is (common/rare).
rare
1.25 cases per 10M people
Malignancy related to hypercalcemia MC results from:
ectopic production of PTHrP from tumor cells [PTH related protein]
less common: skeletal cancer infiltration, lysis of bone
PTHrP can be secreted by many types of cancer cells but is seen MC with:
breast cancer
certain types of lung cancer
T/F: PTHrP is always abnormal.
False
tooth eruption
mammary gland development
co-regulates lactation
A dz or sx that is the consequence of the presence of cancer in the body, but not d/t local presence of cancer cells:
para-neoplastic syndrome [mediated by humoral factors or immune response to tumor]
i.e. PTHrP-related hypercalcemia
T/F: The two functional parts of the adrenal glands are derived from the same tissue type but function as separate glands.
false - derived from different tissues, function separate
outer cortex
inner medulla
Describe the HPA axis.
- hypothalamus releases CRH in response to stress
- CRH stimulates ant pit to release ACTH
- ACTH stimulates adrenals to release cortisol
- CRH under neg feedback by ACTH and cortisol
ACTH is produced by __________ cells which make up ___% of the pituitary. It is released in a _______ fashion throughout the day and in a normal ______ rhythm. Peak levels occur at _______, trough at _________.
corticotroph 15% pulsatile circadian peak: 4-6am trough: 12-2am
3 types of steroid hormones produced by the adrenal cortex:
Overproduction of any is MC result of:
- glucocorticoids (cortisol)
- mineralcorticoids (aldosterone)
- sex steroids (DHEA)
ALL DERIVED FROM CHOLESTEROL
functional adenoma in one cell line
The zona __________ is the outermost layer of the adrenal cortex. It produces ______________. Regulation of production is via the _______.
glomerulosa
mineralcorticoids (aldosterone)
RAS (renin-angiotensis system)
The zona ___________ is the middle layer. It produces __________. Regulation is via _________.
fasciculata
glucocorticoids (cortisol, sm amts of androgen)
CRH and ACTH
The zona _________ is the innermost layer. It produces ___________. Regulation is via __________.
reticularis
sex steroids (adrogens, sm amt of estrogens/cortisol)
CRH and ACTH
The adrenal medulla is essentially a ________________ and 80% of cells produce __________. The rest produce _________.
gland within a gland
epinephrine
norepinephrine
adrenal medulla also produces sm amts of dopamine
Renin is produced by the ___________ cells. It converts:
juxtaglomerular cells of the kidney
angiotensin I to angiotensin II
Aldosterone production/release is controlled by:
** RAS system via Angiotensin II **
also by:
- ACTH
- sympathetic nervous system
- inc serum K+
Conn’s syndrome is _______________________, MC d/t presence of a ______________.
1° hyperaldosteronism
functional adrenal adenoma
mb d/t adrenal hyperplasia
Clinical findings in Conn’s syndrome:
- HTN often the only sign **
- cortisol usu normal
- unexplained hypokalemia/hypernatremia
Describe the mechanism for HTN in Conn’s:
Aldosterone -> sodium retention by the kidney -> fluid retention -> increased intravascular volume -> elevation of blood pressure.
A (majority/minority) of adrenocortical adenomas are functional - ___%.
minority
15%
Abn labs seen in Conn’s:
- high aldosterone
- high sodium
- low potassium
- dec plasma renin
Work up for Conn’s:
Usu treatment:
CT or MRI
Surgical - if adenoma
Aldosterone agonist - if hyperplasia
Adrenal hyperfunction, MC d/t long term use of pharma doses of glucocorticoids:
Cushing’s syndrome
drugs like prednisone act as exogenous glucocorticoids -> suppress CRH and ACTH production
When Cushing’s is non-iatrogenic, it is usu d/t:
tumors
- pituitary (corticotrophin cell line -> ACTH)
- adrenal (zona fasciculata)
- ectopic (lung MC)
T/F: Ectopic ACTH production and resultant excess serum cortisol is dependent on negative feedback inhibition.
False
Independent of negative feedback inhibition!
The majority of Cushing’s syndrome is ACTH (in/dependent).
Dependent (80%)
- pituitary tumors
- lung cancer and other tumors
Independent (20%)
- benign adrenal tumors / adenoma
- malignant adrenal tumors / ACC
Features of Cushing’s:
- Moon facies
- truncal obesity
- striae
- buffalo hump
- flushed appearance
- easy bruising
- muscle wasting
- weakness
Addison’s dz is a condition of _________ insufficiency.
adrenocorticoid
1° - adrenal gland damaged
2° - insufficient ACTH -> adrenal cortex atrophy
MC cause of Addison’s dz is:
Often found in assoc with:
autoimmune destruction of the adrenal cortex
- type 1 DM
- Hashimoto’s thyroiditis
- Vitiligo
Features of Addison’s:
- hypotension
- hyperpigmentation (high ACTH -> inc melanin)
- weakness
- anorexia
- dehydration
Secondary Addison’s mb d/t:
- **usu from inadequate secretion of ACTH by the ant pit
- withdrawal of long term exogenous glucocorticoid use
- pituitary tumors
- damage to pituitary by surgery, trauma, irradiation
- adrenal function loss from trauma or hemorrhage
Adrenal gland failure d/t hemorrhage from sepsis is called:
Waterhouse-Frederickson syndrome
MC - Neisseria meningitidis
What is a differentiating skin symptom for 2° Addison’s?
skin pallor instead of hyperpigmentation
d/t diminished ACTH, no stimulation of melanocytes
Describe the etiology of Addisonian crisis.
Abrupt removal of exogenous glucocorticoid drugs leaves pts low on ACTH, pituitary is unable to compensate with adequate production, and adrenals may not produce sufficient cortisol.
* may also occur in great stress (surgery, infx)
Sx of Addisonian crisis:
Extreme weakness Nausea/vomiting Dehydration Hypotension – often life threatening Hypoglycemia Hyponatremia
Inborn error of metabolism with a specific deficiency of one or more enzymes involved in cortisol synthesis:
Congenital adrenal hyperplasia (CAH)
a group of autosomal recessive disorders that each result in an enzyme deficiency
MC example of CAH enzyme deficiency:
21-hydroxylase - 95%
CYP21A mutation or deletion
21-hydroxylase deficiency results in blockage of ________ production, with subsequent increase in _____ levels. _______________ is also increased with subsequent increase in _______________.
cortisol
ACTH
17-hydroxyprogesterone
androstenedione (virilization in females)
How is 21-hydroxylase CAH diagnosed?
measure 17-hydroxyprogesterone and 17-ketosteroids
both elevated in pt w/21-hydroxylase enzyme deficiency
Embryologically, adrenal medulla tissue is derived from _____________ cells which migrate from the ____________.
pheochromoblast
neural crest
This tissue also secretes amine hormones, epinephrine, norepinephrine, and dopamine.
All catecholamines are derived from the amino acid:
tyrosine
Most significant pathology assoc w/ the adrenal medulla:
pheochromocytoma
catecholamine-secreting tumor of the chromaffin cells
Hallmark sx of pheochromocytoma:
variable and very labile HTN
MEN IIa assoc with:
- pheochromocytoma
- medullary carcinoma of the thyroid
- hyperparathyroidism
MEN IIb assoc with:
- pheochromocytoma
- mucosal neuromas
- hyperparathyroidism
T/F: Adrenocortical incidentalomas are relatively uncommon.
False
relatively common - mb 5-15% of adults
small number are functional
only 1% of tumors found to be malignant
1° adrenal cancers:
- neuroblastomas
- adrenocorticoid carcinomas
- adrenal pheochromocytomas
MC solid extra-cranial malignancy in infants and children:
neuroblastoma
90% by 8y.o.
50% by 2y.o.
10% of childhood cancers in US
Histopathology of neuroblastomas reveals:
rosettes - circular groupings of dark cells surrounding a pale center composed of neurofibrils
The pancreas is both an ________ gland, producing hormones like __________________ and a ________ organ.
endocrine hormones - insulin - glucagon - somatostatin - pancreatic polypeptide digestive
Insulin is produced by the ___ cells in the _____________. These make up the _______ portion of the pancreas.
beta
islets of Langerhans
endocrine (1% of mass)
Surrounding the islets are darker staining ______ cells, which make up the ________ portion of the pancreas which secrete ____________.
acinar
exocrine
digestive enzymes
The islets contain several types of cells - that secrete: alpha cells - beta cells - delta cells - D1 cells - PP cells - Enterochromaffin cells -
alpha - glucagon beta - insulin, amylin delta - somatostatin D1 - VIP (vasoactive intestinal polypeptide) PP - pancreatic polypeptide enterochrom - serotonin
Staining used to help ID the nature of islet cells:
immunoperoxidase
Paracrine feedback system of the islets of Langerhans:
Insulin - activates beta; inhibits alpha
Glucagon - activates alpha -> activate beta and delta
Somatostatin - inhibits alpha and beta
GLUT receptors require _______ to begin the process of moving glucose into the cell. In its absence, transporters remain ______________.
insulin
in cytoplasmic vesicles
T/F: Diabetes mellitus is a single disease notable for marked hyperglycemia.
false
it is a group of metabolic disorders with hyperglycemia being the common underlying feature, mb d/t defects of secretion, action, or both
Diabetes causes secondary damage in:
- kidneys
- eyes
- nerves
- blood vessels
others
Lab criteria for dx of DM:
- fasting glucose >126mg/dL
- non-fasting glucose >200mg/dL w/sx
- positive OGTT w/>200mg/dL 2-3 post-bolus
- Hgb A1C >6.5%
A sugar molecule bonding to a protein or lipid without enzyme:
glycation (vs. glycosylation w/enzyme)
DM I accounts for _____% of cases, whereas DM II accounts for ______%.
I - 5-10%
II - 85-95%
1.5 - ~5%
Type __ DM is an autoimmune disease in which islet destruction is caused by immune effector cells reacting against endogenous β-cell antigens.
1 - islet cell abs and anti-insulin abs
MC develops in childhood, manifest in puberty, progresses w/age
In DM type 1, most islet cell abs are directed against:
GAD (glutamic acid decarboxylase) within pancreatic beta cells
Histopathology finding of DM I:
leukocyte infiltration of islet cells - “insulitis”
The 2 metabolic defects that characterize DM II:
- peripheral insulin resistance
* beta cell dysfunction manifest as inadequate secretion
Insulin resistance assoc w/obesity is induced by:
- adipokines
- FFAs
- chronic inflammation in adipose
Histopathology of DM II:
- pink hyalinization
* amyloid deposition
What is LADA?
late-onset autoimmune diabetes of adulthood
estimated 20% of non-obesity related type 2 mb LADA
How is diabetic retinopathy best controlled?
blood glucose control and early tx of HTN
occurs in 15% of pts w/diabetes x10-15 yrs +1%/yr
Frequency of neuropathy in DM II:
70-80%
* sensorimotor
* autonomic
[slide 39]
Non-proliferative diabetic retinopathy is characterized by:
dilated capillaries that leak RBCs and plasma into retina
- hemorrhage
- edema
- exudative deposits
- neovascularization
- cotton wool spots
MC cause of vision loss d/t diabetic retinopathy:
macular edema
Histopathology of diabetic glomerulonephropathy:
- thickening of capillaries (earliest) -> microalbuminuria
- diffuse inc in mesangial matrix
- acellular PAS-positive nodules
Pancreatic endocrine tumors (PETs) are (common/uncommon) and present as _______________.
uncommon
functional or non-functional
Functional PETs are commonly assoc with:
specific hormonal syndromes
- Zollinger-Ellison
- hyperinsulinemia
Histopathology of pancreatic islet cell adenoma:
“monotonous” appearance
- minimal pleomorphism
- minimal mitotic activity
- amyloid deposition
An insulinoma is a pancreatic tumor derived from ___ cells.
beta
insulin secretion is not properly controlled by feedback mechanisms, thus continue to secrete -> hypoglycemia
What is Whipple’s triad?
- sx of hypoglycemia
* serum glucose of
MC location for insulinoma to arise:
pancreas - 99%
5% assoc w/parathyroid, MEN I
Dx for insulinoma made on:
- low serum glucose
- high serum insulin, proinsulin, C-peptide
confirm by MRI or angiography, then biopsy
Tumor of the pancreas or duodenum that secretes excess gastrin, leading to excess gastric production of HCl -> subsequent development of GI ulcerations:
gastrinoma
HCl also causes hyperperistalsis, inhibits lipase
Sx of gastrinoma:
- hypergastrinemia
- GI ulcers
- severe diarrhea
- cancer sx - anorexia, wt loss, fatigue, malaise
Most gastrinomas are found as (single/multiple) tumor(s) and are found to be (benign/malignant). Most are found in the (pancreas/duodenum/jejunum).
single (notes contradictory)
malignant
duodenum
Malignant gastrinomas MC spread to:
liver
lymph nodes near pancreas and sm intestine
Gastrinomas are frequently the cause of excess gastrin in:
Zollinger-Ellison syndrome (25% MEN I)
Zollinger-Ellison triad:
- gastric acid hypersecretion
- severe peptic ulceration
- gastrinomas (pancreas or duodenum)
self-perpetuating, leading to multiple ulcers
Laughter is the best medicine,
unless your diabetic, then insulin might be better.
THE END
