Download Path 24- Endocrine System [3-20

1. 2 major portions of the pituitary gland? Where derived from? 5 cell types and staining
characteristics of each for anterior pituitary gland? Cell types in posterior? 2 hormones produced
by posterior pituitary?
a. anterior pituitary (adenohypophysis from ratche pouch) and posterior (neruohypophysis
from brain)
b. Somatotrophs (acidophili; GH; 50% of cells), Lactotrophs (acidophillic; prolactin),
Thyrotrophs (basophilic; TSH), Corticotrophs (basophilic; ACTH, POMC, MSH,
endorphins, liptropin), gonadotrophs (basophilic, LH and FSH)
c. pituicytes (modified glial cells) and hypothalamic axon processes--> ADH and oxytocin
2. What signs or symptoms occur from mass effect in pituitary tumors? What is most common cause
of hyperpituitarism? Most common dual hormone secretion of pituitary adenoma?
a. radiographic abnormalities in sella turcica, visual field abnormalities (bitemporal
hemianopsia), elevated intracranial pressure (headache, nausea, vomiting), pituitary
apoplexy (hemorrhage into adenoma)
b. adenoma from anterior lobe; most common dual hormones are GH and prolactin
3. What is distinction b/t pituitary micro- and macro adenomas? Which more likely to be functional?
A mutation in what gene is found in 40% of somatotroph adenomas? What other pituitary
adenoma assoc w/? How does cause prolif?
a. micro <1cm diameter and more likely functional; macro > 1cm diameter
b. GNAS; corticotroph adenomas
c. mutation causes GTPase activity of Gsalpha to be lost, so there is continual cAMP
production triggering unchecked cellular proliferation
4. What tumor supressor loses function in MEN-1? Most common tumors pituitary tumors
developed by these ppl? What tumor is a germ line mutation in the tumor supressor aryl
hydrocarbon receptor interating protein (AIP) assoc?
a. menin; GH-, prolactin-, or ACTH-secreting tumors
b. acromegally from GH-adenoma (often present at yougner ages than sporadic)
5. How can normal pituitary tissue be distinguished from neoplastic parenchyma? When should a
pituitary adenoma be classified as atypical and why? Most frequent type of hyper functioning
pituitary adenoma?
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a. there is cellular monomorphis (1 cell type) and absence of reticulin in neoplastic
parenchyma
b. when it demonstrates brisk mitotic activity (evidence of Ki-67 (prolif marker) and p53
immunoreactivity); have higher propensity for aggressive behavior and recurrence so
need to be distinguished
c. Prolactinoma
Morphologic findings for a prolactinoma? Clinical presentation? Other causes of
hyperprolactinemia?
a. generally sparsely granulated acidophilic cells (rarely densely granulated), stain
immunohistochemically for prolactin, have propensity to undergo calcification 'pituitary
stone'
b. amenorrhea, galactorrhea, loss of libido, infertility; generally in women from 20-40yrs
c. physiologic hyperprolactinemia in pregnancy (peaks at delivery), from nipple
stimulation, from lactotroph hyperplasia (if dopaminergic neruons antagonized or
damaged-head trauma)
Second most common type of functioning pituitary adenoma? Morphologic findings? Clinical
presentation? 3 findings used to diagnose?
a. GH-secreting tumor (somatotroph)- densely granulated or sparsely granulated
(eosinophilic)
b. if b4 epiphysis closure- giantism (long arms and legs); if after- acromegally (enlarged
hands, feet, viscera (liver, thyroid, heart, adrenals), jaw enlargement); may also see
diabetes, HTN, arthritis
c. findings of elevated serum GH, elevated IGF-1, and failure to suppress GH w/ oral
glucose (most sensitive)
Histologic findings of a corticotroph adenoma? Clinical presentation? What happens in Nelson
syndrome?
a. small basophilic micro adenoma (densely granulated) that stains w/ PAS (carbohydrate of
POMC stains)
b. Cushings Disease- covered later in chapter (moon face, buffalo hump, straie, easy
bruising/tears)
c. occurs after removal of adrenals; there is no cortisol to feed back on corticotrophs so they
hypertrophy causing mass effect and elevated ACTH (may present w/ hyper
pigmentation)
Who are gonadotroph adenomas most commonly found in? Symptoms? Most common products
of pituitary carcinomas?
a. middle aged men and women when tumor large enough to cause neurologic symptoms
(vision issues, headaches); may also have decreased energy/libido (men) and amenorrhea
(premonopause)
b. prolactin and ACTH (carcinomas very rare)
How much of anterior pituitary must be damaged before hypo function is observed? How do you
know if problem is hypothalamic in origin? What are some causes of hypopituitarism? Which is
MOST COMMON?
a. 75% damaged; if hypopituitarism is accompanied by DI almost always hypothalamic
origin
b. tumors (compress gland; ie pituitary adenoma), traumatic head injury/subarachnoid
hemorrhage (most common), pituitary surgery, pituitary apoplexy (emergency!), Sheehan
syndrome, rathke cleft cyst, empty sella syndrome, genetic defect, hypothalamic lesion,
inflammatory/infection
What is most common form of clinically significant ischemic necrosis of anterior pituitary? Why?
Difference between primary and secondary empty sella syndrome?
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a. Sheehan syndrome (postpartum)- gland hypertrophies x2 in pregnancy, but vascular
increase does not occur (may also be seen in sickle cell, DIC, trauma, shock)
b. primary- defect in diaphragm sella allowing arachnoid mater and CSF to enter sella and
compress pituitary; secondary- sella enlarged by pituitary adenoma that is then removed
or necroses (both have enlarged sella)
2 significant syndromes of posterior pituitary? Cause and clinical presentation?
a. diabetes insipidus (DI)- neurogenic-head trauma, tumor, inflammatory disorder of
hypothalamus or pituitary surgery; nephrogenic- renal unresponsiveness; Symptoms:
polydipsia, polyuria
b. Syndrome of Inappropriate ADH (SIADH) secretion- caused most freq by ectopic
seceretion of ADH by malignant neoplasm (small cell carcinoma of lung); Sympt:
hyponatremia, cerebral edema, neuro dysfxn
Most common hypothalamic suprasellar tumors (2)? Age distribution? Clinical symptoms?
a. gliomas and craniopharyngiomas (from Rathke pouch remnants); bimodal: peak 5-15 and
>65
b. headache, visual field disturbance, growth retardation in children
Two histologic variants of craniopharyngiomas? Age occur at? Morphologic findings of each?
a. adamantinomatous (children)- dystorphic calcifications, spongy reticulum w/ 'palisading'
squamous epithelium, wet keratin (diagnostic), cyst formation (machine oil-cholesterol
rich)
b. papillary (adults)- solid sheets and papillae of squamous epithelium w/o keratin,
calcifications, cysts, palisading, or spongy reticulum
Signaling cascade of TSH binding it's receptor? Type of signal transduction of TH? Function of
calcitonin?
a. Gs protein (to increase cAMP); thyroid hormone binds nuclear receptor (TR) & regulates
gene transcription
b. promotes absorption of Ca by skeletal system and inhibits resorption by osteoclasts
What is thyrotoxicosis? Most common cause? 3 most common causes of hyperthyroidism?
Symptoms?
a. hyper metabolic state caused by elevated levels of circulating T3 and T4
b. hyper function of thyroid gland (most common cause thyrotoxicosis)
c. Diffuse hyperplasi of thyroid (Graves; 85% cases), hyperfxnl multi nodular goiter,
hyprfxn adenoma
d. increased basal metalloidc rate (weight loss, heat intolerance, flushed skin), cardiac (tach,
palpitations, cardiomegally), tremor, hyperactivity, anxiety, insomnia, staring gaze, GI
motility increase, osteoporosis
What is thyroid storm? What is apathetic hyperthyroidism? How is hyperthyroidism diagnosed?
Treatment?
a. sudden onset of severe hyperthyroidism (Graves most common form); fever, tachycardia,
possible death
b. apathetic is thyrotoxicosis in elderly that doesn't have normal features due to their age
c. measurement of TSH (most useful screen), measurement of free T4 and T3, measurement
of radioactive iodine uptake (increased in Graves and solitary nodule; decreased in
thyroiditis)
d. beta blocker for symptoms, thionamide to block hormone synth, radio iodine ablation,
iodine solution
Gender affected most by hypothyroidism? Most common cause worldwide? Most common cause
in iodine-sufficient areas? Most common cause of dyshormonogenetic goiter? What causes
thyroid resistance syndrome?
a. Women (10:1) and most common cause worldwide ins endemic iodine defiency in diet
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b. Hashimotos thyroidits (anti-microsomal, anti-thyroid peroxidase, and anti-thyroglobin
antibodies)
c. mutation in thyroid peroxidase (TPO) most common; resistance synd. from AD mutation
in TH receptor
d. NOTE: hypothyroidism can be acquired from surgical/radiation ablation of thyroid gland
or drugs
What is cretinism caused by and what are symptoms? What is myxedema? Most sensitive test for
hypothyroid?
a. thyroid hormone deficiency in utero (esp in endemic iodine deficiency areas); short
stature, coarse fascial features, protruding tongue, MENTAL IMPAIRMENT, and
umbilical hernia
b. hypothyroid symptoms in older child or adult; Slowing of physical and mental activity
(fatigue, apathy, mental sluggishness), cold intolerance, overweight, cold/pale skin,
accumulation of glycosaminoglycans in skin and sub-cut tissue causing non-pitting
edema, coarsening of face, and enlargement of tongue
c. measuring serum TSH most sensitive; T4 levels decreased
How does infectious thyroiditis present? Who does it occur in frequently? 2 most common
immunologically mediated diseases of the thyroid?
a. sudden onset of neck pain in gland area w/ fever, chills; in immunocompromised (often
Pneumocystitis)
b. Hashimoto's Thyroiditis and Graves disease
What is Hashimoto thyroiditis characterized by? What gene is most significantly linked to risk of
Hashimoto's? Another important susceptibility gene?
a. characterized by gradual thyroid failure from autoimmune destruction of gland (often
women 40-60)
b. CTLA4 polymorphism (is neg regulator of Tcell responses for tolerance)
c. protein tyrosine phosphatase 22 (PTPN22)- encodes phosphatase that inhibits Tcell fxn
Auto-antibodies to what in majority of Hashimoto ppl? 3 mechanisms that contribute to cell
death? Morph findings?
a. antibodies to thyroglobin and thyroid peroxidase;
b. CTL damage, TH1 production of IFN gamma activating macrophages to damage
follicles, antibody-dependent cell-mediated cytotoxicity from auto-antibodies
c. thyroid diffusely enlarged with extensive mononuclear inflammatory infiltrate, germinal
centers, and atrophic follicles lined w/ Hurthle cells (granular eosinophilic cells)
What aspiration findings are characteristic of Hashimotos? What clinical symptoms in disease?
Increased risk for?
a. presence of Hurthle cells in conduction w/ heterogenous lymphocyte population
b. painless symmetrical enlargement of thyroid, symptoms of hypothyroidism (may have
hyper priorly)
c. increased risk for other autoimmune diseases (diabetes I, SLE, etc) and B-cell nonHodgkin lymphoma
What generally causes DeQuervian thyroiditis? Clinical presentation? Morphologic findings?
a. triggered by viral infection (esp upper respiratory); painful (most common cause of
thyroid pain) transient enlargement of thyroid, hyperthyroid symptoms; has diminished
radioactive iodine uptake (unlike graves)
b. yellow-white gland appearance w/ scattered follicles, lympcyte and macrophage
agregates, and multinucleate giant cells (granulomas)
What painless thyroiditis may occur postpartum? How does it usually present? What is Riedel
thyroiditis?
a. Subacute lymphocytic thyroiditis; presents as mild hyperthyroidism w/ goitrous
enlargement of gland (1/3 eventually progress to hypothroidism w/in 10 yrs)
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b. extensive fibrosis of thyroid and neck structures forming fixed thyroid mass; etiology
unknown
Triad of clinical findings in Grave's Disease? Who generally affected? Genes assoc. w/
susceptibility?
a. Hyperthyroidism, infiltrative ophthalmopathy, pretibial myxedema (dermopathy)
b. generally women (10:1) w/ peak b/t 20-40 yrs age; genes: CTLA4 and PTPN22
What 3 auto-antibodies are produced in Graves? 4 factors contributing to exopthalamous?
Morphologic findings?
a. thyroid stimulating immunoglobins (IgG stimulates TSH receptor), thyroid growthstimulating Igs, TSH-binding inhibitior immunoglobulins
b. infiltration of retro-orbital space w/ Tcells, inflammation/edema of EO muscles,
accumulation of GAGs, and increased number of adipocytes--> all push eyeball forward
and interfere w/ EOMs
c. diffuse hypertrophy and hyperplasia of thyroid gland symmetricially; follicular cells are
tall, more crowded, and somewhat papillary in appearance and colloid has scalloped
margins; germinal centers common
Why can a bruit be heard in Graves disease? What causes lid lag of eye? What laboratory
findings inicate Graves?
a. b/c enlargement of gland is accompanied by INCREASED flow of blood; lid lag from xs
sympathetics
b. Lab: elevated T4 and T3, decreased TSH, radioactive iodine uptake INCREASED
What is most common manifestation of thyroid disease? Most common cause?
a. Goiter (diffuse and multinodular goiters reflect impaired thyroid hormone synth);
endemic iodine deficiency
What is appearance of simple goiter? 2 phases that can be morphologically identified? Clinical
presentation?
a. also called diffuse nontoxic: diffuse enlargement of entire gland w/o nodularity (endemic
or sporadic)
b. Hyperplastic phase (gross: diffuse symmetric gland enlargement; microscopic: follicular
hypertrophy and hyperplasia (not uniform); Colloid involution (when thyroid hormone
demand met)- (gross: glassy, brown; microscopic: involution of follicular epithelium to
form enlarged colloid-rich gland)
c. pateints generally euthyroid, TSH elevated, and symptoms from mass effec of enlarged
gland
What causes most extreme thyroid enlargement? What do they develop from? What causes
nodularity?
a. multinodular goiter (often mistaken for neoplasm); often develop from simple goiters
b. uneven follicular hyperplasia, generation of new follicles, uneven accum of colloid-->
cause stress leading to follicle and vessel rupture, hemorrhage, and scarring--> all leading
to nodularity
What are morphologic findings of multinodular goiter? Symmetrical? How differentiated from
follicular neoplasms? What is a plunging goiter? What clinical features may occur as a result of
the enlargement?
a. LARGE (can reach 2 kg), multilobulated, Asymmetrical gland; microscopically:
follicular hyperplasia w/ evidence of degenerative change
b. follicular neoplasms have a capsule b/t hyperplastic nodules and remaining gland NOT
found in multinodular
c. occurs when the goiter grows down behind sternum and clavicles
d. airway obstruction, dysphagia, superior vena cava syndrome (all from mass effect);
generally EUTHYROID
33. What is Plummer's syndrome? What findings on radioiodine scan would be expected for
multinodular goiter?
a. development of autonomous nodule producing hyperthyroidism in long standing goiter
(10% of multinod)
b. uneven iodine uptake w/ occasional 'hot' autonomous nodule
34. What 5 clinical criteria may suggest a nodule is morelinely to be neoplastic? What test provides
most definitive info?
a. solitary, occuring in younger patient, nodule is in a male, history of radiation of
head/neck, and 'cold' nodule
b. fine-needle aspiration w/ histologic study of resected parenchyma
35. What is a follicular adenoma? Does it lead to carcinoma? What features are important in
distinguishing it from a multinodular goiter and from a follicular carcinoma?
a. solitary mass derived fro follicular epithelium (generally painless)
b. No (though some genetic alterations are shared w/ follic carcinoma; RAS, PIK3CA,
PAX8-PPARG)
c. distiguished by singular nodule and presence of intact well-formed capsule-->
multinodular goiter has multiple nodules and no capsule and follicular carcinoma has
capsular/vascular invasion
36. What thyroid carcinoma is most common? What are 3 other thyroid carcinomas? What genetic
mutations in each?
a. Papillary (85% of cases)--> activation of MAP kinase pathway via transmembrane
receptor forming RET/PTC fusion recptor that is continually active OR via point
mutation in BRAF (worse prognosis)
b. Follicular (5-15%)--> gain of function mutation in RAS or PI-3K/AKT, loss fxn of PTEN
(inhib PI3K), or fusion gene of PAX8:PPARG
c. Anaplastic (<5%)--> higher rate of mutations of RAS or PIK3CA + mutations of p53 or
beta-catenin
d. Medullary (5%)--> occur in MEN-2 or sporatic w/ mutations in RET (though NO fusion
proteins formed)
37. Major environmental risk factor for papillary carcinoma? for Follicular? What are microscopic
hallmarks of papillary?
a. papillary- exposure to ionizing radiation; follicular- edemic iodine deficiency
b. branching papillae w/ fibrovascular stalk, clear/empty nuclei (ground-glass; Orphan
Annie eye nuclei), psamomma bodies (calcified structures) in papillia
38. What is diagnosis of papillary carcinoma based on? Most common variant? Aggressive variant
that tends to occur in older ppl? Varient that tends to occur in younger individuals?
a. diagnosis based on NUCLEAR features; follicular varient most common (follic arcitec
but papillary nuclei)
b. Tall-cell varient: tall eosinophilic cells, often BRAF mutations, high freq of vasc invasion
and metastasis
c. diffuse sclerosis varient in younger ppl- diffuse fibrosis throughout gland w/ lymph node
metastases in all
39. What is often first manifestation of convential papillary carcinoma? What tests used to
diagnose/identify?
a. cervical lymph node metatasis!!
b. scintiscans reveal 'cold' mass; fine needle aspiration to demonstrate nuclear features
40. How are follicular carcinomas differentiated from papillary carcinomas and from follicular
adenomas? How do these carcinomas present? What type of metastasis is most common?
a. distinguished from papillary by lack of nuclear features and lack of psammoma bodies
and from follicular adenomas by evidence of capsular/vascular invasion
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b. present as slowly enlarging painless nodules that are cold on scintigrams; vascular
spread(bone, lungs, liver)
What is the clinical course of anaplastic carcinoma of thyroid? 3 microscopic variants?
a. rapidly enlarging bulky neck mass that is 100% fatal, metastasizes to lungs by time of
diagnosis, and tends to occur in older ppl who have had other thyroid cancers in past
b. Giant cell (large pleomorphic giant cells), spindle, and mixed (giant and spindle)
What do medullary carcinomas secrete? What familial syndrome are they associated with? 2
morphologic differences b/t familial and sporadic medullary carcinomas? What deposits are often
found in stroma?
a. calcitonin; assoc w/ MEN 2A or 2B (activating mutation in RET)
b. sporadic tend to be single nodule w/o c-cell hyperplasia surrounding lesion: familial tend
to be bilateral/multi centric and to demonstrate C-cell hyperplasia in surrounding
parenchyma (multiple clusters of C cells)
c. amyloid deposits (derived from altered calcitonin polypeptide)
What are 2 useful markers for medullary carcinomas? Treatment for MEN-2 ppl w/ RET
mutations? Most common clinically significant congenital anomaly of thyroid?
a. calcitonin levels and carcinoembryonic antigen
b. all asymptomatic MEN-2 w/ germ line RET offered prophylactic thyroidectomy ASAP
c. tyroglossal duct or cyst (can be converted to abscess if infection superimposed)
What are 2 cell types of parathyroid gland? What triggers release of PTH? How does it increase
Ca++?
a. chief cells (contain PTH) and oxyphil cells (many mitochondria, but no PTH); PTH
regulated by free Ca++
b. increases renal reabsorption of Ca++, increases conversion of vitamin D to active form,
increases urinary phosphate excretion (creates gradient for calcium to move from bone),
and augments GI Ca++ absorption
What is the most common cause of clinically apparent hypercalcemia? of incidental
hypercalcemia? How do solid tumors cause hypercalcemia? What 3 lesions lead to primary
hyperparthyroidism?
a. malignancy--> solid tumors can secrete PTH related protein (PTHrP) that increases
RANKL expression on osteoblasts= osteoclast differentiation and inhibits
osteoprotegerin --> increased bone resorption
b. incidental hypercalcemia most common from primary hyperparathyroidism
c. Adenoma (85-95%), primary hyperplasia (diffuse/nodular: 5-10%), parathyroid
carcinoma (1%)
In who/when are parathyroid adenomas identified most often? 2 molecular defects associated w/
sporadic adenomas? How is morphology of adenoma different from primary hyperplasia of
parathyroid?
a. women found incidentally
b. Cyclin D1 gene inversion/over expression (10-40%) and MEN1 mutations (20-30% of
sporadic)
c. adenoma single red/brown nodule on normal or shrunken gland (feedback); gland
enlarged in hyperplasia
What is morphologic appearance in primary hyperplasia? What are only reliable criterion for
diagnosis parathyroid carcinoma? What changes are observed in skeleton and kidney from
hyperparthyroidism?
a. classically all 4 glands involved w/ chief cell hyperplasia in diffuse or multinodular
pattern
b. invasionof surrounding tissue and metastasis (cytology unreliable); tend to be grey-white,
irreg mass
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c. Bone- increased osteoclast and osteoblast activity causes widely spaced delicate
trabeculae and thinned cortex, osteitis fibrous cystic (hemorragic cyst in fibrous tissue),
brown tumors (ostoeoclasts and debris)
d. kidney- urinary tract stones, nephrocalcinosis of tubules
How do serum PTH levels differ depending on cause of hypercalcemia? What symptoms are
observed w/ primary symptomatic hyperparathyroidism (6)?
a. hyperparathyroidism has elevated PTH, while hypercalcemia of malignancy, vit D
toxicity, granulomatous disease all have decreased levels of PTH
b. "painful bones, kidney stones, GI moans, psychic moans"= osteoporosis or osteitis
fibrosa cystica cause bone pain, kidney stones, GI (consultation, gallstones, PUD), CNS
(depression, lethargy), neuromusc (weakness/fatigue), cardiac (aortic or mitral valve
calcification)
Most common cause of secondary hyperparathyroidism? What is appearance of glands in
secondary hyperparathyroidism? What symptoms are most notable and what therapy may help?
a. Renal failure (decreased vit D conversion to active and hyperphosphatemia triggering
PTH release)
b. glands are hyper plastic w/ increased chief cells that have clear cytoplasm 'water-clear
cells'
c. symptoms of renal failure dominant, but vitamin D supplements and phosphate binders
may help PTH
What causes acquired hypoparathyroidism? 4 genetic causes? What are the clinical
manifestations?
a. surgical (accidental removal in thyroid or radical neck surgery)
b. autoimmune polyendocrine syndrome 1 (mutation in AIRE), Autosomal dominant
activating mutation in calcium-sensing receptor (CASR) gene, Familial isolated (AD or
AR), and congenital absence (DiGeorge)
c. Hallmark of hypocalcemia = tetany (neuromuscular irritability ranging from numbness to
spams, to seizure); mental status changes, intracranial manifestations (papilledema,
parkinsons like), cataracts, prologued QT, dental (hypoplasia, failed eruption, defective
enamel, abraded teeth)
What is Chvostek sign? Trousseau sign? What do both test for? What is problem in
pseudohypoparathryoidism?
a. chvostek- tap on course of facial nerve induces contraction of eye, nose, or mouth
muscles
b. trousseau- occlusion of forearm circulate (BP cuff) produces carpal spasms
c. BOTH classic findings on physical exam of hypocalcemia
d. problem is end-organ resistance to PTH (levels of PTH are normal or elevated in blood)
In the US what diseases is diabetes the leading cause of (3)? How is the diagnosis of diabetes
made (1 of 3)? When is person considered to have impaired glucose tolerance?
a. End-stage renal disease, adult-onset blindness, and non-traumatic LE amputations
b. Random glucose >200 mg/dL w/ classic signs, a fasting glucose >126 mg/dL on more
than one occasion, abnormal oral glucose tolerance test w/ over 200mg/dL 2 hrs post load
c. If fasting glucose >100 but <126 or if oral glucose load b/t 140 and 200 mg/dL
Most common diabetes subtype before age 20? Overall? Major postpranidol insulin response site?
a. Type I diabetes (autoimmune); Type II more common overall (90-95%)
b. Skeletal muscle
What is ‘by far’ the most important susceptibility locus for type I diabetes? Other genetic
alterations that may cause increased risk? 3 ways viruses could contribute?
a. HLA locus on chromosome 6 (95% caucasions have HLA-DR3 or –DR4)
b. Insulin gene w/ variable number of tandem repeats (VNTR), CTLA4, PTPN22
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c. Bystander damage (virus damage frees sequestered Bcell antigen), molecular mimicry,
viral déjà vu
What is the fundamental immune abnormality in type I diabetes?What in islets are targets of autoantigens (3)?
a. failure of self-tolerance in T cells
b. insulin, B-cell enzyme- glutamic acid decarboxylase (GAD), and islet cell autoantigen
polymorphism in what gene most often associated w/ type II diabetes? 2 metabolic defects in type
II? What is largest contributor to pathogenesis o insulin resistance in type II? Type of obesity
linked to insulin resistance?
a. transcription factor 7-like 2 (no link to HLA, CTLA4, etc)
b. decreased response of perish tissues to insulin AND beta cell dysfunction (inadequate
secretion)
c. loss of insulin sensitivity in HEPATOCYTES
d. central obesity (abdominal fat)
4 ways obesity can adversely impact insulin sensitivity?
a. increased nonesterified FAs (NEFAs) cause accumulation of cytoplasmic intermediates
that activate serene kinases--> serine kinases inhibit insulin receptor
b. secretes pro-hyperglycemic adipokines (resisting, retinol BP4) and less antihyperglycemic ones (leptin, adiponectin)
c. secretes pro inflammatory cytokines that stress cells causing signaling cascades that
antagonize insulin
d. peroxisome proliferator-activated receptor gamma (PPARg) may have mutation;
normally promotes anti-hyperglycemic adipokine secretion
Replacement of islets w/ what is characteristic of type II diabetes? enzyme involved in MODY-2?
50% of carriers of this mutation will develop what? 4 characteristics of monogenic forms of
diabetes?
a. amyloid
b. glucokinase; 50% carriers will develop gestational diabetes
c. autosomal dominant, early onset (<25), absence of obesity, absence of Bcell
autoantibodies
What causes permanent neonatal diabetes? What is mutated in maternally inherited diabetes and
deafness? 2 types of genetic defects that can cause acanthuses nigricans (skin hyper
pigmentation)?
a. mutation in KCNJ11 (Kir 6.2 of K/ATP channel) or ABCC8 (SUR1 of K/ATP channel)
b. mutations in mitochondrial DNA
c. insulin receptor mutations and lipoatrophic diabetes
What are the main long-term complications of diabetes? What are three ways hyperglycemia
contributes to these injuries? What is the major cause diabetic neuropathy?
a. Macrovascular disease (early athersclerosis w/ risk of MI, stroke, and peripheral
gangrene
b. advanced glycosylation end products (AGEs)--> binds RAGE receptor on macrophages,
endothelial cells, and vascular smooth m (see next ?) and directly cross-links ECM
proteins enhancing protein/LDL deposition
c. activation of PKC--> increased VEGF (diabetic retinopathy), elevated vasoconstrictors,
increased deposition of ECM, reduced fibriolysis (PAI-1), production of pro-inflammatory
cytokines
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d. depletes intracellular NADPH leading to reduced glutathione reduction- more ROS
(cause of glucose neurotoxicity)
What changes in the pancreas may occur in type I? Type II? Hallmark of macrovasc disease?
Most common cause of death? Other manifestations of macrovascular disease?
a. I- reduction in number and size of islets, leukocytic infiltrate (Tcells); II- reduction in islet
cells, amyloid depo
b. accerated atherosclerosis (from endothelial dysfxn)
c. MI from atherosclerosis of coronary arteries; other macro: gangrene of LE and hyaline
atherosclerosis
What are diabetic microangiopathys morphologically characterized by? What 3 kidney lesions are
encountered in diabetic nephropathy? 3most important glomerular lesions? What form do ocular
lesions take in diabetes?
a. diffuse thickening of basement membrane and capillaries that are more leaky than
normal
b. glomerular lesions, renal athro/arteriosclerosis (esp in efferent arteriole), pyonephritis
w/ necrotizing papillits
c. basement membrane thickening, diffuse messangial sclerosis (increased mesangial
matrix), and nodular glomerulosclerosis (intercappilary glomerulosclerosis/KimmelstielWilson disease)
d. retinopathy, cataracts, or glaucoma
A combination of what 2 symptoms should always raise suspicion of diabetes 1? 2 factors that
lead to ketoacidosis?
a. polyphagia and weight loss (other symptoms of DM are polydipsia and polyuria)
b. dehydration (from osmotic diuresis of hyperglycemia) and change in insulin-to-glucagon
ratio= increased oxidation of FAs converted to ketone bodies
When is type II diabetes most frequently diagnosed? Type of coma most common for type II?
a. after routine blood or urine testing in an asymptomatic person
b. hyperosmolar nonketotic coma (from dehydration; usually in elderly disabled diabetic)
3 most common causes of mortality in long standing diabetes? What is earliest manifestation of
diabetic nephropathy? What ocular issue do 60-80% of diabetics eventually get? Most frequent
diabetic neuropahty?
a. MI, renal vascular insufficiency, and cerebrovascular accidents
b. microalbuminuria (later many progress to overt nephropathy w/ macroalbuminuria)
c. diabetic retinopathy (from VEGF over express)
d. distal symmetric polyneuropathy (starts in LE, and eventually UE "glove and stocking"
What infections do diabetics have increased risk of (4)? What factors provide unequivical criteria
for pancreatic endocrine neoplasm malignancy (3)? What type of these neoplasia most
common? 3 most common fxn syndromes?
a. skin infections, tuberculosis, pneumonia, and pyelonephritis
b. metastases, vascular invasion, and local infiltration (fxn often benign, while nonfxn often
malignant)
c. insulinoma most common (generally benign)
d. hyperinsulinism, hypergastrinemia (Zollinger Ellison syndrome), and MEN 9
What 3 symptoms/findings suggest hyperinsulinemia? 2 causes? Who most commonly has
hyperplasia of the islets? What are critical laboratory findings of an insulinoma?
a. blood glucose <50 mg/dL, CNS manifestations (confusion, stupor), precipitated by
fasting/exercise and relieved promptly by feeding
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b. insulinoma and hyperplasia of the islets (most commonly congenital hyperinsulinism (ex
material diabetes))
c. high circulating levels of insulin and a high insulin to glucose ratio
Where do gastrinomas tend to occur (3)? What assoication did Zollinger and Ellison call
attention too? What is the state of the tumor at diagnosis and what finding should point to
Zollinger-Ellison syndrome?
a. duodenum, peripancreatic soft tissue, and pancreas (gastrinoma triangle)
b. association b/t pancreatic cell lesions, hyper secretion of gastric acid, and severe peptic
ulceration
c. over 1/2 are locally invasive or have metastasized by diagnosis; jejunal ulcers should call
attention
What clinical symptoms occur in a glucagonoma (3)? A somatostatinoma? a VIPoma?
a. mild diabetes mellitus, a characteristic skin rash (necrolytic migratory erythema), and
anemia
b. diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorohydria (dec gastric acid)
c. watery diarrhea, hypokalemia, achlorohydria, or WDHA syndrome (combo of first 3)
Thickest layer of adrenal cortex? What hormones are secreted by each layer? Most common
cause of Cushings?
a. zone fasiculata (75% of total cortex)
b. glucocorticoids (fasiculata), sex steroids (reticularis), and aldosterone (glomerulosa)
c. administration of exogenous glucocoriticoids (iatrogenic Cushings syndrome)
What is most common cause of endogenous Cushing's syndrome? Who affected more
commonly? Most common ectopic source of ACTH? Who are CRH producing neoplasms more
common in (still rare)?
a. ACTH-secreting pituitary adenoma (ACTH-dependent); more common in young adult
women
b. small-cell carcinoma of the lung
c. CRH neoplasms more common in men (40-50 yrs)
What is most common cause of ACTH independent Cushings? Gendeer pref? Serum findings?
Glandular findings?
a. primary adrenal neoplasm (adenoma-10%; carcinoma-5%); more common in women
b. high serum cortisol, low ACTH
c. unilateral neoplasm in one gland; atrophy in opposite gland (no ACTH stimulation)
What morphologic change occurs most commonly in the pituitary regardless of cause of
Cushings? How do different causes of Cushings present in terms of adrenal morphology? (Table
24-8 helpful)
a. Crooke hyaline change- change of normal granular basophilic corticotrophin cells in
anterior pituitary to homogenous, more pale looking cells (from keratin accumulation)
b. exogenous Cushings--> bilateral cortical atrophy b/c lack ACTH stim;
c. endogenous ACTH-dependent (pituitary, ectopic)--> diffuse hyperplasia- bilat diffuse
thickened cortex; microscopically: expanded 'lipid-poor' reticularis surrounded by
eosinophilic 'lipid-rich' region (yellow)
d. endog. ACTH-independent (adrenal)--> nodular hyperplasia- prominant macronodules
throughout w/ mixture of lipid-poor and lipid-rich throughout and brown-black
micronodules (lipofusion)
How does Cushing's syndrome present clinically (symptoms)? How is it diagnosed in lab?
a. hypertension (early), weight gain (early- with truncal obesity, moon facies, and buffalo
hump), decreased muscle mass and prox limb weakness (selective atrophy of fast twitch
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fibers), secondary diabetes (hyperglycemia, glucosuria, polydipsia), fragile easily bruised
skin w/ abdominal straie (loss of collagen), osteoporosis (bone resorption), mental
distrubance, poor wound healing, hirsutism, menstral irregularity
b. diagnosed when 24hr urine free-cortisol conc. increased and loss of normal diurnal
cortisol secretion pattern
How can the dexamethasone test help in diagnosis of Cushings?Most common manifestation of
hyperaldosteronism?
a. Give low and high dose of it and measure urinary steroid secretion to determine cause
of Cushings:
i. if high dose decreases urinary steroids and ACTH originally elevated- pituitary
adenoma
ii. if neither dose decreases urinary steroids and ACTH orig elevated- ectopic ACTH
secretion
iii. if neither dose decreases urinary steroids and ACTH orig low- adrenal tumor
b. increased blood pressure
How can primary hyperaldosteronism be distinguished serologically from secondary? 3 causes of
each?
a. Plasma renin levels--> decreased in primary, but increased in secondary
b. Primary: Bilateral idiopathic hyperaldosteronism (nodular hyperplasia of adrenals; most
common), adrenocortical neoplasm, glucocorticoid-remediable hyperaldosteronism
(genetic; Ald under ACTH control)
c. Secondary: decreased renal perfusion (stenosis, arterial nephrosclerosis), arterial
hypovolemia/edema (congestive <3 failure, cirrhosis, nephrotic syndrome), pregnancy
(estrogen increases plasma renin)
What is Conn syndrome? Gender preference? Which side are neoplasms found on more often?
Morphologic appearance on cut section? Characteristic morphologic feature? Symptoms?
a. hyperaldosteronism caused by solitary aldosterone secreting adenoma; more common
in women
b. more often on LEFT (zona glomerulosa); bright yellow on cut (resemble fasiculata cells);
c. characteristic spironolactone bodies- eosinophilic laminated inclusions
d. HTN (most common cause of secondary HTN), endothelial dysfxn (reduced NO
synthesis) with potential for MI and stroke, hypokalemia causing muscle weakness,
paresthesia, visual disturbance, or tetany
2 steroid hormones secreted by adrenals? How different from gonadal androgens? 2 causes of
xs androgens?
a. dehydroepiandrosterone and androstenedione; diff from gonadal b/c under ACTH
regulation
b. adrenocortical neoplasm (more often carcinoma than adenoma) and congen adrenal
hyperplasia (CAH)
Enzyme deficient in CAH (90% cases)? Inheritance pattern? 3 syndromes it can cause and
presentation of each?
a. 21-hydroxylase (CYP21A2; needed to convert progesterone to 11deoxycorticosterone/deoxycortisol)
b. autosomal recessive (highest carrier freq in Hispanics and Ashkenazi Jews)
c. Salt-wasting syndrome- no mineralcorticoid syndrome or corsitol synth; found soon
after birth: virulism, hyponatremia, hyperkalemia, acidosis, hypotension, cardiovascular
collapse, and possible death
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d. Simple virilizing androgenital syndrome- genital ambiguity b/c not enough
glucocorticoids to suppress ACTH, but aldosterone levels normal
e. Non-classic (late onset) adrenal virilism- asymptomatic or mild hirsutism, acne, mestral
irreg (most common)
How/why is the adrenal medulla affected in CAH? When a neonate presents with _____ CAH
should be suspected?
a. glucocorticoids are required to facilitate catecolamine synthesis in medulla, so
developmental defects occur in the medulla (adrenomedullary dysplasia)
b. ambiguous genitalia
What are 3 causes of acute adrenal insufficiency? Potential causes of adrenal hemorrhage?
What 4 symptoms develop in Waterhouse-Friderrichsen syndrome and who most commonly
affected? Most common pathogen?
a. as a crisis in ppl w/ Addison's (usually in response to stress), from immediate w/drawl of
steroids or failure to increase dose in response to acute stress, and from massive
adrenal hemorrhage
b. newborn after prolonged delivery, ppl w/ prolonged anti-coag therapy, DIC, and
complication of infection
c. overwhelming bacterial infection, rapidly progressive hypotension, DIC (w/purpura), and
rapid adrenocortical insufficiency w/ massive bilateral adrenal hemorrhage (like sacs of
blood)
d. Children; Neisseria meningitidis
90% of Primary chronic adrenocortico insufficiency are caused by (4)? Which most common?
What is autoimmune polyendocrine syndrome I (APS1) characterized by? Gene involved?
a. autoimmune adrenalitis (most common), tuberculosis, AIDS, or metastatic cancer
b. chronic mucocutaneous candidiasis, abnormalities of skin/nails/enamel (ectodermal
dystrophy), and organ specific autoimmune diseases (adrenalitis, hypoparathyroidism,
hypogonadism, pernicious anemia)
c. mutation in AIRE gene (expresses periph tissue in thalamus)
What carcinomas are the source of most metastases to the adrenals? 2 genetic causes of
adrenal insufficiency?
a. lung and breast carcinomas
b. congenital adrenal hypophalsia (x-linked; rare) and adrenoleukodystrophy
How does adrenal morphology differ depending on cause of adrenal insufficiency? Clinical
presentation? What symptom would be observed if source of insufficiency is adrenal, but not if
pituitary or hypothalamic?
a. autoimmune--> irreg shrunken glands w/ only scattered remnants of cortex and
lymphoid infiltrate; tuberculous/fungal--> granulomatous inflammatory rxn; metastatic-> glands enlarged and obscured
b. progressive weakness and easy fatigability, GI disturbance, hyperkalemia, hypokalemia,
volume depletion, and hypotension; HyperPIGMENTATION if source is adrenal
How does secondary adrenal cortisolism differ from primary (3)? 2 causes? appearance of
glands?
a. no hyper pigmentation, have deficiency in corisol and androgens w/ near-normal
aldosterone synth, and have low levels of plasma ACTH
b. any disorder of pituitary/hypothalamus or prolongued admin of exogenous
glucocorticoids (dec. ACTH)
c. decreased in size, flattened, with very thin cortex of mostly zona glomerulosa
86. How does age affect likelyhood that an adrenal mass is a carcinoma vs adenoma? Which
syndromes more likely with adenoma? By carcinoma?
a. carinomas predominate in children; equal frequency of adenomas and carcinomas in
adults
b. adenoma- hyperaldostronism or cushings; carcinoma- virulizing
87. How does the morphology of adrenal adenoma differ from adrenal carcinomas? Where do the
carcinomas metastase to? Note: metastasis to adrenals much more common carcinoma than
primary adrenal carcinoma.
a. adenomas are small, well-circumscribed, nodular lesions that are yellow on cut section
(lipid) and may have some degree of pleomorphism (endocrine atypia)
b. carcinomas are large, invasive; cut section is verigated w/ poorly demarcated lesions w/
areas of necrosis, hemorrhage, and cystic change
c. tend to metastasize to reginal and periaortic nodes and hematogenously to lungs and
viscera;
d. metastasis from lungs or breast MUCH more common
e. NOTE: strong tencency to invade adrenal v., vena cava, and lymphatics
88. What makes up the paraganglion system? Where is each part located/type of autonomics
involved?
a. adrenal medulla + branchiomeric(head and neck, carotid bodies; parasymp),
intravagal(along vagal; parasymp), and aorticosympathetic paragangila (along symp
chain; symp)
89. What is the rule of 10s related to? Four 10s involved? What are characteristic morphologic
findings of a pheochromocytoma? How can malignancy be determined?
a. Pheochromocytoma;
b. 10% extra adrenal (in paragangliomas), 10% sporadic are bilateral, 10% biologically
malignant, 10% NOT associated w/ HTN (other 90% are)
c. Large lesions that turn dark brown when exposed to potassium dichromate solution due
to catecolamine oxidation (hence why called chromaffin cells); spindle shaped cells in
nests (zellballen) w/ salt-pepper nuclei
d. only by evidence of metasteses (in lymph nodes or distant: liver, lung, bone)
90. Dominant clinical symptom of pheochromocytoma? Other symptoms? What precipitates the
symptoms? How is laboratory diagnosis made?
a. Hypertension (2/3s have paroxysmal episodes w/ chronic HTN); also tachycardia,
headache, palpitations, sweating, tremor, and sense of apprehension
b. precipitated by emotional stress, exercise, posture change, and palpation in tumor
region
c. evidence of catecholamines in urine or their metabolites: vanillylmadelic acid and
metanephrines
91. What are 5 distinct features of MEN tumors compared to sporadic counterparts? Primary
features of MEN1 (Wermer syndrome)?
a. arise at younger ages, occur in multiple endocrine organs (synchronously or
metachronously), w/in one organ tumors tend to be multifocal, usually preceded by
asymptomatic stage of endocrine hyperplasia, tend to be more aggressive and recur
more often
b. abnormalities in parathyroid (primary hyperparathyroidism; most common), Pancreas
(endocrine tumors that tend to be aggressive), and pituitary (most often prolactinoma)
92. In actuality where is most common site of gastrinomas in MEN? What is mutated in MEN1? 3
syndromes of MEN2? What is mutated and what is clinical presentation? NOTE: all w/ germline
RET mutation = prophylactic thyroidectomy
a. duodenum (way more than pancreas); mutation in MEN1 tumor suppressor gene that
codes for menin
b. MEN-2A (Sipple syndrome)- mutation in RET; parathyroid hyperplasia, medullary thyroid
carcinoma, and pheochromocytoma
c. MEN-2B (RET mutation)- medullary thyroid carcinoma, pheochromocytoma, neuromas
of mucosa/skin/eyes/resptract, and marfanoid habitus (marfan syndrome like)
d. Familial medullary thyroid cancer (variant of MEN-2A)- only medullary thyroid
carcinoma
93. Most common tumor of pineal gland (though still rare)? Tumor that arises from pineocytes?
a. germinoma; pinealoma