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222 Cards in this Set

  • Front
  • Back
What percentage of anterior pituitary cells do somatotrophs make up?
50%
What is the posterior pituitary gland made up of?
Modified glial cells and axonal processes from hypothalamus through stalk
What is the commonest cause of excess anterior pituitary hormone production?
Functional adenoma (prolactinoma 30%, followed by GH 20%, combination 7%)
What percentage of intracranial neoplasms do pituitary tumors make up?
10%
An incidental discovery of a pituitary tumor is made in what percentage of routine autopsies?
25%
What constitutes a micro/macroadenoma of the pituitary?
Macro > 1cm; Micro < 1cm
What gene encodes the Gs-alpha subunit of endrocrine G-proteins?
GNAS1 (increases cAMP); mutations found in 40% of GH adenomas (minority in ACTH adenomas)
What percentage of pituitary adenomas are familial? Which four genes are implicated?
5%
MEN-1 (1/3 get adenomas of GH, prolactin, and/or ACTH)
CDKN1B (p27; MEN-1 like syndrome)
Protein Kinase A regulatory subunit 1-alpha (PRKAR1A)
Aryl Hydrocarbon interacting protein (AIP; Acromegaly (think insurance))
Can pituitary adenomas be unencapsulated and infiltrate bone and dura?
Yes - invasive adenomas (cavernous and sphenoid sinuses)
What is pituitary apoplexy?
This is where you have hemorrhage and necrosis into larger pituitary lesions.
Describe the microscopic details of a pituitary adenoma.
Uniform polygonal cells in sheets and cords
Nuclei uniform or pleomorphic
Few mitoses
Little supporting stroma (lack of reticulin)
What is Ki-67 and what expresses it?
It is a proliferation marker and associated with an increased p53 immujnoreactivity.
>3% of nuclei of atypical pituitary adenomas express Ki-67
Can prolactin microadenomas cause hyperprolactinemia?
Yes
Which pituitary adenomas generally produce dystrophic calcification (psammoma body to entire mass)?
Prolactinomas
Name four clinical side effects of a prolactinoma.
Amenorrhea, galactorrhea, loss of libido, and infertility (potentially bitemporal hemianopia)
What percentage of amenorrhea is accounted for by a prolactinoma?
25%
In what profile of person do prolactinomas tend to be larger? Men or Women? Young, middle age, or older?
Men
Children and older
Describe the Stalk effect.
Any mass in suprasellar compartment may disturb normal inhibition of prolactin release
Name four causes leading to lactotroph hyperplasia.
Pregnancy, Hormone replacement/OC pill (estrogen), Renal failure, and hypothyroidism
Name three systemic effects of acromegaly.
CHF, diabetes (insulin resistance), and muscle weakness
What is the treatment of choice for prolactinomas? Somatotrophoma?
Bromocriptine/L-DOPA/Ropinrole

Surgery/radiation and Ocreotide
Which anterior pituitary adenoma are you able to stain with PAS?
Corticotroph cell adenomas (POMC has a carbohydrate component)
Nelson syndrome: describe
Adrenalectomy due to Cushing syndrome, leads to Corticotroph cell adenoma (ACTH overexpression)
Patients are hyperpigmented, but don't have hypercortisolism
Between LH and FSH, which one does Gonadotroph cell adenomas generally produce?
FSH (lesion found by mass effect)
What percentage of pituitary adenomas are nonfunctioning?
25% (usually silent gonadotroph cell adenomas though)
What percentage of pituitary tumors do carcinomas make up?
<1% (usually make prolactin and/or ACTH)

YOU NEED TO DEMONSTRATE METASTASES (nodes, bone, liver)

Mutations in HRAS gene
What percentage of the thyroid gland must be lost in order to develop hypopituitarism?
75%
What is a potential severe side effect of pituitary apoplexy?
CV collapse and death (past plastic surgery partner story)
Name four causes of pituitary ischemic necrosis.
Pospartum blood loss (SHEEHAN SYNDROME), DIC, Sickle cell anemia, and head trauma
What are the primary and secondary causes for Empty Sella Syndrome?
Primary: defect in sella diaphragm (arachnoid matter plus CSF herniation; obese multiparous women)

Secondary: Surgery or radiation to remove a lesion
Name the inappropriate secretion syndrome for oxytocin.
There is NONE!!
Can craniopharyngiomas affect the hypothalmic functioning? Pituitary functioning?
Yes
Yes
What percentage of intracranial tumors does criopharyngiomas account for?
1-5%
With what age group(s) do you see a peak in craniopharyngiomas?
5-15 (Adamantinomatous: stratified squamous or columnar epithelium in a SPONGY reticulum, keratin formation with calcification and cholesterol-rich cysts)

>65 (Papillary type; No/rare keratin, cysts, calcification, spongy reticulum, but DO still have squamous cells)
What three main functions do thyroid hormones have?
Up-regulate carbohydrate and lipid catabolism, stimulate protein synthesis, and increase sensitivity of vasculature to catecholamines
During which three normal stages in life do you see a normal hyperthyroidism?
Physiologic stress, puberty, and pregnancy
Define goiter.
Hyperplastic enlargement of thyroid gland
What is the difference in action between propylthiouracil and excess iodide?
PTU: inhibits oxidation of iodide, blocks hormone production (these two under action of peroxidase enzyme), and also blocks release of hormones

Iodide: blocks release of hormones

They have 1 overlapping function (release of hormones)
What are thyroglossal duct cysts filled with, and what generally surrounds them?
Filled with mucinous, clear secretions
Surrounded by intense lymphocytic infiltrate
Name two transcription factors, when absent, lead to agenesis of the thyroid.
Thyroid transcription factor-2 (TTF2)
Paired Homeobox-8 (HOX-8)
What is characteristic of hyoplastic thyroids?
They share mutations in the TSH receptor
What percentage of hyperthyroidism is due to Grave's Disease?
85%
What organ is associated with early manifestation of Grave's Disease?
Heart (tachyarrhythmia, palpitations, cardiomegaly, increased CO)
Do you get proximal muscle weakness with hyperthyroidism?
Yes (aka thyroid myopath)
Do you get osteoporosis with hyperthyroidism?
Yes
Name four causes of thyroid storm?
Infection, surgery, stopping medications (e.g. Beta-blockers), and stress (death from arrhythmias)
What is the "triad of Graves"?
Hyperthyroidism with diffuse enlargement of thyroid
Infiltrative ophthalmopathy with exophthalmos
Localized dermopathy (pretibial myxedema)
Name three polymorphisms in immune-function genes associated with Graves disease.
CTLA4, PTPN22, and HLA-DR3
True or false: there are both TSH-binding inhibitor Igs (thyroid growth-stimulating Igs), and anti-TSH receptor abs.
True. This explains why some Graves patients develop episodes of hypothyroidism.
What is the link between orbital preadipocyte fibroblasts and Graves ophthalmopathy?
The orbital preadipocyte fibroblasts have a TSH-receptor, when stimulated, leads to release of cytokines that stimulate fibroblast proliferation and synthesis of ECM
True or false: there is both hyperplasia and hypertrophy of the thyroid gland associated with Graves disease.
True
True or false: the capsule of the thyroid is often breached in Graves disease.
False
What is the difference microscopically between thyroid papillary carcinoma and Graves disease?
With thyroid papillary carcinoma, there is a fibrovascular core to the papilla, but there is NOT a fibrovascular core projecting into the lumen in Graves disease.
What do you see microscopically when you pre-treat a hyperthyroid patient with iodine? Propylthiouracil?
Iodine: involution of epithelium and accumulation of colloid

Propylthiouracil: exaggeration of hypertrophy and hyperplasia
Do you see a lymphoid hyperplasia in Graves disease, both within the thyroid gland and outside the thyroid gland?
Yes
What other autoimmune diseases is a Graves patient at risk for?
SLE, type 1 DM, adrenal insufficiency
Name five features of someone with Cretinism.
Severe mental retardation
Short stature
Coarse facial features
Protruding tongue
Umbilical hernia
Is the thyroid functioning changed with infectious thyroiditis?
No
What is the most significant polymorphism associated with Hashimoto Thyroiditis?
CTLA4 (some as in Graves)
Name the three main effector cells associated with Hashimoto thyroiditis destruction.
CD8 cells
Macrophages (TH1 mediated)
NK cells (ADCC; TH2 mediated)
True or false: with both Graves disease and Hashimoto thyroiditis, the capsule remains intact and the thyroid is diffusely enlarged.
All true
True or false: you see Hurthle cells with Hashimoto Thyroiditis and Hurthle Cell adenoma (subtype of thyroid follicular adenoma).
All true
What is the origin of Hurthle cells?
They are metaplastic thyroid follicular cells with abundant eosinophilic cytoplasm
What is the instigating factor associated with DeQuervain/Subacute Granulomatous Thyroiditis?
Recent history of an URI (viral; seasonal incidence)
True or false: DeQuervain thyroiditis is associated with a painful thyroid, which you should remove.
First part true, but you should NOT remove the thyroid (self-limited process)
True or false: DeQuervain thyroiditis is associated with transient hyperthyroidism (2-6 weeks) sometimes followed by transient hypothyroidism (2-8 weeks).
True
True or false: Subacute lymphocytic thyroiditis is associated with middle aged females postpartum?
True (80% of postpartum are euthyroid in a year)

Accounts for 1-10% of hyperthyroidism (1/3 progress to hypothyroidism though)
What are three differences between DeQuervain thyroiditis and subacute lymphocytic thyroiditis?
DeQuervain thyroiditis has a viral association, but does not have antibodies to various thyroid products (opposite for subacute lymphocytic thyroiditis). Also, DeQuervain thyroiditis is PAINFUL!
What are the defining characteristics associated with Reidel thyroiditis?
Extensive fibrosis extending outside the thyroid gland, has antithyroid antibodies, and can be mistaken for cancer.
True or false: most patients with goiters are euthyroid.
True (the increased size of the gland makes up for the decreased thyroid hormone levels.
True or false: Colloid goiters are aka diffuse nontoxic goiters and are nodular.
First part true, but they are diffuse, not nodular
What determines if a goiter is endemic?
If 10% of that local population has a goiter.
Name five goitrogens.
Cassava root (thiocyanate), cabbage, cauliflower, brussel sprouts, turnips
What happens to the thyroid epithelium and colloid content when you supply iodide to a patient with a goiter?
The thyroid epithelium goes from columnar to cuboidal/flat

The colloid content remains high
True or false: long standing diffuse nontoxic goiters eventually become multinodular goiters.
True (these may be toxic (hot) or nontoxic (cold) nodules)
What are the key features of any lesion in any endocrine gland that is big enough?
Hemorrhage, fibrosis, cystic change, and calcification.
What do the thyroid epithelial cells look like in multinodular goiters?
Flat (cold nodules), but other areas have hypertrophy and hyperplasia (hot nodules)
What is Plummer Syndrome.
This occurs when a multinodular goiter becomes toxic (hot; autonomous hyperfunctional nodule)
What percentage of multinodular goiters develop carcinoma?
<5% (must suspect if sudden change in size or symptoms)
What percentage of thyroid neoplasms are benign?
90%
True or false: Multiple thyroid nodules are more likely to be malignant than a solitary nodule.
False; direct opposite
True or false:
Thyroid nodules in younger patients are more apt to be neoplastic.
Nodules in men are more apt to be neoplastic.
Cold nodules are less apt to be neoplastic.
A history of radiation exposure in the H&N area has no predisposition for thyroid malignancy.
True
True
False
False
True or false: a mutation in the TSH receptor is involved in both nontoxic adenomas and nontoxic multinodular goiters.
False (the mutation is involved in toxic adenomas and toxic multinodular goiters)
True or false: thyroid adenomas are encapsulated.
True (page 1119)
True or false: vast majority of follicular adenomas are hyperthyroid.
False; vast majority are euthyroid
Name the six forms of follicular adenomas of the thyroid.
Macrofollicular/colloid
Microfollicular/fetal
Trabecular
Spindle cell
Atypical
Hurthle cell (oxyphil)
Are thyroid follicular adenomas generally hot or cold nodules? What percent of cold nodules are malignant?
Cold nodules
10% of cold nodules are malignant
Name the two most common hot nodules of the thyroid.
Plummer syndrome (toxic multinodular goiter)
Graves Disease
What is the likelihood of a follicular adenoma transforming into a malignancy
Very low, if at all (those 10% of cold nodules must start out as malignant)
During which period of life is there a female predominance for thyroid carcinoma?
Early and middle adulthood
Which genetic (activating) mutations do you see with Papillary Thyroid Carcinoma?
MAP kinase path (you need a MAP when you ride with "Pap")

RET/PTC (Papillary Thyroid Cancer) gene fusion in 20-40%

Inversions/translocations of NTRK1 in 5-10%

BRAF oncogene (MAP kinase intermediary signaling) in 1/3 to 1/2 (adverse prognostic factor)
Which genetic (activating) mutations do you see with Follicular Thyroid Carcinoma?
PI3K/AKT

Translocation between PAX8-PPAR-gamma1
What is the germline mutation associated with Medullary Thyroid Carcinoma?
RET (MEN-2a/2b)

Also found in 1/2 nonfamilial or sporadic medullary cancer
What three mutations are common found in anaplastic carcinoma of the thyroid?
p53 inactivation

Beta-catenin activation

RAS too
What percentage of children exposed to H&N radiation in first two decades of life develop cancer decades later?
10%
Which cancer does a deficiency of iodide lead to?
Thyroid Follicular Carcinoma
Which thyroid carcinoma is associated with radiation exposure?
Papillary Cancer (Accounts for 85% of the thyroid carcinomas)
True or false: most papillary carcinomas are encapsulated.
False, only 10%
What are the defining characteristics of papillary thyroid carcinoma?
Microscopic evaluation is the ONLY WAY TO MAKE A DIAGNOSIS

Fibrovascular cores (unlike in Graves disease)

Note: nuclear features (below) are defining.

Orphan Annie nuclei
Psammoma bodies
Intranuclear foldings(inclusions)
Name the three variants to Thyroid Papillary Carcinoma.
Follicular
Tall cell (worst prognosis; older patients)
Diffuse sclerosing (younger patients)
Of the three variants of Thyroid Papillary Carcinoma, which one: has more RAS mutations, less RET/PTC rearrangements, is often encapsulated, and has fewer nodal metastases? Tends to be large tumors with vascular invasion and metastases? Has many psammoma bodies, diffuse fibrosis, dense lymphocytic infiltrate, almost all have nodal metastases, and half have RET/PTC translocations?
Follicular
Tall cell
Diffuse Sclerosing
Of papillary or follicular thyroid carcinoma, which one tends to have lymph node metastases? Hematogenous?
Lymph: papillary
Hematogenous: follicular
What is the 10-year survival for: papillary, follicular, and anaplastic thyroid carcinomas?
98%
~80% (50% if widely invasive, 90% in minimally)
~0%
What percentage of papillary thyroid carcinomas have local recurrence? Distant metastases?
5-20% local
10-15% distant (lymphatic generally)
What must you have to diagnose Follicular Thyroid Carcinoma?
Capsular or vascular invasion (usually hematogenous to bone, lung, and liver)
True or false: you generally get invasion of surrounding tissues with both follicular and papillary thyroid carcinomas.
True
True or false: follicular thyroid carcinomas respond to thyroxine administration, leading to inhibition of metastases by I131.
TRUE!
Medullary thyroid carcinoma key features.
Its cancer marker (calcitonin) forms amyloid

C-cells of thyroid parenchyma

Can make other hormones (e.g. ACTH)

MEN 2a/b association

80% sporadic (solitary lesion)

MEN-2b more aggressive
What is the precursor lesion to MEN-2a/b associated Medullary Thyroid Carcinoma?
Multicentric C-cell hyperplasia
True or false: anaplastic thyroid carcinoma has a strong association with more differentiated thyroid carcinomas.
True (`30% had, have, or will have)
What does connective tissue capsule associated with thyroid medullary thyroid carcinoma look like?
There is NOT a capsule!
True or false: connective tissue capsules are more likely to exist with thyroid carcinomas than with adenomas/hyperplasias.
False; exact opposite
Which thyroid disruption is associated with an increased propensity to develop non-Hodgkins Lymphoma?
Hashimoto Thyroiditis
Between parathyroid adenomas and hyperplasias, which one is associated with an enlargement of all four glands?
Parathyroid hyperplasias (adenomas would have one enlarged gland and three (usually) atrophic glands)
What percentage of the parathyroids are constituted by fat?
30%
What is the commonest cause of clinically apparent hypercalcemia? Clinically asymptomatic hypercalcemia?
Malignancy

Parathyroid adenoma
What is the most common cause of hypercalcemia from nonmetastatic solid tumors?
PTHrP (acts like PTH, plus inhibits action of osteoprotegerin (released by osteoblasts as a decoy receptor to block RANKL))
Name a possible therapeutic molecule that could decrease osteolysis from parathyoid tumors.
Osteoprotegerin
Is there a link between H&N radiation and primary hyperparathyroidism?
Yes
Name three gene mutations associated with primary hyperparathyroidism.
Cyclin D1 gene

MEN1 gene (tumor suppressor gene; menin)

Also MEN2 (RET mutation)
What is going on in Familial hypocalciuric hypercalcemia?
This AD disorder occurs when there is a mutation in the parathyroid calcium sensing receptor gene (CASR), leading to decreased sensitivity to extracellular calcium, leading to overformation of PTH.
What percentage of primary hyperparathyroidism is attributed to parathyroid adenomas?
85-90% (usually incidental finding)
What is characteristic about parathyroid adenomas?
There is no fat in the lesion!
True or false: there is usually a rim of compressed non-neoplastic parathyroid gland found in a parathyroid adenoma.
True
What percentage of primary parathyroidism is attributed by the following: parathyroid adenoma, carcinoma, primary hyperplasia?
85-90%
1%
5-10%
What are the three cell types found in parathyroids?
Chief cells (main), oxyphil cells (eosinophilic), and water clear cells (glycogen storage)
What is the local recurrence and distant dissemination associated with parathyroid carcinoma?
1/3
1/3
As with thyroid carcinoma, what do you need to diagnose parathyroid carcinoma? What is different between these two types of carcinoma concerning the capsule?
You need invasion or metastases to diagnose

With parathyroid carcinoma, the lesion is encapsulated (not so with thyroid carcinomas: medullary, anaplastic, follicular, and papillary (10% are though))
True or false: you have an increased secretion of phosphorus but a decreased secretion of calcium associated with hyperparathyroidism.
False: you get an increased excretion of both due to the overflowing amount of both in the blood
Explain the saying: bones, stones, groans, and moans
Clinical features associated with hyperparathyroidism:
bones: increased bone resorption leading to increased pathological fractures
stones: increased kidney calcium stones
groans: constipation, GI ulceration (calcium leads to gastrin release), pancreatitis
moans: depression, fatigue, seizures
What is the most common cause of secondary hyperparathyroidism?
Renal failure
What percentage of newly diagnosed patients with hyperparathyroidism with have kidney stones?
20%
What is calciphylaxis?
This occurs when metastatic calcification occurs in vessels, resulting in skin ischemia

Associated with secondary hyperparathyroidism
Name three causes for hypoparathyroidism.
DiGeorge syndrome
Surgical removal
Autoimmune Polyendocrine Syndrome types 1 & 2
Will a gain in function of the Calcium-sensing receptor (CASR) lead to hypoparathyroidism?
Yes (leads to hypocalcemia and hypercalciuria)
What is going on with Familial isolated hypoparathyroidism?
Either has a mutation in gene for PTH precursor peptide (AD), or loss of function in GCM2 needed for parathyroid development (AR)
Name the disease: papilledema, calcification of basal ganglia, cataracts, prolonged QT interval, hypoplastic teeth.
Hypoparathyroidism leading to hypocalcemia.
What is going on with pseudohypoparathyroidism?
A gene, GNAS1, expressed in pituitary and kidney is from maternal chromosome only.

If you delete this maternal GNAS1 gene, you lose all GNAS1 function in the kidney and pituitary (but only 50% in other tissues).

In Type 1A (aka Albright hereditary osteodystrophy), the patient has round facies, short stature, short metacarpals and metatarsals, and multihormone resistance to PTH/TSH/LH/FSH
What is going on with pseudopseudohypoparathyroidism?
A gene, GNAS1, expressed in pituitary and kidney is from maternal chromosome only.

If you delete the paternal GNAS1 gene, you don't lose any functioning in the pituitary and kidney, but you lose 50% in other tissues.
What type of sequestered cells make up 50-70% of pineal tumors?
Germ cells from development

Two types:
Pineoblastoma (young patient, death in 1-2 years)
Pineocytoma (adults, death in 7 years, have pseudorosettes rimmed by pineocytes)
True or false: pancreatic exocrine tumors are more common than pancreatic endocrine tumors.
True
What are three characteristics that are unequivocally malignant in endocrine pancreas neoplasms.
Metastases to regional nodes or distant organs
Vascular invasion
Gross invasion of adjacent organs
True or false: 90% of insulinomas are benign, but 60-90% other types of endocrine pancreas neoplasms are malignant.
True
State Whipple's Triad, and what does it deal with?
Attacks of hypoglycemia with blood sugar <50mg/dL
Attacks have a large CNS component, such as confusion, loss of consciousness
Attacks are related to exercise or fasting & promptly relieved by glucose

Whipple's Triad deals with Insulinomas
State the breakdown in insulinomas (adenomas, multiple adenomas, malignant, and hyperplasia/adenoma in ectopic pacreatic tissue)
70%
10%
10%
10%
True or false: insulinomas are malignant 10% of the time and cause mild hypoglycemia 20% of the time.
First part true, but insulinomas cause mild hypoglycemia 80% of the time
Where do you more commonly find Zollinger-Ellison lesions: gastric or duodenal?
Duodenal:gastric, 6:1
Since Insulinomas have a triad (Whipple's), as does gastrinomas. What is Zollinger-Ellison's triad?
Fulminant peptic ulcer
Gastric acid hypersecretion
Pancreatic islet cell tumor
True or false: Zollinger-Ellison Syndrome occurs in MEN types 1, 2a, and 2b.
False; it only occurs in type 1
How well do gastrinomas stay in one place?
Not too good. >50% locally invade or metastasize at time of diagnosis
What is the presenting symptom in Zollinger-Ellison Syndrome?
Diarrhea (30% present with this)

>50% have diarrhea though
What is hinderance to a high 10 year survival rate with Zollinger-Ellison Syndrome?
Hepatic mets lead to liver failure
What is the profile of someone with a glucagonoma?
Postmenopausal women with anemia, diabetes, and migratory necrotizing skin erythema.
What are three signs of somatostatinomas?
Diabetes, gallstones, steatorrhea, and HYPOchlorhydria
What is the presenting sign of a VIPoma?
Watery diarrhea, leading to hypokalemia and achlorhydria
True or false: MEN syndromes are AR.
False; AD
Wermer syndrome: what is it and what does it affect?
MEN type 1

Parathyroid (90% have primary hyperparathyroidism)
Pancreas (major cause of M&M; gastrinoma and insulinoma)
Pituitary (prolactinoma commonest)
Duodenal gastrinoma, carcinoids, thyroid and adrenal tumors
Sipple syndrome: what is it and what does it affect?
Men Type 2A

Thyroid (Medullary Carcinoma; 100% develop; RET mutation, must screen family members)
Pheochromocytoma (40-50% develop; bilateral)
Parathyroid (hyperplasia)
MEN 2B: what does it affect?
Pheochromocytoma bilateral, extra adrenal)
Thyroid (Medullary Carcinoma; more aggressive than MEN 2A)
Neuromas of skin, mouth, eye, GI, lungs

Marfanoid habitus
Different RET mutation than MEN 2A
True or false: Familial Medullary Thyroid Cancer is more aggressive than MEN 2A/2B.
False. Plus, these patients are generally older than in MEN 2A/2B.
What does the functional product produced from the PP cells of the pancreas do?
It stimulates gastric and intestinal enzyme secretion and inhibits motility (almost like CCK)
What is the functional product of D1 cells of the pancreas, and what does it cause when in excess?
VIP

VIPoma leads to watery diarrhea
Name three secondary causes for diabetes mellitus.
Pancreatitis, hemochromatosis, and surgical excision of pancreas
Name three racial groups that have a 1.5-2 times higher risk of developing diabetes.
Native Americans, Hispanics, and blacks
What is the principal function of insulin?
Increase rate of glucose transport into striated muscle and fat cells (2/3 of total body weight)
True or false: the PI3K pathway is associated with metabolic effects, whereas the MAPK pathway is associated with proliferation/growth.
True
Since we know that the PI3K pathway is associated with metabolic functions, is it safe to believe that this pathway plus the AKT pathway are the key effectors associated with docking GLUT-4 to the surface of muscle/adipocytes?
Yes sir 'e.
Name two molecules that block insulin signaling.
PTPN2 (dephosphorylates receptor)
PTEN (blocks AKT activation)
What percentage of the thyroid gland Beta-cells must be destroyed to develop type 1 DM?
>90%
Antibodies against glutamic acid decarboxylase (GAD) lead to what disease?
Type 1 DM
Name three autoimmune diseases that have a polymorphism associated with PTPN22 and CTLA-4.
Graves disease
Hashimoto Thyroiditis
Type 1 DM
A polymorphism in CD25 is found in which autoimmune disease?
Type 1 DM
What has happened as far as the incidence of Type 1 DM since the 1960s?
Tripled (maybe associated with decrease in infections)
Name the transcription factor associated with a polymorphism in type II DM.
Transcription factor 7-like-2
What is the largest contributor to the pathogenesis of resistance to insulin in type II DM.
Loss of insulin sensitivity in hepatocytes
What percentage of people with type II DM are obese?
80%
What is the link between increased NEFAs and type II DM?
Excess intracellular NEFAs leads to increased serine/threonine kinase activity, attenuating insulin signaling

NEFAs compete with glucose for oxidation
True or false: leptin is increased, whereas adiponectin is decreased in type II DM
True (leptin resistance)
What is the link between the polymorphism of TCF7L2 and development of Type II DM?
TCF7L2 dysfunction leads to reduced insulin secretion from islets, leading to Beta-cell failure in obese patients with insulin resistance
Which type of DM is associated with amyloid deposition? HLA subtypes? Strong genetic component?
Type II: amyloid
Type I: HLA
Type II: genetic link
What is the MOA of TZDs?
Increase adiponectin, decrease FFAs, and reduce insulin resistance.
Why do some obese people with insulin resistance develop DM, but others don't?
Those that do have a mutation in the TCF7L2 gene (they have reduced insulin secretion from islets)
What two major forms constitute monogenic diabetes?
Primary defect in Beta-cell function

Defect in insulin-insulin receptor signaling
Is MODY inheritable? Describe MODY2.
AD inheritance.

MODY2 has mutation in glucokinase, leading to increase glucose threshold triggering insulin release from the Beta cells (think, if less glucose is trapped in the Beta cells by glucokinase, you will need more glucose coming into the Beta cells to set off the insulin releasing cascade).
What is going on with permanent neonatal diabetes?
There is a mutation in the Potassium channel in the Beta cells, making it constitutively active, leading to hypoinsulinemic diabetes.

Think: an infant is NOT likely to have either Type I or Type II diabetes (viral for type I, and accumulation in type II)
What is going on with mitochondrial diabetes?
Maternal inheritance
mutation in tRNA gene
decreased ATP synthesis by mitochondria in Beta cell, preventing the closure of the Potassium channel, inhibiting insulin release cascade.
What is lipoatrophic diabetes all about?
Dominant negative mutations in DNA binding domain of PPAR-gamma

Leads to hypertriglyceridemia, hepatic steatosis, insulin resistance

Also have acanthosis nigricans, loss of subcutaneous fat, PCOS
What is the AGE-RAGE hypothesis?
AGE (Advanced Glycosylated Endproducts) formed from prolonged glucose exposure.

AGE binds to RAGE (leukocytes and endothelium) leading to (cytokine/oxidative species/procoagulant/proliferative molecules to vascular SM/ECM) release.

This leads to atherosclerosis, vascular damage (think Virchow's triad), vascular linkage, etc.
What are the three main mechanisms associated with pathogenesis of both type I and type II DM?
AGE-RAGE association

Activation of PKC (intracellular hyperglycemia leads to increased DAG, leads to increased PKC signaling, leads to increased VEGF (retinopathy), increased endothelin, decreased NOS, PAI-1 increased, etc.)

Disturbances of polyol pathways (aldose reductase; use up NADPH, decreases GSH synthesis, oxidative damage increases)
Is amyloid deposition in pancreas restricted to type II DM?
No, this is a normal process in aging.
What is first and second most common cause of death in DM?
1) Cardiovascular disease (especially heart attack)
2) Renal failure
As far as diabetic nephropathy, what always is associated with BM thickening?
Diffuse mesangial sclerosis (disease of >10 years duration)

When marked disease, leads to nephrotic syndrome
What percentage of diabetics develop Kimmelstiel-Wilson lesions?
10-35% (major cause of M&M)
Which two kidney lesions are characteristic to diabetics?
Efferent arteriole hyaline arteriolosclerosis

Nodular glomerulosclerosis
What accounts for diabetic retinopathy due to neovascularization?
Increased intracellular glucose increases DAG, which increases PKC signaling, which increases VEGF and the rest is history
What is the leading cause of noninfectious blindness and the fourth leading cause of acquired blindness in the US?
Diabetic Ocular Disease
Which endocrine organ is associated with a higher carcinoma incidence?
Adrenal gland (10-20%)

Carcinoma more likely than adenoma in children, but equal in adults
McCune Albright Syndrome: what's up?
Germline activation mutation in GNAS, leading to primary hyperplasia in adrenal cortex

Hyperplasia, otherwise, is not very common
What is Crooke hyaline change, and what is it associated with?
Occurs in corticotrophs of pituitary gland, replacing their basophilic granular cytoplasm with a homogenous lightly basophilic appearance

Occurs in Cushing Syndrome
Which form of adrenal hyperplasia do you see lipofuscin?
Micronodular hyperplasia (1-3mm)
What is the commonest cause of primary hyperaldosteronism?
Autonomous aldosterone overproduction (usually adenoma (Conn Syndrome, 60%) vs bilateral idiopathic hyperaldosteronism (hyperplasia, 40%))
True or false: since we know adrenal adenomas (Conn Syndrome) is usually unilateral (usually left side), what would you expect the rest of the gland and the contralateral gland to look like?
NOT ATROPHIC (aldosterone does not have a negative feedback on ACTH secretion)

May be spironolactone bodies if treating with that
If you have a very resistant hypertension to therapy, which also accounts for 5-10% of hypertension, what should you start to think about?
Hyperaldosteronism (Conn Syndrome)
Why can you get tetany with primary hyperaldosteronism?
The aldosterone causes an acidic urine (lose protons to urine) leading to metabolic alkalosis. This frees up many negative charges on albumin, which will bind up the calcium, leading to increased sodium permeability and tetany!
Name some causes of secondary hyperaldosteronism.
Cirrohosis, nephrotic syndrome, and hypoalbuminemia (all these have decreased protein, leading to decreased oncotic pressure, which leads to increased renin secretion by liver, targeting the adrenal zona glomerulosa)

CHF, pregnancy, decreased renal perfusion
True or false: adrenocortical neoplasms are more likely to be a carcinoma than an adenoma.
True (think about virilization)
Of the three syndromes of 21-Hydroxylase deficiency (Classic salt wasting, simple virilizing without salt wasting, and non-classic late onset virilism), which one is most common?
Non-classic, late-onset virilism (presents with acne, menstrual abnormalities, or asymptomatic)
True or false: with 21-hydroxylase deficiency the adrenal gland is brown, due to lipid accumulation.
First part true, second part false (lipid DEPLETION)
What kind of affect does a 21-Hydroxylase deficiency have on surrounding tissue?
The adrenal medulla needs a high level of intra-adrenal glucocorticoids to produce catecholamines

This leads to catecholamine levels fall, leading to a perpetuation of hypotension
Name the signs of Autoimmune Polyendocrine Syndrome Type 1.
Chronic mucocutaneous candidiasis
Skin, nail, tooth abnormalities
Autoimmune adrenalitis (others)
Mutations in autoimmune regulator gene (AIRE)
Name the signs of Autoimmune Polyendocrine Syndrome Type 2.
Starts early adulthood
Combo of adrenal insufficiency, autoimmune thyroiditis or type 1 DM
No candidiasis, ectodermal component, and no autoimmmune hypoparathyroidism
What is the most common cause of primary chronic insufficiency of the adrenal (in developed countries)?
Autoimmune Adrenalitis (60-70%; aka Addison disease)

Infections elsewhere (especially TB, CMV, MAI, Histo, Coccidio)
True or false: you get electrolyte abnormalities with long term glucocorticoid supplementation, with abrupt removal.
False. ACTH does NOT control secretion of mineralocorticoids
True or false: Primary adrenal neoplasms are more common than metastatic malignancy.
False
How common is bone metastases from an adrenal carcinoma (think virilism)?
Unusual. It usually metastasizes through veins/lymphatic to lung.
Name two disease associations of adrenocortical carcinomas.
Li-Fraumeni (p53) and Beckwith-Wiedemann
Name the three main distributions of paraganglias, and state their autonomic origin.
Branchiomeric (Parasympathetic; CNs, carotid body, arteries)
Intravagal (Parasympathetic; vagal)
Aorticosympathetic (Sympathetic; organ of Zuckerkandl)
Pheochromocytoma rule of 10:
Extra adrenal (Zuckerkandl and carotid)
Bilateral (unless familial, 50%)
Malignant (worse for extra-adrenal, 20-40%)
Kids (male, familial)
Don't cause hypertension (90% DO CAUSE HYPERTENSION)
What percentage of pheochromocytomas are familial? Which germline mutation do they generally have?
25%
SDHB (Succinate Dehydrogenase), which when lost leads to stabilization of HIF-1alpha (think VHL)
Which two IHC stains do you use for pheochromocytomas?
Chromogranin and synaptophysin
True or false: monomorphic lesions in pheochromocytomas are more aggressive.
True (spindle cells, bizarre cells)
Which one is more common in pheochromocytomas: episodes of hypertension, or sustained hypertension with a labile element?
Sustained hypertension with a labile element