Endocrine - First Aid Flashcards
1
Q
Most common ectopic thyroid tissue site is the _____. Removal may result in hypothyroidism if it is the only thyroid tissue present.
A
Tongue (Lingual Thyroid)
2
Q
_____ presents as an anterior midline neck mass that moves with swallowing or protrusion of the tongue (vs. persistent cervical sinus leading to branchial cleft cyst in lateral neck).
A
Thyroglossal Duct Cyst
3
Q
Thyroid follicular cells are derived from the _____.
A
Endoderm
4
Q
Thyroid parafollicular cells (a.k.a. C cells, produce Calcitonin) are derived from the _____.
A
Neural Crest
5
Q
Adrenal Cortex and Medulla
A
GFR corresponds with Salt (mineralocorticoids), Sugar (glucocorticoids), and Sex (androgens).
The deeper you go, the sweeter it gets.
6
Q
The adrenal cortex is derived from the _____.
A
Mesoderm
7
Q
The medulla is derived from _____.
A
Neural Crest
8
Q
The _____ secretes FSH, LH, ACTH, TSH, prolactin, GH, and β-endorphin. Derived from oral ectoderm (Rathke pouch).
A
Anterior Pituitary (Adenohypophysis)
FLAT PiG: FSH, LH, ACTH, TSH, PRL, GH
9
Q
Melanotropin (MSH) is secreted from _____ of the pituitary.
A
Intermediate Lobe
10
Q
Anterior Pituitary (Adenohypophysis):
hormone subunit common to TSH, LH, FSH, and hCG
A
α subunit
11
Q
Anterior Pituitary (Adenohypophysis):
determines hormone specificity
A
β subunit
12
Q
Anterior Pituitary (Adenohypophysis):
ACTH, MSH, and β-endorphin are derivatives of _____.
A
Proopiomelanocortin
13
Q
Anterior Pituitary (Adenohypophysis):
Basophils secrete _____.
A
B-FLAT: Basophils—FSH, LH, ACTH, TSH
14
Q
Anterior Pituitary (Adenohypophysis):
Acidophils secrete _____.
A
- GH
- PRL
15
Q
The _____ stores and releases vasopressin (antidiuretic hormone, or ADH) and oxytocin.
A
Posterior Pituitary (Neurohypophysis)
16
Q
Vasopressin (antidiuretic hormone, or ADH) and Oxytocin are made in the _____.
A
Hypothalamus (Supraoptic and Paraventricular Nuclei)
17
Q
The posterior pituitary (neurohypophysis) derived from the _____.
A
Neuroectoderm
18
Q
Endocrine Pancreas Cell Types
A
Islets of Langerhans are collections of α, β, and δ endocrine cells. Islets arise from pancreatic buds.
- α = glucagon (peripheral)
- β = insulin (central)
- δ = somatostatin (interspersed)
Insulin is inside (β cells).
19
Q
Insulin Synthesis
A
Preproinsulin (synthesized in RER) → cleavage of “presignal” → Proinsulin (stored in secretory granules) → cleavage of Proinsulin → exocytosis of Insulin and C-peptide equally
20
Q
_____ are ↑ in insulinoma and sulfonylurea use, whereas exogenous insulin lacks _____.
A
C-Peptide
21
Q
Insulin Function
A
- Released from pancreatic β cells.
- Binds insulin receptors (tyrosine kinase activity ①), inducing glucose uptake (carrier-mediated transport) into insulin-dependent tissue ② and gene transcription.
- Unlike glucose, insulin does not cross placenta.
- Brain utilizes glucose for metabolism but ketone bodies during starvation.
- RBCs utilize glucose, as they lack mitochondria for aerobic metabolism.
22
Q
Anabolic Effects of Insulin
A
- ↑ glucose transport in skeletal muscle and adipose tissue
- ↑ glycogen synthesis and storage
- ↑ triglyceride synthesis
- ↑ Na+ retention (kidneys)
- ↑ protein synthesis (muscles)
- ↑ cellular uptake of K+ and amino acids
- ↓ glucagon release
- ↓ lipolysis in adipose tissue
23
Q
Insulin-Dependent Glucose Transporters
A
GLUT4: adipose tissue, striated muscle (exercise can also ↑ GLUT4 expression)
24
Q
Insulin-Independent Transporters
A
- GLUT1: RBCs, brain, cornea, placenta
- GLUT2 (bidirectional): β islet cells, liver, kidney, small intestine
- GLUT3: brain, placenta
- GLUT5 (Fructose): spermatocytes, GI tract
- SGLT1/SGLT2 (Na+-glucose cotransporters): kidney, small intestine
25
Insulin-Independent Glucose Uptake
**BRICK LIPS**:
* **B**rain
* **R**BCs
* **I**ntestine
* **C**ornea
* **K**idney
* **L**iver
* **I**slet (β) Cells
* **P**lacenta
* **S**permatocytes
26
Insulin Regulation
* Glucose is the major regulator of insulin release
* ↑ insulin response with oral vs. IV glucose due to incretins (eg. glucagon-like peptide 1 [GLP-1], glucose-dependent insulinotropic polypeptide [GIP]), which are released after meals and ↑ β cell sensitivity to glucose.
* Release ↓ by α2, ↑ by β2 (2 = regulates insulin).
* Glucose enters β cells ③ → ↑ ATP generated from glucose metabolism ④ closes K+ channels (target of sulfonylureas) ⑤ and depolarizes β cell membrane ⑥. Voltage-gated Ca2+ channels open → Ca2+ ⑦ influx and stimulation of insulin exocytosis ⑧.
27
Glucagon is made by the _____ and is secreted in response to hypoglycemia.
α Cells of the Pancreas
28
Glucagon promotes \_\_\_\_\_. It elevates blood sugar levels to maintain homeostasis when concentration of bloodstream glucose falls too low (ie. fasting state).
* Glycogenolysis
* Gluconeogenesis
* Lipolysis
* Ketone Production
29
Hypothalamic-Pituitary Hormones:
* ↑ water permeability of distal convoluted tubule and collecting duct cells in kidney to ↑ water reabsorption
* stimulus for secretion is ↑ plasma osmolality
ADH
30
Hypothalamic-Pituitary Hormones:
* ↑ ACTH, MSH, β-endorphin
* ↓ in chronic exogenous steroid use
CRH
31
Hypothalamic-Pituitary Hormones:
* ↓ prolactin, TSH
* antagonists (eg. antipsychotics) can cause galactorrhea due to hyperprolactinemia
Dopamine
32
Hypothalamic-Pituitary Hormones:
* ↑ GH Analog (tesamorelin) used to treat
* HIV‑associated lipodystrophy
GHRH
33
Hypothalamic-Pituitary Hormones:
* ↑ FSH, LH
* suppressed by hyperprolactinemia
* tonic _____ suppresses HPG axis
* pulsatile _____ leads to puberty and fertility
GnRH
34
Hypothalamic-Pituitary Hormones:
* ↑ melanogenesis by melanocytes
* causes hyperpigmentation in Cushing disease, as MSH and ACTH share the same precursor molecule, proopiomelanocortin
MSH
35
Hypothalamic-Pituitary Hormones:
* causes uterine contractions during labor
* responsible for milk letdown reflex in response to suckling
Oxytocin
36
Hypothalamic-Pituitary Hormones:
* ↓ GnRH
* pituitary prolactinoma → amenorrhea, osteoporosis, hypogonadism, galactorrhea
Prolactin
37
Hypothalamic-Pituitary Hormones:
* ↓ GH, TSH
* analogs used to treat acromegaly
Somatostatin
38
Hypothalamic-Pituitary Hormones:
* ↑ TSH, prolactin
* ↑ TRH (eg. in 1°/2° hypothyroidism) may increase prolactin secretion → galactorrhea
TRH
39
Prolactin is secreted mainly by the \_\_\_\_\_.
Anterior Pituitary
40
Prolactin is structurally homologous to \_\_\_\_\_.
Growth Hormone
41
\_\_\_\_\_ stimulates milk production in breast; inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release. Excessive amounts is associated with ↓ libido.
Prolactin
42
Prolactin Regulation
* Prolactin secretion from anterior pituitary is tonically inhibited by dopamine from tuberoinfundibular pathway of hypothalamus.
* Prolactin in turn inhibits its own secretion by ↑ dopamine synthesis and secretion from hypothalamus.
* TRH ↑ prolactin secretion (eg. in 1° or 2° hypothyroidism).
* Dopamine agonists (eg. bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma.
* Dopamine antagonists (eg. most antipsychotics) and estrogens (eg. OCPs, pregnancy) stimulate
prolactin secretion.
43
Growth Hormone (Somatotropin) is secreted by the \_\_\_\_\_.
Anterior Pituitary
44
\_\_\_\_\_ stimulates linear growth and muscle mass through IGF-1 (somatomedin C) secretion by
liver. It ↑ insulin resistance (diabetogenic).
Growth Hormone (Somatotropin)
Somato**stati**n keeps your growth **stati**c.
Somato**medi**n **medi**ates your growth.
45
Growth Hormone (Somatotropin) Regulation
* Released in pulses in response to growth hormone–releasing hormone (GHRH).
* Secretion ↑ during exercise, deep sleep, puberty, hypoglycemia.
* Secretion is inhibited by glucose and somatostatin release via negative feedback by somatomedin.
* Excess secretion of GH (eg. pituitary adenoma) may cause acromegaly (adults) or gigantism (children).
46
Excess growth hormone (somatotropin) is treated with \_\_\_\_\_.
Somatostatin Analogs (eg. Octreotide)
47
Appetite Regulation:
* stimulates hunger (orexigenic effect) and GH release (via GH secretagogue receptor)
* produced by the stomach
* sleep deprivation or Prader-Willi syndrome → ↑ production
* acts via lateral area of hypothalamus to ↑ appetite (hunger center)
Ghrelin
**Ghr**elin makes you hun**ghr** and **ghr**ow.
48
Appetite Regulation:
* satiety hormone
* produced by adipose tissue
* mutation of gene → congenital obesity
* sleep deprivation or starvation → ↓ production
* acts via ventromedial area of hypothalamus to ↓ appetite (satiety center)
Leptin
Lept**in** keeps you th**in**.
49
Appetite Regulation:
* act at cannabinoid receptors in hypothalamus and nucleus accumbens, two key brain areas for the homeostatic and hedonic control of food intake → ↑ appetite
* cause “the munchies”
Endocannabinoids
50
Antidiuretic Hormone (Vasopressin) is synthesized in the \_\_\_\_\_.
Hypothalamus (Supraoptic and Paraventricular Nuclei)
51
Antidiuretic Hormone (Vasopressin) is stored and secreted by the \_\_\_\_\_.
Posterior Pituitary
52
\_\_\_\_\_ regulates serum osmolality (V2-receptors) and blood pressure (V1-receptors). Primary function is serum osmolality regulation (↓ serum osmolality, ↑ urine osmolality) via regulation of aquaporin channel insertion in principal cells of renal collecting duct.
Antidiuretic Hormone (Vasopressin)
53
ADH level is ↓ in \_\_\_\_\_.
Central Diabetes Insipidus (DI)
54
ADH level is ↑ in \_\_\_\_\_.
Nephrogenic Diabetes Insipidus (DI)
55
Nephrogenic DI can be caused by mutation in \_\_\_\_\_.
V2-receptor
56
\_\_\_\_\_ is a treatment for central DI and nocturnal enuresis.
Desmopressin (ADH Analog)
57
Adrenal Steroids
58
Congenital Adrenal Hyperplasias
59
Congenital Adrenal Hyperplasias:
* ↑ Mineralocorticoids
* ↓ Cortisol
* ↓ Sex Hormones
* ↑ BP
* ↓ K+
* ↓ Androstenedione
* XY: ambiguous genitalia, undescended testes
* XX: lacks 2° sexual development
17α-Hydroxylase Deficiency
60
Congenital Adrenal Hyperplasias:
* ↓ Mineralocorticoids
* ↓ Cortisol
* ↑ Sex Hormones
* ↓ BP
* ↑ K+
* ↑ Renin activity
* ↑ 17-Hydroxyprogesterone
* most common
* presents in infancy (salt wasting) or childhood (precocious puberty)
* XX: virilization
21-Hydroxylase
61
Congenital Adrenal Hyperplasias:
* ↓ Aldosterone
* ↑ 11-Deoxycorticosterone (results in ↑ BP)
* ↓ Cortisol
* ↑ Sex Hormones
* ↑ BP
* ↓ K+
* ↓ renin activity
* XX: virilization
11β-Hydroxylase
62
Cortisol is formed in the \_\_\_\_\_.
Adrenal Zona Fasciculata
63
Cortisol Functions
Cortisol is a **A BIG FIB**:
* ↑ **A**ppetite
* ↑ **B**lood pressure:
* upregulates α1-receptors on arterioles → ↑ sensitivity to norepinephrine and epinephrine (permissive action)
* at high concentrations, can bind to mineralocorticoid (aldosterone) receptors
* ↑ **I**nsulin resistance (diabetogenic)
* ↑ **G**luconeogenesis, lipolysis, and proteolysis (↓ glucose utilization)
* ↓ **F**ibroblast activity (poor wound healing, ↓ collagen synthesis, ↑ striae)
* ↓ **I**nflammatory and **I**mmune responses:
* inhibits production of leukotrienes and prostaglandins
* inhibits WBC adhesion → neutrophilia
* blocks histamine release from mast cells
* eosinopenia, lymphopenia
* blocks IL-2 production
* ↓ **B**one formation (↓ osteoblast activity)
64
Exogenous corticosteroids can cause reactivation of _____ (blocks IL-2 production).
* TB
* Candidiasis
65
Cortisol Regulation
* CRH (Hypothalamus) stimulates ACTH release (Pituitary) → Cortisol production in Adrenal Zona Fasciculata.
* Excess Cortisol ↓ CRH ACTH, and Cortisol secretion.
* Chronic stress induces prolonged secretion.
66
Calcium Homeostasis
* ↑ in pH → ↑ affinity of albumin (↑ negative charge) to bind Ca2+ → hypocalcemia (eg. cramps, pain, paresthesias, carpopedal spasm).
* Ionized/free Ca2+ is 1° regulator of PTH; changes in pH alter PTH secretion, whereas changes in albumin do not.
67
Parathyroid Hormone is formed by the \_\_\_\_\_.
Chief Cells of Parathyroid
68
Parathyroid Hormone Functions
* ↑ bone resorption of Ca2+ and PO43−
* ↑ kidney reabsorption of Ca2+ in distal convoluted tubule
* ↓ reabsorption of PO43− in proximal convoluted tubule
* ↑ 1,25-(OH)2 D3 (Calcitriol) production by stimulating kidney 1α-hydroxylase in proximal convoluted tubule
* PTH ↑ serum Ca2+, ↓ serum PO43–, ↑ urine PO43–, ↑ urine cAMP.
* ↑ RANK-L (receptor activator of NF-κB ligand) secreted by osteoblasts and osteocytes.
* Binds RANK (receptor) on osteoclasts and their precursors to stimulate osteoclasts and ↑ Ca2+ → bone resorption. Intermittent PTH release can also stimulate bone formation.
**PTH** = **P**hosphate-**T**rashing **H**ormone
69
\_\_\_\_\_ functions like PTH and is commonly increased in malignancies (eg. squamous cell carcinoma of the lung, renal cell carcinoma).
PTH-Related Peptide (PTHrP)
70
Parathyroid Hormone Regulation
* ↓ serum Ca2+ → ↑ PTH secretion
* ↑ serum PO43− → ↑ PTH secretion
* ↓ serum Mg2+ → ↑ PTH secretion
* ↓↓ serum Mg2+ → ↓ PTH secretion
* Common causes of ↓ Mg2+ include diarrhea, aminoglycosides, diuretics, alcohol abuse.
71
Calcitonin is formed by the \_\_\_\_\_.
Parafollicular Cells (C Cells) of the Thyroid
72
\_\_\_\_\_ ↓ bone resorption of Ca2+.
Calcitonin
73
Calcitonin Regulation
↑ serum Ca2+ → Calcitonin secretion
74
Calcitonin opposes the actions of \_\_\_\_\_. Not important in normal Ca2+ homeostasis.
PTH
Calcit**on**in t**on**es down serum Ca2+ levels and keeps it in b**on**es.
75
Thyroid Hormone Production
* Occurs in the follicles of the thyroid.
* **5**′-deiodinase converts T**4** (the major thyroid product) to T**3** in peripheral tissue (**5**-**4**-**3**).
* Peripheral conversion is inhibited by glucocorticoids, β-blockers and propylthiouracil (PTU).
* Functions of thyroid peroxidase include oxidation, organification of iodide and coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT).
* Inhibited by PTU and methimazole.
* DIT + DIT = T4
* DIT + MIT = T3
76
\_\_\_\_\_ occurs when excess iodine temporarily ⊝ thyroid peroxidase → ↓ T3/T4 production.
Wolff-Chaikoff Effect
77
Signaling Pathways of Endocrine Hormones:
cAMP
**FLAT ChAMP**:
* **F**SH
* **L**H
* **A**CTH
* **T**SH
* **C**RH
* **h**CG
* **A**DH (V2-receptor)
* **M**SH
* **P**TH
* Calcitonin
* GHRH
* Glucagon
* Histamine (H2-receptor)
78
Signaling Pathways of Endocrine Hormones:
cGMP
**BAD** **G**ra**MP**a:
* **B**NP
* **A**NP
* **E**DRF (NO)
\*vasodilators
79
Signaling Pathways of Endocrine Hormones:
IP3
**GOAT HAG**:
* **G**nRH
* **O**xytocin
* **A**DH (V1-receptor)
* **T**RH
* **H**istamine (H1-receptor)
* **A**ngiotensin II
* **G**astrin
80
Signaling Pathways of Endocrine Hormones:
Intracellular Receptor
**PET CAT** on **TV**:
* **P**rogesterone
* **E**strogen
* **T**estosterone
* **C**ortisol
* **A**ldosterone
* **T**3/**T**4
* **V**itamin D
81
Signaling Pathways of Endocrine Hormones:
Receptor Tyrosine Kinase
**G**rowth **F**actors:
* Insulin
* I**GF**-1
* F**GF**
* PD**GF**
* E**GF**
\*MAP kinase pathway
82
Signaling Pathways of Endocrine Hormones:
Nonreceptor Tyrosine Kinase
**PIGG**L**ET**:
* **P**rolactin
* **I**mmunomodulators (eg. cytokines IL-2, IL-6, IFN)
* **G**H
* **G**-CSF
* **E**rythropoietin
* **T**hrombopoietin
\*JAK/STAT Pathway
\*acidophils and cytokines
83
Signaling Pathways of Steroid Hormones
* Steroid hormones are lipophilic and therefore must circulate bound to specific binding globulins, which ↑ their solubility.
* In men, ↑ sex hormone–binding globulin (SHBG) lowers free testosterone → gynecomastia.
* In women, ↓ SHBG raises free testosterone → hirsutism.
* OCPs, pregnancy → ↑ SHBG
84
Cushing Syndrome ↑ Cortisol due to \_\_\_\_\_.
* _Exogenous Corticosteroids_—result in ↓ ACTH, bilateral adrenal atrophy. Most common cause.
* _Primary Adrenal Adenoma, Hyperplasia, or Carcinoma_—result in ↓ ACTH, atrophy ofuninvolved adrenal gland.
* _ACTH-Secreting Pituitary Adenoma_ (Cushing Disease); _Paraneoplastic ACTH Secretion_ (eg. small cell lung cancer, bronchial carcinoids)—result in ↑ ACTH, bilateral adrenal hyperplasia. Cushing Disease is responsible for the majority of endogenous cases of Cushing Syndrome.
85
Findings in Cushing Syndrome
* hypertension
* weight gain
* moon facies
* abdominal striae
* truncal obesity
* buffalo hump
* skin changes (eg. thinning, striae)
* hirsutism
* osteoporosis
* hyperglycemia (insulin resistance)
* amenorrhea
* immunosuppression
\*can also present with pseudohyperaldosteronism
86
Diagnosis of Cushing Syndrome
Screening Tests:
* ↑ free cortisol on 24-hr urinalysis
* ↑ midnight salivary cortisol
* no suppression with overnight low-dose dexamethasone test
Serum ACTH:
* If ↓, suspect adrenal tumor or exogenous glucocorticoids.
* If ↑, distinguish between Cushing Disease and ectopic ACTH secretion (eg. from small cell lung cancer).
87
\_\_\_\_\_ is the inability of adrenal glands to generate enough glucocorticoids +/− mineralocorticoids for the body’s needs. Symptoms include weakness, fatigue, orthostatic hypotension, muscle aches, weight loss, GI disturbances, sugar and/or salt cravings. Treatment glucocorticoid/mineralocorticoid replacement.
Adrenal Insufficiency
88
Diagnosis of Adrenal Insufficiency
* Measurement of:
* _Serum Electrolytes_
* _Morning/Random Serum Cortisol and ACTH_ (low cortisol, high ACTH in 1° adrenal insufficiency; low cortisol, low ACTH in 2°/3° adrenal insufficiency due to pituitary/hypothalamic disease)
* _ACTH Stimulation Test_
* _Metyrapone Stimulation Test_:
* Metyrapone blocks last step of cortisol synthesis (11-deoxycortisol → cortisol).
* Normal response is ↓ cortisol and compensatory ↑ ACTH and 11-deoxycortisol. In 1° adrenal insufficiency, ACTH is ↑ but 11-deoxycortisol remains ↓ after test.
* In 2°/3° adrenal insufficiency, both ACTH and 11-deoxycortisol remain ↓ after test.
89
Adrenal Insufficiency:
* deficiency of aldosterone and cortisol production due to loss of gland function → hypotension (hyponatremic volume contraction), hyperkalemia, metabolic acidosis, skin and mucosal hyperpigmentation (due to ↑ MSH, a byproduct of ACTH production from proopiomelanocortin)
* associated with autoimmune polyglandular syndromes
Primary Adrenal Insufficiency
**P**rimary **P**igments the skin/mucosa.
90
Adrenal Insufficiency:
* sudden onset (eg. due to massive hemorrhage)
* may present with shock in acute adrenal crisis
Acute Primary Adrenal Insufficiency
91
Adrenal Insufficiency:
* due to adrenal atrophy or destruction by disease
* autoimmune destruction most common in the Western world
* TB most common in the developing world
Chronic Primary Adrenal Insufficiency
(Addison Disease)
92
\_\_\_\_\_ is acute 1° adrenal insufficiency due to adrenal hemorrhage associated with septicemia (usually *Neisseria meningitidis*), DIC, endotoxic shock.
Waterhouse-Friderichsen Syndrome
93
Adrenal Insufficiency:
* seen with ↓ pituitary ACTH production
* no skin/mucosal hyperpigmentation
* no hyperkalemia (Aldosterone synthesis preserved due to intact Renin-Angiotensin-Aldosterone axis)
Secondary Adrenal Insufficiency
**S**econdary **S**pares the skin/mucosa.
94
Adrenal Insufficiency:
* aeen in patients with chronic exogenous steroid use, precipitated by abrupt withdrawal
* Aldosterone synthesis unaffected
Tertiary Adrenal Insufficiency
**T**ertiary is from **T**reatment.
95
\_\_\_\_\_ is the increased secretion of aldosterone from adrenal gland. Clinical features include hypertension,
↓ or normal K+, metabolic alkalosis.
Hyperaldosteronism
96
Hyperaldosteronism:
* seen with adrenal adenoma (Conn Syndrome) or bilateral adrenal hyperplasia
* ↑ aldosterone, ↓ renin
* causes resistant hypertension
Primary Hyperaldosteronism
97
Hyperaldosteronism:
seen in patients with renovascular hypertension, juxtaglomerular cell tumors (renin-producing), and edema (eg. cirrhosis, heart failure, nephrotic syndrome
Secondary Hyperaldosteronism
98
Most neuroendocrine tumors arise in the \_\_\_\_\_.
Top 3:
* GI System (eg. carcinoid, gastrinoma)
* Pancreas (eg. insulinoma, glucagonoma)
* Lungs (eg. small cell carcinoma)
Others:
* thyroid (eg. medullary carcinoma)
* adrenals (eg. pheochromocytoma)
99
Neuroendocrine Tumors:
* most common tumor of the adrenal medulla in children, usually \< 4 years old
* originates from neural crest cells
* occurs anywhere along the sympathetic chain
Neuroblastoma
100
Neuroendocrine Tumors:
* most common presentation is abdominal distension and a firm, irregular mass that can cross the midline (vs. Wilms tumor, which is smooth and unilateral)
* less likely to develop hypertension than with Pheochromocytoma
* can also present with Opsoclonus-Myoclonus Syndrome (“dancing eyes-dancing feet”)
Neuroblastoma
**N**euroblastoma is **N**ormotensive.
101
Neuroendocrine Tumors:
* ↑ HVA and VMA (catecholamine metabolites) in urine
* Homer-Wright rosettes
* Bombesin and NSE ⊕
* associated with overexpression of N-myc oncogene
* classified as an APUD tumor
Neuroblastoma
102
Neuroendocrine Tumors:
* most common tumor of the adrenal medulla in adults
* derived from chromaffin cells (arise from neural crest)
* may be associated with germline mutations (eg. NF-1, VHL, RET [MEN 2A, 2B])
Pheochromocytoma
Rule of **10**’s:
* 10% **malignant**
* 10% **bilateral**
* 10% **extra-adrenal** (eg. bladder wall, organ of Zuckerkandl)
* 10% **calcify**
* 10% **kids**
103
Neuroendocrine Tumors:
* most tumors secrete epinephrine, norepinephrine, and dopamine, which can cause episodic hypertension
* may also secrete EPO → polycythemia
* symptoms occur in “spells”—relapse and remit
Pheochromocytoma
Episodic Hyperadrenergic Symptoms (**5 P**’s):
* **P**ressure (↑ BP)
* **P**ain (headache)
* **P**erspiration
* **P**alpitations (tachycardia)
* **P**allor
104
Neuroendocrine Tumors:
↑ catecholamines and catecholamine metabolites (eg. metanephrines) in urine and plasma
Pheochromocytoma
105
Pheochromocytoma is treated with \_\_\_\_\_.
* Irreversible α-antagonists (eg. phenoxybenzamine) followed by β-Blockers prior to tumor resection
* α-blockade must be achieved before giving β-blockers to avoid a hypertensive crisis (**A before B**)
* **Phenoxybenzamine** (16 letters) is given for **Pheochromocytoma** (also 16 letters)
106
Neuroendocrine Tumors:
* rare neuroendocrine tumor that secretes Vasoactive Intestinal Peptide (VIP)
* most commonly arises in the pancreas
* associated with MEN-1
* primary symptom is secretory diarrhea
* associated with WDHA (Watery Diarrhea, Hypokalemia, Achlorhydria) syndrome
VIPoma
107
Skin/Hair Findings in Hypothyroidism
* dry, cool skin (due to ↓ blood flow)
* coarse, brittle hair
* diffuse alopecia
* brittle nail
* puffy facies and generalized nonpitting edema (myxedema) due to ↑ GAGs in interstitial spaces → ↑ osmotic pressure → water retention
108
Ocular Findings in Hypothyroidism
Periorbital Edema
109
Muskuloskeletal Findings in Hypothyroidism
* Hypothyroid Myopathy (proximal weakness, ↑ CK)
* Carpal Tunnel Syndrome
* Myoedema (small lump rising on the surface of a muscle when struck with a hammer)
110
Laboratory Findings in Hypothyroidism
* ↑ TSH (if 1°)
* ↓ free T3 and T4
* Hypercholesterolemia (due to ↓ LDL receptor expression)
111
Skin/Hair Findings in Hyperthyroidism
* warm, moist skin (due to vasodilation)
* fine hair
* onycholysis
* pretibial myxedema in Graves disease
112
Ocular Findings in Hyperthyroidism
* ophthalmopathy in Graves disease (including periorbital edema, exophthalmos)
* lid lag/retraction (↑ sympathetic stimulation of levator palpebrae superioris)
113
Laboratory Findings in Hyperthyroidism
* ↓ TSH (if 1°)
* ↑ free T3 and T4
* ↓ LDL, HDL, and total cholesterol
114
Hypothyroidism:
* most common cause of hypothyroidism in iodine-sufficient regions
* autoimmune disorder with antithyroid peroxidase (antimicrosomal) and antithyroglobulin antibodies
* associated with HLADR3
* ↑ risk of non-Hodgkin lymphoma (typically of B-cell origin)
* may be hyperthyroid early in course due to thyrotoxicosis during follicular rupture
* Histology:
* Hürthle cells
* lymphoid aggregates with germinal centers
* Findings:
* moderately enlarged, nontender thyroid
Hashimoto Thyroiditis
115
Hypothyroidism:
* self-limited thyroiditis arising up to 1 year after delivery
* presents as transient hyperthyroidism, hypothyroidism, or hyperthyroidism followed by hypothyroidism
* majority of women are euthyroid following resolution
* thyroid is usually painless and normal in size
* Histology:
* lymphocytic infiltrate with occasional germinal center formation
Postpartum Thyroiditis
116
Hypothyroidism:
* severe fetal hypothyroidism due to antibody-mediated maternal hypothyroidism, thyroid agenesis, thyroid dysgenesis (most common cause in US), iodine deficiency, or dyshormonogenetic goiter
* Findings:
* pot-bellied
* pale
* puffy-faced
* protruding umbilicus
* protuberant tongue
* poor brain development
Congenital Hypothyroidism (Cretinism)
**6 P**’s:
* **P**ot-bellied
* **P**ale
* **P**uffy-faced
* **P**rotruding umbilicus
* **P**rotuberant tongue
* **P**oor brain development
117
Hypothyroidism:
* self-limited disease often following a flu-like illness (eg. viral infection)
* may be hyperthyroid early in course, followed by hypothyroidism (permanent in ~15% of cases)
* Histology:
* granulomatous inflammation
* Findings:
* ↑ ESR
* jaw pain
* very tender thyroid.
Subacute Granulomatous Thyroiditis (de Quervain)
De Querv**ain** is associated with p**ain**.
118
Hypothyroidism:
* thyroid is replaced by fibrous tissue with inflammatory infiltrate
* fibrosis may extend to local structures (eg. trachea, esophagus), mimicking anaplastic carcinoma. 1⁄3 are hypothyroid
* considered a manifestation of IgG4-related systemic disease (eg. autoimmune pancreatitis, retroperitoneal fibrosis, noninfectious aortitis)
* Findings:
* fixed, hard (rock-like), painless goiter
Riedel Thyroiditis
119
Causes of Hyperthyroidism
* Graves Disease
* Toxic Multinodular Goiter
* Thyroid Storm
* Jod-Basedow Phenomenon
120
Hyperthyroidism:
* most common cause of hyperthyroidism
* thyroid-stimulating immunoglobulin (IgG; type II hypersensitivity) stimulates TSH receptors on thyroid (hyperthyroidism, diffuse goiter) and dermal fibroblasts (pretibial myxedema)
* infiltration of retroorbital space by activated T-cells → ↑ cytokines (eg. TNF-α, IFN-γ) → ↑ fibroblast secretion of hydrophilic GAGs → ↑ osmotic muscle swelling, muscle inflammation, and adipocyte count → exophthalmos
* often presents during stress (eg. pregnancy)
* associated with HLA-DR3 and HLA-B8
* Histology:
* tall, crowded follicular epithelial cells
* scalloped colloid
Graves Disease
121
Hyperthyroidism:
* focal patches of hyperfunctioning follicular cells distended with colloid working independently of TSH (due to TSH receptor mutations in 60% of cases)
* ↑ release of T3 and T4
* hot nodules are rarely malignant
Toxic Multinodular Goiter
122
Hyperthyroidism:
* uncommon but serious complication that occurs when hyperthyroidism is incompletely treated/untreated and then significantly worsens in the setting of acute stress such as infection, trauma, or surgery
* presents with agitation, delirium, fever, diarrhea, coma, and tachyarrhythmia (cause of death)
* may see ↑ LFTs
Thyroid Storm
Treat with the **4 P**’s:
* β-Blockers (eg. **P**ropranolol)
* **P**ropylthiouracil
* Corticosteroids (eg. **P**rednisolone)
* **P**otassium iodide (Lugol iodine)
123
Hyperthyroidism:
* thyrotoxicosis if a patient with iodine deficiency and partially autonomous thyroid tissue (eg. autonomous nodule) is made iodine replete
* can happen after iodine IV contrast
* opposite to Wolff-Chaikoff effect
Jod-Basedow Phenomenon
124
Causes of Smooth/Diffuse Goiter
* Graves Disease
* Hashimoto Thyroiditis
* Iodine Deficiency
* TSH-Secreting Pituitary Adenoma
125
Causes of Nodular Goiter
* Toxic Multinodular Goiter
* Thyroid Adenoma
* Thyroid Cancer
* Thyroid Cyst
126
Thyroid Pathology:
* benign solitary growth of the thyroid
* most are nonfunctional (“cold”)
* can rarely cause hyperthyroidism via autonomous thyroid hormone production (“hot” or “toxic”)
* most common histology is follicular
* absence of capsular or vascular invasion (unlike follicular carcinoma)
Thyroid Adenoma
127
Thyroid Pathology:
* typically diagnosed with fine needle aspiration
* treated with thyroidectomy
* complications of surgery include hoarseness (due to recurrent laryngeal nerve damage), hypocalcemia (due to removal of parathyroid glands), and transection of recurrent and superior laryngeal nerves (during ligation of inferior thyroid artery and superior laryngeal artery, leading to dysphagia, dysphonia)
Thyroid Cancer
128
Thyroid Cancer:
* most common, excellent prognosis
* empty-appearing nuclei with central clearing (“Orphan Annie” eyes)
* psammoma bodies
* nuclear grooves
* ↑ risk with RET/PTC rearrangements and BRAF mutations, childhood irradiation
Papillary Carcinoma
**Papi** and **Moma** adopted **Orphan Annie**.
129
Thyroid Cancer:
* good prognosis
* invades thyroid capsule and vasculature (unlike follicular adenoma)
* uniform follicles
* hematogenous spread is common
* associated with RAS mutation and PAX8-PPAR-γ translocations
Follicular Carcinoma
130
Thyroid Cancer:
* from parafollicular “C cells”
* produces calcitonin
* sheets of cells in an amyloid stroma (stains with Congo red)
* associated with MEN 2A and 2B (RET mutations)
Medullary Carcinoma
131
Thyroid Cancer:
* older patients
* invades local structures
* very poor prognosis
Undifferentiated/Anaplastic Carcinoma
132
Thyroid Cancer:
associated with Hashimoto thyroiditis
Lymphoma
133
Diagnosing Parathyroid Disease
134
\_\_\_\_\_ is due to accidental surgical excision of parathyroid glands, autoimmune destruction, or DiGeorge syndrome. It presents with tetany, hypocalcemia, and hyperphosphatemia.
Hypoparathyroidism
135
tapping of facial nerve (tap the cheek) → contraction of facial muscles
Chvostek Sign
136
occlusion of brachial artery with BP cuff (cuff the triceps) → carpal spasm
Trousseau Sign
137
Hypoparathyroidism:
* unresponsiveness of kidney to PTH → hypocalcemia despite ↑ PTH levels
* presents as a constellation of physical findings known as _Albright Hereditary Osteodystroph_y:
* shortened 4th/5th digits
* short stature
* obesity
* developmental delay
* autosomal dominant
* due to defective Gs protein α-subunit causing end-organ resistance to PTH
* defect must be inherited from mother due to imprinting
Pseudohypoparathyroidism Type 1A
138
Hypoparathyroidism:
* physical exam features of Albright Hereditary Osteodystrophy but without end-organ PTH resistance (PTH level normal)
* occurs when defective Gs protein α-subunit is inherited from father
Pseudopseudohypoparathyroidism
139
Hyperparathyroidism:
* usually due to parathyroid adenoma or hyperplasia
* hypercalcemia, hypercalciuria (renal stones), polyuria, hypophosphatemia, ↑ PTH, ↑ ALP, ↑ cAMP in urine
* most often asymptomatic
* may present with weakness and constipation, abdominal/flank pain (kidney stones, acute pancreatitis), neuropsychiatric disturbances
Primary Hyperparathyroidism
**stones**, **thrones**, **bones**, **groans**, and **psychiatric overtones**
* hypercalciuria (renal **stones**)
* polyuria (**thrones**)
* Osteitis Fibrosa Cystica (**bones**)
* weakness and constipation (“**groans**”)
* neuropsychiatric disturbances (“**psychiatric overtones**”)
140
\_\_\_\_\_ is characterized by cystic bone spaces
filled with brown fibrous tissue (“brown tumor” consisting of osteoclasts and deposited hemosiderin from hemorrhages; causes bone pain). Due to ↑ PTH, classically associated with 1° (but also seen with 2°) hyperparathyroidism.
Osteitis Fibrosa Cystica
141
Hyperparathyroidism:
* 2° hyperplasia due to ↓ Ca2+ absorption and/or ↑ PO43−
* most often in chronic renal disease (causes hypovitaminosis D and hyperphosphatemia → ↓ Ca2+)
* hypocalcemia, hyperphosphatemia in chronic renal failure (vs. hypophosphatemia with most other causes), ↑ ALP, ↑ PTH
Secondary Hyperparathyroidism
142
Hyperparathyroidism:
* refractory (autonomous) hyperparathyroidism resulting from chronic renal disease
* ↑↑ PTH
* ↑ Ca2+
Tertiary Hyperparathyroidism
143
renal disease → 2° and 3° hyperparathyroidism → bone lesions
Renal Osteodystrophy
144
\_\_\_\_\_ is caused by defective G-coupled Ca2+-sensing receptors in multiple tissues (eg. parathyroids, kidneys). Higher than normal Ca2+ levels required to suppress PTH. Excessive renal Ca2+ reuptake → mild hypercalcemia and hypocalciuria with normal to ↑ PTH levels.
Familial Hypocalciuric Hypercalcemia
145
\_\_\_\_\_ causes enlargement of existing ACTH-secreting pituitary adenoma after bilateral adrenalectomy for refractory Cushing disease (due to removal of cortisol feedback mechanism). Presents with hyperpigmentation, headaches and bitemporal hemianopia. Treated with pituitary irradiation or surgical resection.
Nelson Syndrome
146
Endocrine Pathologies:
* excess GH in adults
* typically caused by pituitary adenoma.
* large tongue with deep furrows
* deep voice
* large hands and feet
* coarsening of facial features with aging
* frontal bossing
* diaphoresis (excessive sweating)
* impaired glucose tolerance (insulin resistance)
* hypertension
* ↑ risk of colorectal polyps and cancer
Acromegaly
147
↑ GH in children → _____ (↑ linear bone
growth). HF most common cause of death.
Gigantism
148
Endocrine Pathologies:
* ↑ serum IGF-1
* failure to suppress serum GH following oral glucose tolerance test
* pituitary mass seen on brain MRI
Acromegaly
149
Endocrine Pathologies:
* treated with pituitary adenoma resection
* if not cured, treat with Octreotide (Somatostatin analog) or Pegvisomant (growth hormone receptor antagonist), or Dopamine agonists (eg. Cabergoline).
Acromegaly
150
\_\_\_\_\_ is caused by defective growth hormone receptors → ↓ linear growth (↑ GH, ↓ IGF-1). It presents with short height, small head circumference, characteristic facies with saddle nose and prominent forehead, delayed skeletal maturation, and small genitalia.
Laron Syndrome (Dwarfism)
151
Endocrine Pathologies:
characterized by intense thirst and polyuria with inability to concentrate urine due to lack of ADH (central) or failure of response to circulating ADH (nephrogenic)
Diabetes Insipidus
152
Diabetes Insipidus:
* _Etiology_:
* pituitary tumor
* autoimmune
* trauma
* surgery
* ischemic encephalopathy
* idiopathic
* _Findings_:
* ↓ ADH
* urine specific gravity \< 1.006
* serum osmolality \> 290 mOsm/kg
* hyperosmotic volume contraction
* _Water Deprivation Test_:
* \> 50% ↑ in urine osmolality only after administration of ADH analog
* _Treatment_:
* Desmopressin
* hydration
Central DI
153
Diabetes Insipidus:
* _Etiology_:
* hereditary (ADH receptor mutation)
* 2° to hypercalcemia
* hypokalemia
* lithium
* Demeclocycline (ADH antagonist)
* _Findings_:
* normal or ↑ ADH levels
* urine specific gravity \< 1.006
* serum osmolality \> 290 mOsm/kg
* hyperosmotic volume contraction
* _Water Deprivation Test_:
* minimal change in urine osmolality, even after administration of ADH analog
* _Treatment_:
* HCTZ
* Indomethacin
* Amiloride
* hydration
* dietary salt restriction
* avoidance of offending agent
Nephrogenic DI
154
Water Deprivation Test
* No water intake for 2–3 hr followed by hourly measurements of urine volume and osmolality and plasma Na+ concentration and osmolality.
* ADH analog (Desmopressin) is administered if serum osmolality \> 295–300 mOsm/kg, plasma Na+ ≥ 145 mEq/L, or urine osmolality does not rise despite a rising plasma osmolality.
155
Endocrine Pathologies:
* excessive free water retention
* euvolemic hyponatremia with continued urinary Na+ excretion
* urine osmolality \> serum osmolality
* body responds to water retention with ↓ aldosterone and ↑ ANP and BNP → ↑ urinary Na+ secretion → normalization of extracellular fluid volume → euvolemic hyponatremia
* very low serum Na+ levels can lead to cerebral edema, seizures
* corrected slowly to prevent Osmotic Demyelination Syndrome (formerly known as Central Pontine Myelinolysis)
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
156
Causes of SIADH
* ectopic ADH (eg. small cell lung cancer)
* CNS disorders/head trauma
* pulmonary disease
* drugs (eg. Cyclophosphamide)
157
Treatment for SIADH
* fluid restriction (first line)
* salt tablets
* IV hypertonic saline
* diuretics
* Conivaptan
* Tolvaptan
* Demeclocycline
158
Increased urine osmolality during water deprivation test indicates \_\_\_\_\_.
Psychogenic Polydipsia
159
Causes of Hypopituitarism
* Nonsecreting Pituitary Adenoma
* Craniopharyngioma
* Sheehan Syndrome
* ischemic infarct of pituitary following postpartum bleeding
* pregnancy-induced pituitary growth → ↑ susceptibility to hypoperfusion
* usually presents with failure to lactate, absent menstruation, and cold intolerance
* Empty Sella Syndrome
* atrophy or compression of pituitary (which lies in the sella turcica)
* often idiopathic
* common in obese women
* associated with idiopathic intracranial hypertension
* Pituitary Apoplexy
* sudden hemorrhage of pituitary gland, often in the presence of an existing pituitary adenoma
* usually presents with sudden onset severe headache, visual impairment (eg. bitemporal hemianopia, diplopia due to CN III palsy), and features of hypopituitarism
* brain injury
* radiation
160
Treatment for Hypopituitarism
Hormone Replacement Therapy
* corticosteroids
* thyroxine
* sex steroids
* human growth hormone
161
Acute Manifestations of Diabetes Mellitus
* polydipsia
* polyuria
* polyphagia
* weight loss
* DKA (type 1)
* hyperosmolar hyperglycemic state (type 2)
\*Rarely, can be caused by unopposed secretion of GH and epinephrine. Also seen in patients on glucocorticoid therapy (_steroid diabetes_).
162
Chronic Manifestations of Diabetes Mellitus
* Nonenzymatic Glycation:
* _small vessel disease_ (diffuse thickening of basement membrane) → retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-Wilson nodules → progressive proteinuria [initially microalbuminuria; ACE inhibitors are renoprotective] and arteriolosclerosis → hypertension; both lead to chronic renal failure).
* _large vessel atherosclerosis_, CAD, peripheral vascular occlusive disease, gangrene → limb loss, cerebrovascular disease
* MI is the most common cause of death.
* Osmotic Damage (sorbitol accumulation in organs with aldose reductase and ↓ or absent sorbitol dehydrogenase):
* neuropathy (motor, sensory [glove and stocking distribution], and autonomic degeneration)
* cataracts
163
Diagnosis of Diabetes Mellitus:
reflects average blood glucose over prior 3 months
HbA1c
* cutoff: ≥ 6.5%
164
Diagnosis of Diabetes Mellitus:
fasting for \> 8 hours
Fasting Plasma Glucose
* cutoff: ≥ 126 mg/dL
165
Diagnosis of Diabetes Mellitus:
2 hours after consumption of 75g of glucose in water
2-Hour Oral Glucose Tolerance Test
* cutoff: ≥ 200 mg/dL
166
Diabetes Mellitus Type 1:
1° defect
autoimmune destruction of β cells (eg. due to glutamic acid decarboxylase antibodies)
167
Diabetes Mellitus Type 1:
Insulin treatment
always
168
Diabetes Mellitus Type 1:
age
\< 30 y.o.
169
Diabetes Mellitus Type 1:
obesity
no
170
Diabetes Mellitus Type 1:
genetic predisposition
* relatively weak (50% concordance in identical twins)
* polygenic
171
Diabetes Mellitus Type 1:
HLA system
Yes
* HLA-DR4
* HLA-DR3
**4** – **3** = type **1**
172
Diabetes Mellitus Type 1:
insulin sensitivity
high
173
Diabetes Mellitus Type 1:
ketoacidosis
common
174
Diabetes Mellitus Type 1:
β-cells in islets
low
175
Diabetes Mellitus Type 1:
serum insulin level
low
176
Diabetes Mellitus Type 1:
classic symptoms of polyuria, polydipsia, polyphagia and weight loss
common
177
Diabetes Mellitus Type 1:
histology
islet leukocytic infiltrate
178
Diabetes Mellitus Type 2:
1° defect
* ↑ resistance to insulin
* progressive pancreatic β-cell failure
179
Diabetes Mellitus Type 2:
genetic predisposition
* relatively strong (90% concordance in identical twins)
* polygenic
180
Diabetes Mellitus Type 2:
HLA system
no
181
Diabetes Mellitus Type 2:
insulin sensitivity
low
182
Diabetes Mellitus Type 2:
ketoacidosis
rare
183
Diabetes Mellitus Type 2:
β-cells in islets
variable (with amyloid deposits)
184
Diabetes Mellitus Type 2:
serum insulin level
variable
185
Diabetes Mellitus Type 2:
histology
islet amyloid polypeptide (IAPP) deposits
186
Diabetes Mellitus:
* one of the most feared complications of diabetes
* usually due to insulin noncompliance or ↑ insulin requirements from ↑ stress (eg. infection)
* excess fat breakdown and ↑ ketogenesis from ↑ free fatty acids, which are then made into ketone bodies (β-hydroxybutyrate \> acetoacetate)
* usually occurs in type 1 diabetes, as endogenous insulin in type 2 diabetes usually prevents lipolysis
Diabetic Ketoacidosis
187
Signs and Symptoms of Diabetic Ketoacidosis
**DKA** is **D**eadly:
* **D**elirium/psychosis
* **K**ussmaul respirations (rapid, deep breathing)
* **A**bdominal pain/nausea/vomiting
* **D**ehydration
* fruity breath odor (due to exhaled acetone)
188
Laboratory Findings in Diabetic Ketoacidosis
* hyperglycemia
* ↑ H+
* ↓ HCO3
* ↑ anion gap metabolic acidosis
* ↑ blood ketone levels
* leukocytosis
* hyperkalemia
* depleted intracellular K+ due to transcellular shift from ↓ insulin and acidosis
* osmotic diuresis → ↑ K+ loss in urine → total body K+ depletion
189
Complications of Diabetic Ketoacidosis
* life-threatening mucormycosis (usually caused by *Rhizopus* infection)
* cerebral edema
* cardiac arrhythmias
* heart failure
190
Treatment for Diabetic Ketoacidosis
* IV fluids
* IV insulin
* K+ (to replete intracellular stores)
* glucose if necessary to prevent hypoglycemia
191
Diabetes Mellitus:
* state of profound hyperglycemia-induced dehydration and ↑ serum osmolality, classically seen in elderly type 2 diabetics with limited ability to drink
* hyperglycemia → excessive osmotic diuresis → dehydration
* Symptoms:
* thirst,
* polyuria
* lethargy
* focal neurological deficits (eg. seizures)
* can progress to coma and death if left untreated
* Labs:
* hyperglycemia (often \> 600 mg/dL)
* ↑ serum osmolality (\> 320 mOsm/kg)
* no acidosis (pH \> 7.35, ketone production inhibited by presence of insulin)
* Treatment:
* aggressive IV fluids
* insulin therapy
Hyperosmolar Hyperglycemic State
192
Endocrine Pathologies:
* tumor of pancreatic α cells → overproduction of glucagon
* presents with dermatitis (necrolytic migratory erythema), diabetes (hyperglycemia), DVT, declining weight, depression
* Treatment:
* Octreotide
* surgery
Glucagonoma
193
Endocrine Pathologies:
* tumor of pancreatic β cells → overproduction of insulin → hypoglycemia
* Whipple Triad:
* low blood glucose
* symptoms of hypoglycemia (eg. lethargy, syncope, diplopia)
* resolution of symptoms after normalization of glucose levels
* symptomatic patients have ↓ blood glucose and ↑ C-peptide levels (vs. exogenous insulin use)
* ∼ 10% of cases associated with MEN 1 syndrome
* treated with surgical resection
Insulinoma
194
Endocrine Pathologies:
* tumor of pancreatic δ cells → overproduction of somatostatin → ↓ secretion of secretin, cholecystokinin, glucagon, insulin, gastrin, and gastric inhibitory peptide (GIP)
* may present with diabetes/glucose intolerance, steatorrhea, gallstones, and achlorhydria
* Treatment:
* surgical resection
* Somatostatin analogs (eg. Octreotide) for symptom control
Somatostatinoma
195
Endocrine Pathologies:
* most common malignancy in the small intestine
* rare syndrome caused by carcinoid tumors (neuroendocrine cells with prominen rosettes), especially metastatic small bowel tumors, which secrete high levels of serotonin (5-HT)
* not seen if tumor is limited to GI tract (5-HT undergoes first-pass metabolism in liver)
* results in recurrent diarrhea, cutaneous flushing, asthmatic wheezing, right-sided valvular heart disease (tricuspid regurgitation, pulmonic stenosis) due to lung MAO-A enzymatic breakdown of 5-HT before left heart return
* ↑ 5-hydroxyindoleacetic acid (5‑HIAA) in urine, niacin deficiency (pellagra)
* associated with neuroendocrine tumor markers chromogranin A and synaptophysin
* Treatment:
* surgical resection
* Somatostatin analog (eg. Octreotide)
Carcinoid Syndrome
Rule of **1/3**s:
* **1/3** metastasize
* **1/3** present with 2nd malignancy
* **1/3** are multiple
196
Endocrine Pathologies:
* gastrin-secreting tumor (gastrinoma) of pancreas or duodenum
* acid hypersecretion causes recurrent ulcers in duodenum and jejunum
* presents with abdominal pain (peptic ulcer disease, distal ulcers), and diarrhea (malabsorption)
* positive secretin stimulation test—gastrin levels remain elevated after administration of secretin, which normally inhibits gastrin release
* may be associated with MEN 1
Zollinger-Ellison Syndrome
197
Multiple Endocrine Neoplasias have _____ inheritance.
Autosomal Dominant
All **MEN** are **dominant** (or so they think).
198
Multiple Endocrine Neoplasias
MEN 1 = **3 P**’s
* **P**ituitary
* **P**arathyroid
* **P**ancreas
MEN 2A = **2 P**’s
* **P**arathyroid
* **P**heochromocytoma
MEN 2B = **1 P**
* **P**heochromocytoma
199
Multiple Endocrine Neoplasias:
* pituitary tumors (prolactin or GH)
* pancreatic endocrine tumors—Zollinger-Ellison syndrome, insulinomas, VIPomas, glucagonomas (rare)
* parathyroid adenomas
* associated with mutation of MEN1 (menin, a tumor suppressor, chromosome 11), angiofibromas, collagenomas, and meningiomas
MEN 1
200
Multiple Endocrine Neoplasias:
* parathyroid hyperplasia
* medullary thyroid carcinoma—neoplasm of parafollicular or C cells; secretes calcitonin; prophylactic thyroidectomy required
* pheochromocytoma (secretes catecholamines)
* associated with mutation in RET (codes for receptor tyrosine kinase) in cells of neural crest origin
MEN 2A
201
Multiple Endocrine Neoplasias:
* medullary thyroid carcinoma
* pheochromocytoma
* mucosal neuromas (oral/intestinal ganglioneuromatosis)
* associated with marfanoid habitus
* mutation in RET gene
MEN 2B
202
Treatment for Type 1 DM
insulin replacement
203
Treatment for Type 2 DM
* oral agents (Metformin is first line)
* non-insulin injectables
* insulin replacement
* weight loss is particularly helpful in lowering blood glucose
204
Treatment for Gestational DM
insulin replacement if nutrition therapy and exercise alone fail
205
Regular (short-acting) insulin is preferred for \_\_\_\_\_.
* DKA (IV)
* hyperkalemia (+ glucose)
* stress hyperglycemia
206
Diabetes Mellitus Management:
Injectables
* Insulin Preparations
* Amylin Analogs
* GLP-1 Analogs
207
Diabetes Mellitus Management:
Rapid Acting Insulin Preparations
1-hr peak, "no **LAG**":
* **L**ispro
* **A**spart
* **G**lulisine
208
Diabetes Mellitus Management:
Short Acting Insulin Preparations
2–3 hr peak: regular
209
Diabetes Mellitus Management:
Intermediate Acting Insulin Preparations
4–10 hr peak: NPH
210
Diabetes Mellitus Management:
Long Acting Insulin Preparations
no real peak:
* Detemir
* Glargine
211
Diabetes Mellitus Management:
* bind insulin receptor (tyrosine kinase activity)
* Liver: ↑ glucose stored as glycogen
* Muscle: ↑ glycogen, protein synthesis
* Fat: ↑ TG storage
* Cell Membrane: ↑ K+ uptake
* can cause hypoglycemia, lipodystrophy, and rare hypersensitivity reactions
Insulin Preparations
212
Diabetes Mellitus Management:
* ↓ glucagon release
* ↓ gastric emptying
* ↑ satiety
* can cause hypoglycemia (in setting of mistimed prandial insulin) and nausea
Amylin Analogs
* Pramlintide
213
Diabetes Mellitus Management:
* ↓ glucagon release
* ↓ gastric emptying
* ↑ glucose-dependent insulin release
* ↑ satiety
* can cause nausea, vomiting, and pancreatitis
* promotes weight loss (often desired)
GLP-1 Analogs
* Exenatide
* Liraglutide
214
Diabetes Mellitus Management:
Oral Drugs
* Biguanides
* Sulfonylureas
* Meglitinides
* DPP-4 Inhibitors
* Glitazones/Thiazolidinediones
* Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors
* α-Glucosidase Inhibitors
215
Diabetes Mellitus Management:
* inhibit hepatic gluconeogenesis and the action of glucagon, by inhibiting mGPD
* ↑ glycolysis and peripheral glucose uptake (↑ insulin sensitivity)
* can cause GI upset, lactic acidosis (use with caution in renal insufficiency), and B12 deficiency
* promotes weight loss (often desired)
Biguanides
* Metformin
216
Diabetes Mellitus Management:
* close K+ channel in pancreatic β cell membrane → cell depolarizes → insulin release via ↑ Ca2+ influx
* can cause hypoglycemia (↑ risk with renal failure) and weight gain
Sulfonylureas
* 1st Generation :
* causes disulfiram-like effects
* Chlorpropamide
* Tolbutamide
* 2nd Generation:
* causes hypoglycemia
* Glimepiride
* Glipizide
* Glyburide
217
Diabetes Mellitus Management:
* close K+ channel in pancreatic β cell membrane → cell depolarizes → insulin release via ↑ Ca2+ influx (binding site differs from sulfonylureas)
* can cause hypoglycemia (↑ risk with renal failure) and weight gain
Meglitinides
* Nateglinide
* Repaglinide
218
Diabetes Mellitus Management:
* inhibit DPP-4 enzyme that deactivates GLP-1
* ↓ glucagon release and gastric emptying
* ↑ glucose-dependent insulin release and satiety
* causes mild urinary or respiratory infections
* does not affect weight
DPP-4 Inhibitors
* Linagliptin
* Saxagliptin
* Sitagliptin
219
Diabetes Mellitus Management:
* binds to PPAR-γ nuclear transcription regulator → ↑ insulin sensitivity and levels of adiponectin → regulation of glucose metabolism and fatty acid storage
* causes weight gain, edema, HF, and ↑ risk of fractures
* delayed onset of action (several weeks)
Glitazones/Thiazolidinediones
* Pioglitazone
* Rosiglitazone
220
Diabetes Mellitus Management:
* block reabsorption of glucose in proximal convoluted tubule
* causes glucosuria, UTIs, vaginal yeast infections, hyperkalemia, dehydration (orthostatic hypotension), and weight loss
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors
* Canagliflozin
* Dapagliflozin
* Empagliflozin
221
Diabetes Mellitus Management:
* inhibit intestinal brush-border α-glucosidases → delayed carbohydrate hydrolysis and glucose absorption → ↓ postprandial hyperglycemia
* can cause GI upset
* not recommended if kidney function is impaired
α-Glucosidase Inhibitors
* Acarbose
* Miglitol
222
Endocrine Drugs:
* blocks thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling of iodine → inhibition of thyroid hormone synthesis
* used for hyperthyroidism
* not used to treat Graves ophthalmopathy (treated with corticosteroids)
* causes skin rash, agranulocytosis (rare), aplastic anemia, and hepatotoxicity
Thioamides
* Propylthiouracil
* Methimazole
223
Endocrine Drugs:
* blocks thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling of iodine → inhibition of thyroid hormone synthesis
* also blocks 5′-deiodinase → ↓ peripheral conversion of T4 to T3
* used for hyperthyroidism
* blocks peripheral conversion
* used in first trimester of pregnancy (due to methimazole teratogenicity)
* not used to treat Graves ophthalmopathy (treated with corticosteroids)
* can cause kin rash, agranulocytosis (rare), aplastic anemia, and hepatotoxicity
Propylthiouracil
224
Endocrine Drugs:
* blocks thyroid peroxidase, inhibiting the oxidation of iodide and the organification and coupling of iodine → inhibition of thyroid hormone synthesis
* used for hyperthyroidism
* used in second and third trimesters of pregnancy (due to risk of PTU-induced hepatotoxicity)
* not used to treat Graves ophthalmopathy (treated with corticosteroids)
* causes skin rash, agranulocytosis (rare), aplastic anemia, and hepatotoxicity
* possible teratogen (can cause aplasia cutis)
Methimazole
225
Endocrine Drugs:
* used in thyroid hormone replacement
* used for hypothyroidism and myxedema
* may be abused for weight loss
* causes tachycardia, heat intolerance, tremors, and arrhythmias
* Levothyroxine (T4)
* Liothyronine (T3)
226
Hypothalamic/Pituitary Drugs:
* used in SIADH
* blocks action of ADH at the V2-receptor
ADH Antagonists
* Conivaptan
* Tolvaptan
227
Hypothalamic/Pituitary Drugs:
used in central DI, von Willebrand disease, sleep enuresis, and hemophilia A
Desmopressin
228
Hypothalamic/Pituitary Drugs:
used in GH deficiency and Turner syndrome
GH
229
Hypothalamic/Pituitary Drugs:
* used in labor induction (stimulates uterine contractions)
* facilitates milk letdown
* controls uterine hemorrhage
Oxytocin
230
Hypothalamic/Pituitary Drugs:
used in acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, and esophageal varices
Somatostatin (Octreotide)
231
Endocrine Drugs:
* ADH antagonist (member of tetracycline family)
* used in SIADH
* causes nephrogenic DI, photosensitivity, and abnormalities of bone and teeth
Demeclocycline
232
Endocrine Drugs:
* synthetic analog of aldosterone with little glucocorticoid effects
* used in mineralocorticoid replacement in 1° adrenal insufficiency
* adverse effects are similar to glucocorticoids; also edema, exacerbation of heart failure, and hyperpigmentation
Fludrocortisone
233
Endocrine Drugs:
* sensitizes Ca2+-sensing receptor (CaSR) in parathyroid gland to circulating Ca2+ → ↓ PTH
* used in refractory hypercalcemia in 1° hyperparathyroidism, 2° hyperparathyroidism, or parathyroid carcinoma
* causes hypocalcemia
Cinacalcet
234
Endocrine Drugs:
* nonabsorbable phosphate binder that prevents phosphate absorption from the GI tract
* used in hyperphosphatemia in CKD
* causes hypophosphatemia and GI upset
Sevelamer
