Endocrine Flashcards Preview

USMLE Step 1. > Endocrine > Flashcards

Flashcards in Endocrine Deck (88):
1

Thyroid embryology

Thyroid diverticulum arises from floor of primitive pharynx and descends into neck. Connected to tongue by thyroglossal duct, which normally disappears but may persist as pyramidal lobe of thyroid.

Foramen cecum is normal remnant of thyroglossal duct. Most common ectopic thyroid tissue site is the tongue

Thyroglossal duct cyst presents as an anterior midline neck mass that moves with swallowing or protrusion of the tongue (vs persistent cervical sinus leading to brachial cleft cyst in lateral neck)

2

Adrenal cortex and medulla

Adrenal cortex (mesoderm) and medulla (neural crest)

1) Cortex
Zona Glomerulosa - regulates RAAS, secretes Aldosterone

Zona Fasiculata - regulates ACTH, CRH; secretes Cortisol, sex hormones

Zona Reticularis - regulates ACTH, CRH; secretes Sex hormone (androgens)

2) Medulla
Chromaffin Cells - regulate preganglionic sympathetic fibers; secrete catecholamines (Epi, NE)

Pheochromocytoma - most common tumor of the adrenal medulla in adults - episodic HTN

Neuroblastoma - most common tumor of the adrenal medulla in children - rarely causes HTN

3

Anterior Pituitary (adenohypophysis)

Secretes: FLAT PiG
FSH
LH
ACTH
TSH
Prolactin
GH

Acidophils secrete GH, prolactin
Basophils secrete the rest of them

Melanotropin (MSH) is secreted by intermediate lobe of pit - derived from oral ectoderm (Rathke Pouch)
- Alpha subunit - hormone subunit common to TSH, LH, FSH, and hCG
- Beta subunit - determines hormone specificity

4

Posterior Pituitary (neurohypophysis)

Secretes:
Vasopression (ADH)
Oxytocin

Made in hypothalamus (supraoptic - ADH, and paraventricular - oxy nuclei) and transported to posterior pituitary via neurophysins (carrier proteins)

Derived from neuroectoderm.

5

Endocrine pancreas cell types

Islets of Langerhans are collections of alpha, beta, and delta endocrine cells. Islets arise from pancreatic buds

a = glucagon (peripheral)
B = insulin (central)
d = somatostatin (interspersed)

6

Insulin synthesis

Preproinsulin (synthesized in RER) becomes proinsulin after cleavage of a "presignal"

Proinsulin (stored in secretory granules) is cleaved and then insulin + C-peptide are exocytosed equally

Insulin and C peptide are both elevated in insulinoma and sulfonylurea use, whereas exogenous insulin lacks C peptide

7

Source of insulin

Pancreatic Beta cells

8

Insulin function

Binds insulin receptors (tyrosine kinase activity), inducing glucose uptake (carrier-mediated transport) into insulin-dependent tissue and gene transcription

Anabolic effects of insulin:
1) Increased glucose transport in skeletal muscle and adipose tissue

2) Increased glycogen synthesis and storage

3) Increased triglyceride synthesis

4) Increased Na retention (kidneys)

5) Increased protein synthesis (muscles)

6) Increased cellular uptake of K and amino acids

7) Decreased glucagon release

Unlike glucose, insulin does NOT cross the placenta

Insulin-dependent glucose transporters:
GLUT4: adipose, striated muscle (exercise can also increase GLUT4 expression)

Insulin-independent transporters:
GLUT1 - RBCs, brain, cornea

GLUT2 - (bidirectional) - B islet cells, liver, kidney, SI

GLUT3 - brain

GLUT5 - (fructose) - spermatocytes, GI tract

Brain utilizes glucose for metabolism normally and ketone bodies during starvation. RBCs always utilize glucose bc they lack mitochondria for aerobic metabolism

BRICK L - insulin independent glucose uptake

Brain, Rbcs, Intestine, Cornea, Kidney, Liver

9

Regulation of Insulin

Glucose is a major regulator of insulin release.

GH (causes insulin resistance leading to increased insulin release)

B2 agonists lead to increased insulin

Glucose enters B cells leading to increased ATP generated from glucose metabolism.

This increased ATP closes K channels (target of sulfonylureas) and depolarizes B cell membrane

Voltage gated Ca channels open leading to Ca influx and stimulation of insulin exocytosis.

10

Glucagon

Made by alpha cells of pancreas

Function:
Catabolic effects of glucagon -
1) Glycogenolysis, gluconeogenesis
2) Lipolysis and ketone production

Regulation:
Secreted in response to hypoglycemia.

Inhibited by insulin, hyperglycemia, and somatostatin*

11

Hypothalamic-pituitary hormones (7)

1) CRH
Increases ACTH, MSH, B-endorphin

Lower CRH in chronic exogenous steroid use

2) Dopamine
Decreases prolactin

Dopamine antagonists (antipsychotics) can cause galactorrhea due to hyperprolactinemia

3) GHRH
Increases GH

Analog (tesamorelin) used to treat HIV-associated lipodystrophy

4) GnRH
Increases FSH and LH

Regulated by prolactin. Tonic GnRH suppresses HPA axis. Pulsatile GnRH leads to puberty and fertility.

5) Prolactin
Decreases GnRH

Pituitary prolactinoma leads to amenorrhea, osteoporosis, hypogonadism, galactorrhea

6) Somatostatin
Decreases GH and TSH

Analogs used to treat acromegaly

7) TRH
Increases TSH and prolactin

12

Prolactin source and function

Secreted by anterior pit

1) Stimulates milk production in breast

2) Inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH synthesis and release

Excessive amounts of prolactin is associated with decreased libido

13

Prolactin regulation

Prolactin secretion from anterior pit is tonically inhibited by dopamine from hypothalamus

Prolactin in turn inhibits its own secretion by increasing dopamine synthesis and secretion from hypothalamus

TRH increases prolactin secretion (in primary or secondary hypothyroidism)

Dopamine agonists (bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma

Dopamine antagonists (most antipsychotics) and estrogens (OCPs, pregnancy) stimulate prolactin secretion

14

Growth hormone (somatotropin) source and function

Secreted by anterior pit

Stimulates linear growth and muscle mass through IGF-1 (somatomedin C) secretion

Increases insulin resistance (diabetogenic)

15

Growth hormone (somatotropin) regulation

Released in pulses in response to growth hormone-releasing hormone (GHRH)

Secretion is higher during exercise and sleep

Secretion inhibited by glucose and somatostatin release via negative feedback by somatomedin

Excess secretion of GH (pituitary adenoma) may cause acromegaly (adults) or gigantism (children)

16

Appetite regulation: Ghrelin

Stimulates hunger (orexigenic effect) and GH release (via GH secretagog receptor)

Produced by stomach.

Increases with sleep loss and Prader-Willi Syndrome

17

Appetite regulation: Leptin

Satiety hormone

Produced by adipose tissue.

Decreases during starvation.

Mutation of leptin gene leads to congenital obesity

Sleep deprivation lowers leptin production

18

Appetite regulation: Endocannabinoids

Stimulate cortical reward centers leading to increased desire for high-fat foods

19

ADH

Made in hypothalamus (supraoptic nuclei), released by posterior pit

regulates serum osmolarity (V2 receptors) and blood pressure (V1 receptors)

Primary function is serum osmolarity regulation (ADH lowers serum osmolarity, increases urine osmolarity) via regulation of aquaporin channel insertion in principal cells of renal collecting duct

ADH levels are decreased in central diabetes insipidus, normal or elevated in nephrogenic DI

Nephrogenic DI can be caused by mutation in V2 receptor

Demopressin acetate (ADH analog) is a treatment for central DI

Regulation of ADH:
Osmoreceptors in hypothalamus (primary); hypovolemia (secondary)

20

17a-hydroxylase deficiency

Congenital adrenal enzyme deficiency - ALL characterized by an enlargement of both adrenal glands due to high ACTH stimulation (due to low cortisol)

Mineralocorticoids: Up

Cortisol: Down

Sex hormones: Down

BP: Up

[K]: Down

Labs: Low androstenedione

Presentation: XY - pseudo-hermaphroditism (ambiguous genitalia, undescended testes) XX - lack secondary sexual development

21

21-hydroxylase deficiency

Congenital adrenal enzyme deficiency - ALL characterized by an enlargement of both adrenal glands due to high ACTH stimulation (due to low cortisol)

Mineralocorticoids: Down

Cortisol: Down

Sex hormones: Up

BP: Down

[K]: Up

Labs: Higher renin activity. High 17-hydroxy-progesterone

Presentation: Most common one** Presents in infancy (salt wasting) or childhood (precocious puberty). XX - virilization

22

11B-hydroxylase deficiency

Congenital adrenal enzyme deficiency - ALL characterized by an enlargement of both adrenal glands due to high ACTH stimulation (due to low cortisol)

Mineralocorticoids: Low aldosterone, High 11-deoxycorticosterone (results in higher BP)

Cortisol: Down

Sex hormones: Up

BP: Up

[K]: Down

Labs: Low renin activity

Presentation: XX - virilization

23

Cortisol source and function

From adrenal zona fasciculata - bound to corticosteroid-binding globulin

Functions: BIG GIB (Blood pressure, Insulin, Gluconeo, Fibroblast, Inflammatory/Immune, Bone)

1) Increases BP
- Upregulates a1-receptors on arterioles leading to higher sensitivity to NE and Epi
- At high concentrations, can bind to mineralocorticoid (aldosterone) receptors

2) Increases Insulin resistance (Diabetogenic)

3) Increases Gluconeogenesis, lipolysis, and proteolysis

4) Lowers Fibroblast activity (causes striae)

5) Lower inflammatory/immune responses
- Inhibits production of leukotrienes and prostaglandins
- Inhibits WBC adhesion leading to neutrophilia
- Blocks histamine release from mast cells
- Reduces eosinophils
- Blocks IL-2 production

6) Lower bone formation (lower osteoblast activity)

24

Cortisol regulations

CRH (hypothalamus) stimulates ACTH release (pit) leading to cortisol production in adrenal zona fasciculata

Excess cortisol lowers CRH, ACTH, and cortisol secretion

Chronic stress induced prolonged secretion

25

Calcium homeostasis

Plasma Ca exists in 3 forms
1) Ionized (45%)
2) Bound to albumin (40%)
3) Bound to anions (15%)

Increase in pH leads to increased affinity of albumin (increased negative charge) to bind to Ca

This leads to hypocalcemia (cramps, pain, paresthesias, carpopedal spasm)

26

Vitamin D

1) Source: D3 from sun exposure in skin. D2 ingested from plants. Both converted to 25-OH in liver and to 1,25-(OH)2 (active form) in kidney

2) Function:
- Increased absorption of dietary Ca and PO4
- Increased bone resorption leads to increased Ca and PO4

3) Regulation:
Increased PTH, low Ca, low PO4 all lead to increased 1,25-(OH)2 production

1,25-(OH)2 feedback inhibits its own production

Deficiency leads to rickets in kids, osteomalacia in adults. Caused by malabsorption, lower sunlight, poor diet, chronic kidney failure

24,25-(OH)2D3 is an inactive form of vitamin D.

PTH leads to increased Ca reabsorption and lower PO4 reabsorption in the kidney, whereas 1,25-(OH)2D3 leads to increased absorption of both Ca and PO4 in the gut

27

PTH source and function

Chief Cells of parathyroid

1) Increases bone resorption of Ca and PO4

2) Increased kidney reabsorption of Ca in DCT

3) Decreased reabsorption of PO4 in PCT

4) Increased 1,25-(OH)2D3 (calcitriol) production by stimulating kidney 1a-hydroxylase in PCT

PTH increases serum Ca and lowers serum PO4.
PTH increases urine PO4

Increased production of macrophage colony-stimulating factor and RANK-L (receptor activator of NF-kB ligand). RANK-L (ligand) secreted by osteoblasts and osteocytes binds RANK (receptor) on osteoclasts and their precursors to stimulate osteoclasts and increase Ca

Intermittent PTH release can stimulate bone formation

PTH = Phosphate Trashing Hormone

PTH-related peptide (PTHrP) functions like PTH and is commonly increased in malignancies

28

PTH regulation

Lower serum Ca leads to higher PTH secretion

High serum PO4 leads to higher PTH secretion

Low serum Mg leads to high PTH secretion

Very low serum Mg leads to lower PTH secretion

Common causes of lower Mg include diarrhea, aminoglycosides, diuretics, alcohol abuse

29

Calcitonin

1) Source: Parafollicular cells (C cells) of thyroid

2) Function: Lowers bone resorption of Ca

3) Regulation: Increased serum Ca leads to calcitonin secretion

Calcitonin opposes action of PTH. Not important in normal Ca homeostasis. CalciTONin TONes done Ca levels

30

Endocrine hormones utilizing cAMP signaling

FSH
LH
ACTH
TSH
CRH
hCG
ADH (V2 receptor)
MSH
PTH
calcitonin
GHRH
glucagon

FLAT ChAMP + cgg

31

Endocrine hormones utilizing cGMP signaling

ANP
BNP
NO (EDRF)

Think vasodilation

32

Endocrine hormones utilizing IP3 signaling

GnRH
Oxytocin
ADH (V1 receptor)
TRH
Histamine (H1 receptor)
Angiotensin II
Gastrin

GOAT HAG

33

Endocrine hormones utilizing intracellular receptor signaling

Vitamin D
Estrogen
Testosterone
T3/T4
Cortisol
Aldosterone
Progesterone

VETTT CAP

34

Endocrine hormones utilizing Intrinsic tyrosine kinase signaling

Insulin
IGF-1
FGF
PDGF
EGF

MAP kinase pathway - think growth factors

35

Endocrine hormones utilizing receptor-associated tyrosine kinase signaling

Prolactin
Immunomodulators (cytokines IL2, IL6, IFN)
GH
G-CSF
Erythropoietin
Thrombopoietin

JAK/STAT pathway - think acidophils and cytokines

PIGG(L)ET

36

Signaling pathway of steroid hormones

Steroid hormones are lipophilic and therefore must circulate bound to specific binding globulins, which increase their solubility

In men, increased sex hormone-binding globulin (SHBG) lowers free testosterone leading to gynecomastia

In women, lower SHBG raises free testosterone and leads to hirsutism

OCPs, pregnancy raise SHBG (free estrogen levels remain unchanged)

37

Thyroid hormones (T3/T4) source and function

Iodine-containing hormones that control the body's metabolic rate

Source: Follicles of thyroid. Most T3 formed in target tissues

Functions:
1) Bone growth (synergism with GH)
2) CNS maturation
3) Increases B1 receptors in heart = Higher CO, HR, SV, contractility
4) Increases basal metabolic rate via N/K/ATPase activity leads to higher O2 consumption, RR, body temperature
5) Increases glycogenolysis, gluconeogenesis, lipolysis

T3 functions - 4 B's
Brain maturation
Bone growth
B-adrenergic effects
Basal metabolic rate goes up

Thyroxine-binding globulin (TBG) binds most T3/T4 in blood; only free hormone is active. Lower TBG in hepatic failure, steroids;

Increased TBG in pregnancy or OCP use (estrogen increases TBG)

T4 is major thyroid product; converted to T3 in peripheral tissue by 5'-deiodinase

T3 binds nuclear receptor with greater affinity than T4

Peroxidase is the enzyme responsible for oxidation and organification of iodide as well as coupling of monoiodotyrosine (MIT) and di-iodotyrosine (DIT)

Propylthiouracil inhibits both peroxidase and 5'deiodinase. Methimazole inhibits peroxidase only

38

Thyroid hormones (T3/T4) regulation

TRH (hypothal) stimulates TSH (pit), which stimulates follicular cells.

Negative feedback by free T3, T4 to anterior pit lowers sensitivity to TRH

Thyroid-stimulating immunoglobulins (TSH) stimulate follicular cells (Graves Disease)

Wolff-Chaikoff Effect - excess iodine temporarily inhibits thyroid peroxidase leading to lower iodine organification leading to low T3/T4 production

39

Cushing Syndrome Etiology

High cortisol due to a variety of causes
1) Exogenous corticosteroids - results in lower ACTH, bilateral adrenal atrophy. Most common cause.

2) Primary adrenal adenoma, hyperplasia, or carcinoma - result in lower ACTH, atrophy of uninvolved adrenal gland. Can also present with pseudohyperaldosteronism

3) ACTH-secreting pituitary adenoma (Cushing Disease*); paraneoplastic ACTH secretion (small cell lung cancer, bronchial carcinoids) - result in high ACTH, bilateral adrenal hyperplasia.

*Cushing disease is responsible for the majority of endogenous cases of Cushing Syndrome

40

Cushing Syndrome findings

HTN, weight gain, moon facies, truncal obesity, buffalo hump, skin changes (thinning, striae), osteoporosis, hyperglycemia (insulin resistance), amenorrhea, immunosuppression

41

Cushing Syndrome Diagnosis

Screening tests include:

1) Increased free cortisol on 24-hr urinalysis

2) Increased midnight salivary cortisol, and no suppression with overnight low-dose dexamethasone test

3) Measure serum ACTH. If low, suspect adrenal tumor. If high, distinguish between Cushing disease and ectopic ACTH secretion with a high dose (8mg) dexamethasone suppression test and CRH stimulation test.

Ectopic secretion will not decrease with dexamethasone bc the source is resistant to negative feedback; ectopic secretion will not increase with CRH bc pit ACTH is suppressed

42

Adrenal insufficiency - general

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

Diagnosis involves measurement of serum electrolytes, morning/random serum cortisol and ACTH, and response to ACTH stimulation test

Alternatively, can use metyrapone stimulation test: metyrapone blocks last step of cortisol synthesis (11-deoxycortisol becomes cortisol). Normal response is decreased cortisol and compensatory increased ACTH.

In adrenal insufficiency, ACTH remains low after test.

43

Adrenal insufficiency - Primary

Deficiency of aldosterone and cortisol production due to loss of gland function leading to hypotension (hyponatremic volume contraction), hyperkalemia, metabolic acidosis, skin and mucosal hyperpigmentation (due to MSH, a byproduct of increased ACTH production from pro-opiomelanocortin)

Acute - sudden onset (due to massive hemorrhage) - may present with shock in acute adrenal crisis

Chronic - aka Addison Disease. Due to adrenal atrophy or destruction by disease (e.g. autoimmune, TB, metastasis)

Primary Pigments the skin/mucosa.

Autoimmunity most common cause of primary chronic adrenal insufficiency in Western world. Associated with autoimmune polyglandular syndromes

Waterhouse-Friderichsen Syndrome - acute primary adrenal insufficiency due to adrenal hemorrhage associated with septicemia (usually N. Meningitides), DIC, endotoxic shock

44

Adrenal insufficiency - secondary

Seen with lower pituitary ACTH production

No skin/mucosal hyperpigmentation, no hyperkalemia (aldosterone synthesis preserved)

Secondary Spares the Skin/mucosa

45

Adrenal insufficiency - tertiary

Seen in patients with chronic exogenous steroid use, precipitated by abrupt withdrawal. Aldosterone synthesis unaffected

Tertiary from Treatment

46

Neuroblastoma

Most common tumor of the adrenal medulla in children, usually less than 4 years old.

Originates from neural crest cells; Homer-Wright rosettes characteristic

Occurs anywhere along the sympathetic chain. Most common presentation is abdominal distension and a firm, irregular mass that can cross the midline (vs Wilms Tumor, which is smooth and unilateral)

Can also present with opsoclonus-myoclonus syndrome ("dancing eyes-dancing feet").

Homovanillic acid (HVA; a breakdown product of dopamine) and vanillylmandelic acid (VMA; a breakdown product of NE) are increased in urine

Bombesin and neuron-specific enolase (+).

Less likely to develop HTN.

Associated with overexpression of N-myc oncogene

47

Pheochromocytoma etiology and symptoms

Most common tumor of the adrenal medulla in adults

Derived from chromaffin cells (arise from neural crest)

Rule of 10's

10% malignant
10% bilateral
10% extra-adrenal
10% calcify
10% kids

Symptoms:

Most tumors secrete Epinephrine, NE, and dopamine, which can cause episodic HTN

Associated with neurofibromatosis type 1, von Hippel-Lindau disease, MEN 2A and MEN 2B

Symptoms occur in "spells" - relapse and remit

Episodic hyperadrenergic symptoms (5 Ps)

Pressure (higher BP)
Pain (HA)
Perspiration
Palpitations (tachycardia)
Pallor

48

Pheochromocytoma Findings and Tx

Increased catecholamines and metanephrines in urine and plasma

Tx = Irreversible alpha-antagonists (phenoxybenzamine) followed by B-blockers prior to tumor resection. Alpha blockade must be achieved before giving B-blockers to avoid a hypertension crisis

49

Hypothyroidism - general

Cold intolerance (lower heat production)

Weight gain, lower appetite

Hypoactivity, lethargy, fatigue, weakness

Constipation

Lower reflexes

Myxedema (facial/ periorbital)

Dry, cool skin; coarse, brittle hair

Bradycardia, dyspnea on exertion

Labs:
High TSH (sensitive test for primary hypothyroidism)

Low free T3 and T4

Hypercholesterolemia (due to lower LDL receptor expression)

50

Hyperthyroidism - general

Heat intolerance (higher heat production)

Weight loss, increased appetite

Hyperactivity

Diarrhea

Higher reflexes

Pretibial myxedema (Graves), periorbital edema

Warm, moist skin; fine hair

Chest pain, palpitations, arrhythmias, increased number and sensitivity of B-adrenergic receptors

Labs:
Low TSH (if primary)

High free or total T3 and T4

Hypocholesterolemia (due to increased LDL receptor expression)

51

Hashimoto thyroiditis

Most common cause of hypothyroidism in iodine-sufficient regions; an autoimmune disorder (anti-thyroid peroxidase, antimicrosomal and antithyroglobulin antibodies).

Associated with HLA-DR5

Increased risk of NH Lymphoma

May be hyperthyroid early in course due to thyrotoxicosis during follicular rupture

Histologic findings: Hurthe cells, lymphoid aggregate with germinal centers

Findings: moderately enlarged, nontender thyroid

52

Congenital hypothyroidism (Cretinism)

Severe fetal hypothyroidism due to maternal hypothyroidism, thyroid agensis, thyroid dysgenesis (most common cause in US), iodine deficiency, dyshormonogenetic goiter

Findings = 6Ps

Pot-bellied,
Pale,
Puffy-faced child with
Protruding umbilicus,
Protuberant tongue, and
Poor brain development

53

Subacute thyroiditis (de Quervain)

A hypothyroidism

Self-limited disease often following a flu-like illness

May be hyperthyroid early in course, followed by hypothyroidism

Histology: granulomatous inflammation

Findings: Increased ESR, jaw pain, early inflammation, very tender thyroid

dequerVAIN = PAIN

54

Riedel thyroiditis

A hypothyroidism

Thyroid replaced by fibrous tissue (hypothyroid)

Fibrosis may extend to local structures (airway), mimicking anaplastic carcinoma

Considered a manifestation of IgG4 related systemic disease (autoimmune pancreatitis, retroperitoneal fibrosis, noninfectious aortitis)

Findings: fixed, hard (rock-like) painless goiter

55

Other causes of hypothyroidism

Iodine deficiency
Goitrogens
Wolff-Chaikoff effect (thyroid gland downregulation in response to increased iodine)

56

Graves Disease

Most common cause of hyperthyroidism. Autoantibodies (IgG) stimulates TSH receptors on thyroid (hyperthyroidism, diffuse goiter), retro-orbital fibroblasts (exophthalmos: proptosis, extraocular muscle swelling), and dermal fibroblasts (pretibial myxedema)

often presents during stress (childbirth)

57

Toxic multinodular goiter

A hyperthyroidism

Focal patches of hyperfunctioning follicular cells working independently of TSH due to mutation in TSH receptor.

Increased release of T3 and T4. Hot nodules are rarely malignant

58

Thyroid storm

Hyperthyroidism cause

Stress-induced catecholamine surge seen as a serious complication of thyrotoxicosis due to disease and other hyperthyroid disorders

Presents with agitation, delirium, fever, diarrhea, coma, and tachyarrhythmia (cause of death)

May see increased ALP due to increased bone turnover.

Treat with 3Ps = B blockers (Proranolol), Propylthiouracil, corticosteroids (prednisolone)

59

Jod-Basedow phenomenon

Hyperthyroidism cause

Thyrotoxicosis if a patient with iodine deficiency goiter is made iodine replete

60

Thyroid cancer - general Tx and risk of Tx

Thyroidectomy is an option for thyroid cancers and hyperthyroidism. Complications of surgery include hoarseness (due to recurrent laryngeal nerve damage), hypocalemia (due to removal of parathyroid glands), and transection of recurrent and superior laryngeal nerves (during ligation of inferior and superior laryngeal arteries respectively)

61

Papillary carcinoma

Most common thyroid cancer, excellent prognosis

Empty-appearing nuclei with central clearing ("Orphan Annie" eyes), psammoma bodies, nuclear grooves.

Lymphatic invasion common

Increased risk with RET and BRAF mutations, childhood irradiation

62

Follicular carcinoma

Thyroid cancer

Good prognosis, invades thyroid capsule (unlike follicular adenoma), uniform follicles

63

Medullary carcinoma

Thyroid cancer

From parafollicular "C Cells"

Produces calcitonin, sheets of cells in an amyloid stroma, hematogenous spread common

Associated with MEN 2A and 2B (RET mutations)

64

Undifferentiated/Anaplastic Carcinoma

Thyroid cancer

Older patients

Invades local structures (airway)

Very poor prognosis

65

Lymphoma - Thyroid

Associated with Hashimoto thyroiditis

66

Hypoparathyroidism

Due to accidental surgical excision of parathyroid glands, autoimmune destruction, or DiGeorge

Findings = hypocalcemia, tetany

Chvostek sign - tapping of facial nerve (tap the Cheek) leads to contraction of facial muscles

Trousseu sign - occlusion of brachial artery with BP cuff (cuff the Triceps) leads to carpal spasm

67

Pseudohypoparathyroidism

"Albright hereditary osteodystrophy"

Unresponsiveness of kidney to PTH. Hypocalcemia, shortened 4th/5th digits, short stature

Autosomal dominant

68

Familial hypocalciuric hypercalcemia

Defective Ca sensing receptor on parathyroid cells

PTH cannot be suppressed by an increase in Ca level

This causes mild hypercalcemia with normal to increased PTH levels

69

Hyperparathyroidism - Primary

usually due to parathyroid adenoma or hyperplasia

Hypercalcemia, hypercalciuria (renal STONES), hypophosphatemia, increased PTH, ALP, cAMP in urine.

Most often asymptomatic. May present with weakness and constipation ("groans"), abdominal/flank pain (kidney stones, acute pancreatitis), depression ("psychiatric overtones"

Stones, groans, and psychiatric overtones

Osteitis fibrosa cystica - cystic BONE spaces filled with brown fibrous tissue ("brown tumor" consisting of deposited hemosiderin from hemorrhages; causes bone pain)

Stones, bones, groans and psych overtones

70

Hyperparathyroidism - secondary

Secondary hyperplasia due to low Ca absorption and/or high PO4, most often in chronic renal disease (causes hypovitaminosis D leading to low Ca absorption)

Hypocalcemia, hyperphosphatemia in chronic renal failure (vs hypophosphatemia with most other causes), high ALP, high PTH

Renal Osteodystrophy - bone lesions due to secondary or tertiary hyperparathyroidism due in turn to renal disease.

71

Hyperparathyroidism - tertiary

Refractory (autonomous) hyperparathyroidism resulting from chronic renal disease. HUGE increase in PTH, high Ca

Renal Osteodystrophy - bone lesions due to secondary or tertiary hyperparathyroidism due in turn to renal disease.

72

Pituitary adenoma

Most commonly prolactinoma (benign).

Adenoma may be functional (hormone producing) or nonfunctional (silent.

Nonfunctional tumors present with mass effect (bitemporal hemianopia, hypopituitarism, HA)

Functional tumor presentation is based on the hormone produced (prolactinoma: amenorrhea, galactorrhea, low libido, infertility; somatotropic adenoma: acromegaly)

Tx for prolactinoma = dopamine agonists (bromocriptine or cabergoline), transsphenoidal resection

73

Acromegaly

Excess GH in adults. Typically caused by pituitary adenoma

Findings: Large tongue with deep furrows, deep voice, large hands and feet, coarse facial features, impaired glucose tolerance (insulin resistance)

Increased risk of colorectal polyps and cancer

Dx: Increased serum IGF-1; failure to suppress serum GH following oral glucose tolerance test; pituitary mass seen on brain MRI

Tx: Pit adenoma resection: If not cured, treat with octreotide (somatostatin analog) or pegvisomant (GH receptor antagonist)

Increased GH in children leads to gigantism (increased linear bone growth). HF most common cause of death

74

Diabetes insipidus

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)

1) Central DI

Cause: Pit tumor, autoimmune, trauma, surgery, ischemic encephalopathy, idiopathic

Findings:
Low ADH
Urine specific gravity 290 mOsm/kg
Hyperosmotic volume contraction

Water deprivation test (No water intake for 2-3 hrs followed by hourly measurements of urine volume and osmolarity and plasma Na concentration and osmolarity. ADH analog - desmopressin acetate - is administered if normal values are not clearly reached)

> 50% increase in urine osmolality only after administration of ADH analog

Tx: Intranasal desmopressin acetate. Hydration.

2) Nephrogenic DI

Cause: hereditary (ADH receptor mutation), secondary to hypercalcemia, lithium, demeclocycline (ADH antagonist)

Findings:
Normal ADH levels
Urine specific gravity 290 mOsm/kg
Hyperosmotic volume contraction

Water deprivation test:
Minimal change in urine osmolality, even after administration of ADH analog

Tx: HCTZ, indomethacin, amiloride. Hydration.

75

SIADH

Syndrome of Inappropriate ADH secretion

Excessive free water retention

Euvolemic hyponatremia with continued urinary Na excretion

Urine osmolality > Serum osmolality

Body responds to water retention with reduced aldosterone (hyponatremia) to maintain near-normal volume status. Very low serum Na levels can lead to cerebral edema, seizures.

Correct slowly to prevent osmotic demyelination syndrome (formerly known as central pontine myelinolysis)

Causes include:
Ectopic ADH (small cell lung cancer)
CNS disorder/head trauma
Pulmonary disease
Drugs (cyclophosphamide)

Tx: Fluid restriction, IV hypertonic saline, conivaptan, tolvaptan, demeclocycline

76

Hypopituitarism

Undersecretion of pituitary hormones due to:

1) Nonsecreting pituitary adenoma, craniopharyngioma

2) Sheehan Syndrome - ischemic infarct of pituitary following postpartum bleeding; usually presents with failure to lactate, absent menstruation, cold intolerance

3) Empty Sella Syndrome - atrophy or compression of pituitary, often idiopathic, common in obese women

4) Pituitary apoplexy - sudden hemorrhage of pituitary gland, often in the presence of an existing pituitary adenoma

5) brain injury

6) Radiation

Tx: hormone replacement therapy (corticosteroids, thyroxine, sex steroids, human growth hormone)

77

Diabetes Mellitus - acute manifestations

Insulin deficiency or insensitivity (and glucagon excess) leads to:

1) Decreased serum glucose uptake. This leads to hyperglycemia, glycosuria, osmotic diuresis, electrolyte depletion. All this leads to dehydration +/- acidosis. Finally this can cause coma, death.

2) Increased protein catabolism leading to increased plasma amino acids, nitrogen loss in urine. This leads to hyperglycemia, glycosuria, osmotic diuresis, electrolyte depletion. All this leads to dehydration +/- acidosis. Finally this can cause coma, death.

3) Increased lipolysis (insulin deficiency only). This leads to increased plasma FFAs, ketogenesis, ketonuria, ketonemia. This all leads to dehydration +/- acidosis. Finally this can cause coma, death.

Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar coma (type 2)

Rarely, can be caused by unopposed secretion of GH and Epinephrine. Also seen in patients on glucocorticoid therapy (steroid diabetes)

78

Diabetes mellitus - chronic complications

1) Nonenzymatic glycation:
- small vessel disease (diffuse thickening of basement membrane) leads to retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-Wilson nodules leads to progressive proteinuria and arteriolosclerosis leading to HTN; both lead to chronic renal failure)

- Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease, gangrene leading to limb loss, cerebrovascular disease. MI most common cause of death

2) Osmotic damage (sorbitol accumulation in organs with aldose reductase and low or absent sorbitol dehydrogenase):
Neuropathy (motor, sensory, and autonomic degeneration)
Cataracts

79

Diabetes mellitus Dx

Fasting serum glucose, oral glucose tolerance test, HbA1C (reflects avg blood glucose over prior 3 months)

80

Type 1 vs Type 2 Diabetes mellitus

1) Type 1

Primary defect = Autoimmune destruction of B cells

Insulin necessary in Tx? Always

Age: Less than 30

Association with obesity? No

Genetic predisposition? Relatively weak (50% concordance in identical twins), polygenic

Association with HLA system? Yes (HLA-DR3 and DR4)

Glucose intolerance: Severe

Insulin sensitivity: High

Ketoacidosis: Common

B-cell numbers in the islets: Low

Serum insulin: Low

Classic symptoms of polyuria, polydipsia, polyphagia, weight loss: Common

Histology: Islet leukocytic infiltrate

2) Type 2

Primary defect = Increased resistance to insulin, progressive pancreatic B cell failure

Insulin necessary in Tx? Sometimes

Age: Over 40

Association with obesity? Yes

Genetic predisposition? Relatively strong (90% concordance in identical twins), polygenic

Association with HLA system? No

Glucose intolerance: Mild to moderate

Insulin sensitivity: Low

Ketoacidosis: Rare

B-cell numbers in the islets: Variable (with amyloid deposits)

Serum insulin: Variable

Classic symptoms of polyuria, polydipsia, polyphagia, weight loss: Sometimes

Histology: Islet amyloid polypeptide (IAPP) deposits

81

Diabetic ketoacidosis

One of the most feared complications of diabetes. Usually due to increased insulin requirements from increased stress (infection). Excess fat breakdown and increased ketogenesis from increased free fatty acids, which are then made into ketone bodies (B-hydroxubutyrate > acetoacetate). Usually occurs in type 1 diabetes, as endogenous insulin in type 2 diabetes usually prevents lipolysis.

Signs/Symptoms: Kussmaul respirations (rapid/deep breathing), nausea/vomiting, abdominal pain, psychosis/delirium, dehydration. Fruity breath odor (due to exhaled acetone)

Labs: Hyperglycemia, increased H, Low HCO3 (higher anion gap metabolic acidosis), increased blood ketone levels, leukocytosis. Hyperkalemia, but depleted intracellular K due to transcellular shift from low insulin insulin (therefore total body K is depleted)

Complications: Life-threatening mucormycosis (usually Rhizopus infection), cerebral edema, cardiac arrhythmias, heart failure

Tx: IV fluids, IV insulin, and K (to replete intracellular stores); glucose if necessary to prevent hypoglycemia

82

Glucagonoma

Tumor of pancreatic alpha cells leading to overproduction of glucagon

Presents with dermatitis (necrolytic migratory erythema), diabetes (hyperglycemia), DVT, and depression

83

Insulinoma

Tumor of pancreatic B cells leading to overproduction of insulin leading to hypoglycemia.

May see Whipple triad: Low blood glucose, symptoms of hypoglycemia (lethargy, syncope, diplopia), and resolution of symptoms after normalization of glucose levels.

Symptomatic patients have low blood glucose and increased C peptide levels (vs exogenous insulin use).

Tx = surgical resection

84

Carcinoid Syndrome

Rare syndrome caused by carcinoid tumors (neuroendocrine cells), especially metastatic small bowel tumors, which secrete high levels of 5-HT (serotonin)

not seen if tumor is limited to GI tract (5HT undergoes first-pass metabolism in liver)

Results in recurrent diarrhea, cutaneous flushing, asthmatic wheezing, right-sided valvular disease

Increased 5-hydroxyindoleacetic acid (5-HIAA) in urine

Niacin deficiency (pellagra)

Tx = surgical resection, somatostatin analog (octreotide)

85

Zollinger-Ellison syndrome

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), 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

86

MEN 1

Auto Dom

3 P's

Parathyroid tumors

Pituitary tumors (prolactin or GH)

Pancreatic endocrine tumors - Zollinger-Ellison Syndrome, insulinomas, VIPomas, glucagonomas (rare)

Associated with mutation of MEN1 gene (menin, a tumor suppressor)

87

MEN 2A

Auto Dom

2 P's

Parathyroid hyperplasia

Pheochromocytoma

Medullary thyroid carcinoma (secretes calcitonin)

Associated with marfanoid habitus; mutations in RET gene (codes for receptor tyrosine kinase)

88

MEN-2B

Auto Dom

Only 1 P now

Pheochromocytoma

Medullary thyroid carcinoma (secretes calcitonin)

Oral/intestinal ganglioneuromatosis (mucosal neuromas)

Associated with marfanoid habitus; mutations in RET gene