Week 1, 2, etc (Endocrinology)

Question 1

3 different types of hormones

Answer 1

Peptide hormones: derived from polypeptide, no binding protein, membrane receptor, degraded in stomach, short half life (minutes to hours), examples are insulin, GH

Amino acid (tyrosine-derived) hormones: derived from tyrosine, some protein bound but most are not, membrane or nuclear receptor, not generally degraded in stomach, variable half life, examples are dopamine, catecholamines, thyroid hormone

Steroid hormones: derived from cholesterol, lipid soluble, nuclear receptor, not degraded in stomach, long half life, examples are progesterone, estrogen, glucocorticoids

Question 2

Different ways of making/processing hormones

Answer 2

1) Make mature hormone or pro-hormone that is turned into hormone (GH, PTH)
2) Polyprotein undergoes processing to create hormones (POMC, glucagon, somatostatin, calcitonin precursors)
3) Pro-hormone cleaved to make hormone (insulin)
4) Separate genes for alpha and beta subunits get further glycosylated and combine to form hormone (TSH, LH, FSH, hCG)

Question 3

C-peptide

Answer 3

Measures endogenous insulin production because is produced when insulin is produced by the body

C-peptide will not be increased if given exogenous insulin!

Question 4

Hormone receptor types

Answer 4

Cell surface linked to tyrosine kinase: insulin, IGF-1 are growth factor receptors with intrinsic TK; GH, prolactin, leptin are cytokine receptors which recruit TK

Cell surface linked to G proteins and increase adenylate cyclase: TRH, GnRH, TSH, LH, FSH, ACTH, vasopressin, catecholamines, glucagon, PTH, PTHrP, PGE2, GHRH

Cell surface linked to G proteins and increase PLC: TRH, GnRH, TSH, LH, FSH, vasopressin, PTH, PTHrP, somatostatin, oxytocin, angiotensin II, Ca2+, calcitonin

Nuclear receptors: PPARs, steroid hormones, thyroid hormones (T3, T4), vitamins (calcitrol)

Question 5

Laron syndrome

Answer 5

Resistance to GH because GH receptor does not work (inactivating mutation)

Short stature, truncal obesity, small penis, prominent forehead, depressed nasal bridge, under-developed mandible

Looks like GH deficiency but see elevated GH with undetectable IGF-1

Question 6

Pseudohypoparathyroidism

Answer 6

Due to end organ resistance to PTH

Low Ca2+, high phosphorus, HIGH PTH

Question 7

Pseudohypoparathyroidism Type !a

Answer 7

Albright’s Hereditary Osteodystrophy: short 4th metacarpal, short stature, round face, mental retardation

Due to inactivating mutation of GNAS1 gene

Resistance to other hormones (TSH, LH, FSH, glucagon) because all are G protein coupled receptors

50% reduction in Gs alpha subunit (used for activation)

Question 8

McCune-Albright Syndrome

Answer 8

Due to activating mutation of Gs alpha subunit of GnRH receptor, causing increased LH, FSH

Age 6 but breast development and vaginal bleeding

Cafe-au-lait spots because increased MSH, fibrous dysplasia of bones, Cushing syndrome, thyrotoxicosis (constitutive overactivity manifests many places)

Question 9

Thyroid hormone receptors

Answer 9

Nuclear receptors of two types: alpha or beta

Different types of receptor at different target tissues (for TSH suppression in anterior pituitary, bone, neural diff, cardiac/heart rate, etc)

Question 10

Resistance to thyroid hormone

Answer 10

AKA Refetoff syndrome

Usually due to heterozygous mutation of TR-beta gene, but dominant negative

Manifestations include goiter, hearing deficit, hyperactive behavior, learning disability, developmental delay, tachycardia (because still sensitive alpha receptors); associated with ADHD

Elevated T3, T4 and “non-suppressed” TSH (because beta receptor is responsible for TSH suppression!)

Treatment: high dose T3 every other day to suppress TSH and reduce goiter; treatment to reduce T4 during pregnancy to reduce miscarriage rate

Question 11

Resistance to thyroid hormone variant from TR alpha gene mutations

Answer 11

TR alpha heterozygous dominant negative mutation

Manifestations: short stature, delayed bone development, transient delay in motor development, mild impairment of cognitive development, chronic constipation

Serum free T4 and rT3 in low normal range; T3 in high normal range; normal TSH

Treat with thyroxine to normalize TSH resulted in improved growth and metabolic rate in a few patients

Note: specific mutation that blocks TR co-activator

Question 12

Severe resistance to thyroid hormone

Answer 12

Due to TR beta homozygous dominant negative mutation

Manifestations: large goiter, dysmorphic features, severe tachycardia, developmental and growth delay, mental retardation, hearing deficit

Elevated serum T4 (3-6x), elevated serum T3, elevated TSH

Treatment: cardiac protection with beta blockers, but developmental defects are irreversible

Question 13

Hereditary Nephrogenic DI

Answer 13

Symptoms in first week of life

Hypernatremia and low urine osmolality

Polyuria, fever, vomiting, constipation, failure to thrive

Diagnosis and treatment is life saving

Question 14

DIfferent types of diabetes insipidus

Answer 14

Hereditary Nephrogenic DI (AVP receptor X-linked recessive)

Congenital nephrogenic autosomal recessive DI (defective aquaporins)

Question 15

SIADH

Answer 15

Plasma AVP increased

Constitutively activated V2 receptor

Water retention

Question 16

Treatment for SIADH

Answer 16

Tolvaptan

ADH antagonist so ADH doesn’t have as much action and can increase serum sodium

Question 17

Daily equivalents of glucocorticoids

Answer 17

15-25mg hydrocortisone

3.75-6mg prednisone

3-5mg methylprednisone

0.6-1.1mg dexamethasone

Question 18

Why is dexamethasone so good?

Answer 18

No Na+ retention

Maximum anti-inflammatory

Longest half-life

Question 19

Why do we give hydrocortisone 2x per day?

Answer 19

To try to mimic diurnal variation

Do this even though patients less likely to be compliant, and not sure this even is necessary

Question 20

How do we follow patients who are on GCs?

Answer 20

Use clinical symptoms (pigmentation, cushing signs)

Morning ACTH

24 hour urinary 17-hydroxysteroids

Question 21

When do we need to give fludrocortisone (synthetic aldosterone)?

Answer 21

Only if primary adrenal insufficiency

If secondary adrenal insufficiency that means no ACTH but since ATII stimulates aldosterone, don’t need to give synthetic aldosterone!

Monitor renin (high if too low dose (not enough Na+ retained so renin to increase BP); low if too high dose), electrolytes (causes Na+ retention and K+ excretion), pulse and BP

Question 22

Pharmacologic uses of GCs

Answer 22

Inflammatory disease (Crohn’s)

Autoimmune disease (lupus, RA)

Allergic disease (asthma)

Hematologic malignancies (myeloma, some leukemias)

Question 23

Modes of GC administration

Answer 23

Oral

Topical

Inhaled

IV

IM

Intra-articular

Question 24

Side effects of high-dose or prolonged GC therapy

Answer 24

Adrenal gland: adrenal atrophy, Cushing’s syndrome

Cardio: dyslipidemia, HTN, thrombosis, vasculitis

CNS: changes in behavior, cognition, memory, mood (GC-induced psychosis), cerebral atrophy; maybe related to suppressed CRH/POMC (beta-endorphin), altered dopamine system

GI tract: GI bleeding, pancreatitis, peptic ulcer

Immune system: immunosuppression, activation of latent viruses

Integument: atrophy, delayed wound healing, erythema, hypertrichosis, perioral dermatitis, petechiae, acne, stria rubrae distensae, telangiectasia

MSK: bone necrosis, muscle atrophy, osteoporosis, retardation of longitudinal bone growth

Eye: cataracts, glaucoma

Kidney: increased Na+ retention and K+ excretion (act on mineralcorticoid receptor)

Reproductive: delayed puberty, fetal growth retardation, hypogonadism

Note: GCs do NOT impair response to sepsis, they actually help with this stress response

Question 25

Do inhaled GCs get into systemic circulation?

Answer 25

**YES!** **90%** of inhaled steroid is swallowed and absorbed! Can get **systemic side effects** with inhalers

Question 26

Bone effects of GCs

Answer 26

**Enhanced bone resorpion** and **impaired formation** Bone loss within a few weeks/months Prophylaxis with bisphosphonates if treatment with GCs for more than 1 month **Avascular necrosis** of the hip

Question 27

Risks of acute excessive GCs

Answer 27

**Reduced tissue repair** rates **Reduced muscle mass** Increased susceptibility to **infection** **Glucose intolerance** (treat with insulin)

Question 28

Cortisol in response to stress

Answer 28

With severe infection, trauma, burns, illness or surgery, **cortisol increases** in proportion to severity of illness by as much as 6-fold the daily normal secretion Diurnal variation is lost **More CRH, ACTH** made **CBG** (cortisol binding globulin) levels **decrease**

Question 29

How do we change GC treatment when a patient gets critically ill?

Answer 29

**Increase** **the** **dose** so they can have good stress response to illness! Cough/cold without fever: no change **Minor** febrile illness (pneumonia): increase GC dose **2-3 fold** for a few days **Moderate** illness: **hydrocortisone 50mg IV/PO bid-**taper rapidly to maintenance dose as patient recovers **Severe** illness: **hydrocortisone 100mg IV g 8hr** taper dose to maintenance by decreasing half/day intil clinically improved

Question 30

Adrenal crisis

Answer 30

**Stress** induced in patient with **existing adrenal insufficiency** or by **acute destruction of adrenal gland** by hemorrhage, infarction, sepsis, necrosis, steroid withdrawal Combined **mineralocorticoid and GC deficiency** make problem **worse** Presentation: **hypotension**/shock, **abdominal pain**, **hyponatremia**, **hyperkalemia**, acidosis, fever, N/V, **hypoglycemia** Treatment: draw blood but don't wait for lab results, look for infection/underlying condition, infuse IVF normal saline to raise BP, **100mg IV of** **hydrocortisone** then 100mg q 8hrs for 24 hours, no mineralocorticoids

Question 31

How does insulin promote triglyceride storage?

Answer 31

Increased **glucose uptake** Increased **FFA uptake** Increased **lipogenesis** **Inhibits** **lipolysis**

Question 32

Is it just obese people that are insulin resistant?

Answer 32

Both obese and very skinny people (**lipoatrophy**) are insulin resistant Note: lipoatrophy is defect in adipocyte differentiation from preadipocytes

Question 33

Leptin

Answer 33

Secreted by **adipocytes** (fat) Is a product of the ***obese* gene** (ob) **Cytokine-like** molecule secreted from fat **Decreases feeding** behavior, **increases energy expenditure** and decreases lipid storage Leptin receptor is product of the *diabetic* gene (db) and looks just like a cytokine receptor (signals through Jak-STAT pathway)

Question 34

What happens when you give recombinant leptin to a patient with congenital leptin deficiency?

Answer 34

Fat child grows up to be normal?

Question 35

Adiponectin

Answer 35

Another factor secreted by **adipocytes** **Antidiabetic adipokine** linked to human **insulin resistance** Involved in insulin sensitivity, glucose regulation, lipid homeostasis, prevention of atherosclerosis

Question 36

Obese adipose tissue (in those with no leptin)

Answer 36

Get **macrophage** **infiltration** --\> adipocyte death Secretes resistance-causing molecules like **TNF-alpha** and **FFA**, which have **detrimental** effect on **liver** and **muscle**

Question 37

What may be involved in obesity-linked insulin resistance?

Answer 37

**Inflammation** in adipose tissue **Macrophages** infiltrate adipose tissue in obese people and may be involved in development of insulin resistance

Question 38

PPAR-gamma

Answer 38

Master regulator for **adipogenesis**, expressed in **fat** and **macrophages**, controls expression of genes involved in **TG storage in fat** Member of **nuclear** hormone receptor transcription factor family **activated by fatty acids** Is required to form fat, promotes lipid storage in adipose tissue (FFA into TGs in white adipose) **Inhibits macrophage inflammation** **TZD** antidiabetic drugs are **ligands** for **PPAR-gamma** (Rosiglitazone/Avandia, pioglitazone/Actos): promote storage of TGs in adipose tissue, sparing muscle and liver, may reduce adipose tissue inflammation through effects on macrophages

Question 39

Mechanisms of TZD action in insulin resistance

Answer 39

**Decrease glucose output** from liver (decrease lipid accumulation, increase FA oxidation) Increase PPAR-gamma activation to **increase** **adiponectin** and **decrease TNF-alpha, resistin, MCP-1** **Increase glucose uptake** and **decrease lipid accumulation in muscle**

Question 40

Main difference between brown fat and white fat

Answer 40

**Brown** fat expresses **UCP-1** and white fat does not UCP-1 short circuits mitochondrial respiratory chain to let proton gradient leak and **generate heat**

Question 41

Brown fat

Answer 41

Expresses UCP-1 In **infants** **Adults** have brown fat too, is activated to produce heat when we're cold Located around **supraclavicular region**

Question 42

Beige fat

Answer 42

Distinct from white or brown fat (**3rd type of fat cell**) Different gene expression Are **thermogenic** (produce heat) like brown adipose tissue (BAT) cells but occur in white fat depots **Human**"brown fat" is most likely actually **beige fat**

Question 43

What do you need to absorb Ca2+ from the GI tract?

Answer 43

In order to express Ca2+ transporters in the GI tract to absorb Ca2+ from the intestine, you need PTH to activate 1-hydroxylase in the kidney to activate vitamin D Vitamin D is needed to cause expression of Ca2+ transporters in the gut so that Ca2+ can be absorbed in the intestine Vitamin D (activated, D3) and PTH work together to promote Ca2+ and PO4- absorption from the intestine (alse increase osteoclastic activity, promote Ca2+ reabsorption in the kidney, and oppose PO4- losses from the kidney (?)