1
Q
causes of 1º hypothyroidism
A
2
Q
how do fT4 and TSH levels differ in 1º vs 2º hypothyroidism
A
high TSH levels in 1º
while TSH levels in 2º are low or normal
3
Q
3 most impt symptoms of hypothyroidism
that you should look for in patients
A
- (for women) irregular menses
- constipation
- weight gain
4
Q
The drugs used in management of hypothyroidism are
synthetic preparations of the sodium salts of the natural isomers of thyroid hormones.
What are the 2 drugs and which thyroid hormones are they isomers of respectively?
A
- Levothyroxine (T4)
- Liothyronine (T3)
5
Q
which of the hypothyroidism drug need to be taken on an empty stomach?
A
levothyroxine
30 mins - 1h before meals
6
Q
why is levothyroxine preferred over liothyronine
A
longer half-life
(= less frequent dosing)
7
Q
clinical indications for levothyroxine vs liothyronine
A
- levothyroxine: chronic
(thus basically normal hypothyroidism) - liothyronine: acute
8
Q
what should be used for the treatment of myxedema coma?
drug(s) and route
myxedema coma: SEVERE form of hypothyroidism
A
IV LEVOthyroxine
levothyroxine > liothyronine
bcos levothyroxine has lower risk of precipitating life-threatening arrhythmias and myocardial ischemia
⇒ provides a more physiologic and safer restoration of thyroid hormone levels
9
Q
adverse effects of levothyroxine and liothyronine
A
- hyperthyroidism
(and symptoms associated with it) - levothyroxine:
increased bone resorption
→ decreased bone mineral density (BMD)
⇒ increased fracture risk
10
Q
what drug-food interaction do you have to look out for when giving levothyroxine?
A
- IRON
- others: antacids, coffee
11
Q
what drug-drug interaction do you have to look out for when calculating dosing of levothyroxine?
A
patients with estrogen hormone replacement treatment
as increase thyroxine-binding globulin levels
→ increase in bound levothyroxine
→ decrease in amt available for action
⇒ increase in levothyroxine dose required
12
Q
in what groups of patients are there special considerations in regards to dosing of levothyroxine
A
- elderly: decrease in dosing
- pregnant: increase DURING pregnancy, but reduction AFTER
- patients with IHD: same dosing,
but START with small, and slowly up titrate
13
Q
clinical triad of symptoms associated with Graves’ disease
A
- Hyperthyroidism
- Infiltrative ophthalmopathy
- Infiltrative dermopathy
pathophysio of opthalmopathy:
B & T cells migrate into the retro-orbital tissue.
→ mistakenly recognize antigens on orbital fibroblasts as “abnormal.”
→ T cells release cytokines TNF-α and IFN-γ which activate fibroblasts
→ fibroblasts produce glycosaminoglycans (GAGs)
→ attract water
⇒ swelling
“infiltrative” as changes are due to the ACCUMULATION of abnormal material (glycosaminoglycans/mucin) and immune cells which infiltrated the tissues
14
Q
epidemiology of Graves disease:
* predominantly affects (men/women) of (what age range)
* strong family history and genetic predisposition: (which genes)
A
- predominantly affects women of childbearing age (20-40 y/o)
- strong family history and genetic predisposition:
HLA-B8 and HLA-DR3
“If you step on GRAVES, the zombies will B8 (bite) you and chase you up the DR3 (tree)”
15
Q
what are some other features of Graves
(other than the classical triad)
hint: can be seen during thyroid PE
A
- diffuse goiter ⇒ bruit on auscultation
- onycholysis and clubbing
16
Q
pathophysiology of Graves
A
AUTOimmunity involving B and T cells
→ production of IgG antibodies against TSH-receptors (TRAb)
→ increased thyroid hormone production (T3/T4) + thyroid cell growth
⇒ hyperthyroidism and diffuse goiter
- it is a type II hypersensitivity rxn
- 3 types of TRAbs:
1) Thyroid stimulating immunoglobulin (TSI) → mimics TSH ⇒ increase thyroid hormones
2) Thyroid growth stimulating immunoglobulin (TGI) **→ **promotes follicular hyperplasia ⇒ thyroid cell growth
3) TSH-binding inhibitor immunoglobulin → block normal TSH from binding but also stimulate TSH receptors
17
Q
investigations for Graves
A
- thyroid function test: increased T3/T4, low TSH
- presence of TRAb
- radioiodine uptake scan: diffuse increased uptake
possible to see all 3 antibodies (TRAb, anti-TPO and anti-thyroglobulin),
just that it is MOST LIKELY to be TRAb for Graves
18
Q
complications of Graves
A
- osteopenia
- (in severe cases) thyroid storm
19
Q
describe the biosynthesis of T4 and T3
A
20
Q
histological description of Islets of Langerhans
A
- compact spherical or ovoid masses of endocrine cells embedded within the acinar cells
- composed of cords of cuboidal cells separated by fenestrated capillaries,
and surrounded by a thin reticular capsule - pale-staining
21
Q
anatomical features of thyroid:
* butterfly shaped:
(…) + (…)
* highly vascularised: (…) arteries
* surrounded by (…) fascia ⇒ moves with swallowing
A
- butterfly shaped:
2 lobes + isthmus - highly vascularised: superior and inferior thyroid arteries
- surrounded by pretracheal fascia ⇒ moves with swallowing
22
Q
anatomical relations of thyroid gland:
* anterior: (4, from superficial to deep)
* posteriorly: (3)
* lateral: (2)
* inferior: (1)
A
- anterior:
skin, superficial fascia, platysma, deep cervical fascia - posteriorly:
trachea, eosophagus, parathyroid glands - lateral:
carotid sheath, sternocleidomastoid muscle - inferior:
superior thoracic aperture (thoracic inlet)
23
Q
anatomical features of parathyroid glands:
* (…) ovoid masses on (…) surface of thyroid gland
* supplied by (…) arteries
A
anatomical features of parathyroid glands:
* 4 ovoid masses on posterior surface of thyroid gland
* supplied by inferior thyroid arteries
24
Q
histology of thyroid gland
hint: 4 components!
A
- thyroid follicles:
filled with colloid,
which stores thyroid hormone in large amts
until required - follicular cells:
cuboidal columnal cells which surrounds thyroid follicles
and produces thyroid hormone - parafollicular C cells:
secrete calcitonin - stroma:
connective tissue capsule that extends into gland
calcitonin functions to LOWER blood calcium levels!
25
histology of parathyroid glands
| 2 types of cells!
* chief cells: produce **parathyroid** hormone (PTH)
* oxyphil cells: **degenerated** chief cells
## Footnote
PTH functions to RAISE **calcium** levels!
26
anatomical features of pituitary gland:
* located in (...) fossa of (...)
* (...) lies ABOVE sella turcica
⇒ enlargement of gland can limit (...)
anatomical features of pituitary gland:
* located in **hypophyseal** fossa of **sella turcica**
* **optic chiasm** lies ABOVE sella turcica
⇒ enlargement of gland can **LIMIT visual field**
27
blood supply of pituitary gland
| it's a whole system involving hypothalamic hormones and AP hormones
28
parts of anterior pituitary
| 3 parts, including 1 with subparts
* pars *distalis*: main functional region, containing
1. chromo**phils**: **HORMONE-producing**, includes acidophils and basophils
2. chromo**phobes**: **degranulated** chromophils
* pars *intermedia*: contains **melanotrophs** (which produces **melanocyte-stimulating HORMONE**)
* pars *tuberalis*: mostly **undifferentiated** cells
29
parts of the posterior pituitary
* **axons** of neurosecretory cells in supraoptic nucleus (SON) and paraventricular nucleus (PVN) of hypothalamus
* **Herring** bodies: dilated swellings in axon terminals which **store hormones**
* **pituicytes**: cells which **support** hormone RELEASE
## Footnote
hormones stored are **ADH** and **oxytocin**!
30
how does hormone release work in posterior pituitary
axons terminate near the **capillaries** of the pars nervosa
→ when the hypothalamic neuron fires an **action potential**
→ stored hormones in Herring bodies is released by **exocytosis** into the capillary bed
→ then enter systemic circulation via **hypophyseal veins**
31
what are the different zones in the adrenal cortex
and what do each of them produce?
from outer to inner:
* zona **G**lomerulosa: mineralocorticoids (e.g. aldosterone)
* zona **F**asciculata: mainly glucocorticoids (e.g. cortisol), some androgens
* zona **R**eticularis: mainly androgens, some glucocorticoids
! recall that adrenal glands sit on top of kidney
and **GFR** is impt marker of kidney fn !
32
what cells are found in the adrenal medulla
and what do they produce
* **chromaffin** cells: majority, produces **epinephrine** and **norepinephrine**
* ganglion cells: minority, carries out LOCAL autonomic regulation
(e.g. dilation/constriction of blood vessels WITHIN adrenal gland)
33
What do you call excess cortisol and cortisol deficiency respectively
* excess of cortisol = **Cushing's** syndrome
* deficiency in cortisol = **adrenal** insufficiency
## Footnote
Cushing's DISEASE is diff from Cushing's SYNDROME,
it is a **subset** in which the excess cortisol is due to excessive ACTH secretion by pituitary gland
34
common signs and symptoms of Cushing's syndrome
"MOON FACE"
"**MOON FACE**"
* **M**uscle weakness/wasting
* **O**BESITY (CENTRAL)
* **O**steoporosis
* **N**OTICEABLE FAT PADS (= BUFFALO HUMP)
* **F**ACIAL FULLNESS (= MOON FACE)
* **A**BDOMINAL STRIA (PURPLE)
* **C**ataracts, hyperglycaemia/DM
* **E**asy bruising , excess hair (hirsutism)
## Footnote
also can use
"CUSHINGOID"
* **C**ataracts
* **U**lcers
* **S**triae/Skin thinning
* **H**ypertension/Hirsutism/HYPERNatremia
* **I**nfections
* **N**ecrosis (of the femoral head)
* **G**lucose elevation - Hyperglycemia
* **O**steoporosis/Obesity - weight gain
* **I**mmunosuppression
* **D**epression/Diabetes
35
causes of Cushing's syndrome
| ALSO what is the most common cause
primary:
* endrogenous:
1) adrenal cortical adenoma/carcinoma
2) ectopic
* exogenous:
glucocorticoids/steroids
secondary:
* cushing's disease: excessive **ACTH** production by PITUITARY (e.g. pituitary adenoma)
* ECTOPIC **ACTH** production (e.g. small cell lung carcinoma)
| most common cause = **exogenous glucocorticoids**
36
causes of adrenal insufficiency
primary
* Addison's disease
* congenital adrenal hyperplasia
secondary:
* diseases of **hypothalamus or pituitary**
37
more about 2º adrenal insufficiency:
* possible cause related to exogenous steroids?
* hyponatremia?
* hypoglycemia?
* long-term high dose **exogenous steroids** results in **suppressed ACTH** production
-> adrenal glands become **atrophic**
-> thus a **sudden stop** to exogenous steroids
-> body NOT able to produce endogenous cortisol
=> 2º adrenal insufficiency
* cortisol **inhibits** production of **ADH**
-> thus **low cortisol** = lack of inhibition of production of ADH
-> **increased** ADH
-> increased **water retention**
=> dilution of sodium and thus dilutional hyponatremia
* cortisol promotes HEPATIC **gluconeogenesis**
=> thus low blood cortisol = low blood glucose
38
what are some signs and symptoms which differentiate bet 1º and 2º adrenal insufficiency? (2)
* skin colour:
**MSH has the same PRECURSOR as ACTH**
→ changes in ACTH will result in changes in MSH
(e.g. increased ACTH → increased MSH)
⇒ changes in **melanocyte** stimulation and thus amt of **pigmentation** produced
* deficiency of other hormones:
1º: adrenal gland as a whole not working well
⇒ deficiency in **other hormones produced by adrenal gland** (e.g. aldosterone)
2º: possibly pituitary as a whole not working well
⇒ deficiency in **other hormones produced by pituitary** (e.g. growth hormone),
but NOT aldosterone
39
other than cortisol lvl, what is 1 other test you can use to test for Cushing's syndrome
**low-dose** dexamethasone suppression test
* bcos dexamethasone is a glucocorticoid and thus should suppress ACTH and cortisol
* (+) result: **failure** of cortisol suppression
40
what is 1 test you can use to differentiate bet cause of Cushing's syndrome
**high-dose** dexamethasone suppression test
* (+) test: **failure** of cortisol suppression
⇒ **2º ectopic**
41
other than cortisol lvl, what is 1 other test you can use to test for adrenal insufficiency?
synacthen (= synthetic ACTH) stimulation test
* (+) test: **failure** to stimulate
⇒ **Addison's** disease (= 1º adrenal insufficiency)
42
what is the pathophysiology behind the signs of Conn syndrome
| but 1st WHAT is Conn syndrome
**1º HYPERaldosteronism**
* hypertension
due to increased **Na+ retention**
⇒ ECF vol retention
* hypokalaemia
due to increased **K+ secretion**
* decreased plasma **renin activity**
43
quick facts about aldosterone:
1. aldosterone (does/does not) cause hypernatraemia
2. excessive aldosterone secretion (frequently/rarely) causes oedema
3. ACTH (can/cannot) increase aldosterone secretion
quick facts about aldosterone:
1. aldosterone does **NOT** cause **hypernatraemia**
bcos water is also reabsorbed
⇒ while amt of Na+ has changed, [Na+] has not
2. excessive aldosterone secretion **rarely** causes **oedema**
bcos increased pressure from volume expansion
→ increased filtration pressure (**pressure natriuresis**)
⇒ more water to be **excreted in urine**
3. **ACTH** can increase aldosterone secretion
bcos ACTH **promotes the first step of the common cholesterol synthesis pathway** for ALL steroids (e.g. aldosterone, cortisol and androgens) in the adrenal cortex
44
what is pheochromocytoma
| associated presenting symptoms and diagnosis
adrenal **medullary** tumour
* presenting symptoms:
tachycardia/palpitations, sweating, HTN, headache
* diagnosis:
serum/urine catecholamines
and **metanephrines** (= metabolic pdts of catecholamines)
## Footnote
note that it specifically affects the chromaffin cells
45
what syndrome is pheochromocytoma associated with
| recall: pheochromocytoma is an adrenal medullary tumour!
**MEN** syndrome
(= Multiple Endocrine Neoplasia syndromes)
46
SIADH:
* due to (...)
* hallmark sign: (...)
* causes:
most impt is (...)
SIADH:
* due to **excess** ADH
* hallmark s&s: **hyponatraemia**
* causes:
most impt is **small cell LUNG cancer** (SCLC)
47
central vs nephrogenic DI
and how to differentiate bet them
| DI = diabetes INSIPIDUS = ADH **deficiency**
* central = **absolute** deficiency of ADH
← pathology of hypothalamus or posterior pituitary
* nephrogenic = **relative** deficiency of ADH
← ADH "resistance" by kidney
* administering **ADH** to patient helps to differentiate them
→ **patients w/ central DI will respond** and start producing LESS urine which has a HIGHER osmolarity
48
what stimulates release of PTH
| recall: PTH synthesised by chief cells of parathyroid gland
* IONISED **Ca2+** binds to calcium sensing receptor (GPCR)
→ downstream signalling **inhibits PTH release**
THUS hypocalcaemia (**low Ca2+**)
→ decrease in inhibition
⇒ release of PTH
* **high phosphate**
→ **bind** to more free **Ca2+** in blood
→ decrease in ionised Ca2+
→ ...
⇒ release of PTH
49
MOA of parathyroid hormone
* Bone: stimulates **bone resorption**
⇒ releases **Ca2+**
* Kidneys:
increases **Ca2+ reabsorption** at DCT
decreases **PO4- reabsorption** at PCT
increases **vit D** production
(via increasing **1a-hydroxylase** activity)
| 1a-hydroxylase involved in **last step of vit D synthesis** (in kidney)
## Footnote
vit D will increase BOTH Ca2+ and PO4-
but note that high [PO4-]
→ increased **FGF23**
⇒ inhibition of 1a-hydroxylase and thus decrease in active vit D
50
causes of hypercalcaemia
## Footnote
recall: main hormones involved in calcium regulation are PTH, vit D and calcitonin!
* 1º hyperparathyroidism
(e.g. parathyroid adenoma/hyperplasia/carcinoma)
* vit D excess
* **malignancies**:
bony metastases,
multiple myeloma,
Humoural Hypercalcaemia of Malignancy
## Footnote
Bony metastases - directly **destroy the bone** and release calcium
Multiple myeloma - cytokines and osteoclast activating factor which also promote **bone destruction**
HHM - release **PTH mimicking** hormone which like PTH promotes bone resorption
51
MOA of vit D
* intestines: increase BOTH Ca2+ and PO4- **absorption**
* kidneys: increase BOTH Ca2+ and PO4- **reabsorption**
* (minor) promotes PTH effect on bone resorption and thus release of Ca2+
← amplifies PTH’s ability to stimulate osteoclast activity
52
presenting features of hypercalcaemia
"Moans, groans, stones and bones"
* Moans = neurological
(e.g. seizures, confusion, irritability, coma)
* Groans = GI
(e.g. abdominal pain, anorexia, constipation)
* Bones
* Stones = renal
(e.g. renal stones, thirst, polyuria)
* also + Cardiac
(e.g. arrhythmias)
53
treatment for hypercalcaemia
1. **rehydrate** with IV **saline**
2. give **bisphosphonates**
which inhibit osteoclast activity
→ reduce bone resorption
3. treat **underlying cause**
54
causes of hypocalcaemia
* 1º hypoparathyroidism: **low PTH**
(e.g. parathyroidectomy, idiopathic)
* **vit D deficiency**:
think of the pathway of vit D
→ problems could be
e.g. acquiring vit D (insufficient dietary intake),
e.g. activating vit D (renal or liver disease)
* pseudohypoparathyroidism
in which there is **normal PTH** lvls, but PTH receptors do NOT respond to PTH
## Footnote
in **vit D deficiency**, **PTH** levels will be **high**
← increase as a feedback mechanism to try to increase Ca2+ levels
55
presenting features of hypocalcaemia
* neurological - tetany, spasm, seizures
* cardiovascular - arrhythmia, heart failure
* poor **dendition** + **nail and dermatological** issues
56
treatment for hypocalcaemia
* **oral** calcium
* vit D supplements
57
calcitonin:
* functions to (...) by (...)
* what derangement does it cause in calcium levels if in excess/deficient?
* functions to **decrease Ca2+** by
1. decreasing **bone resorption**
2. decreasing **Ca2+ reabsorption** in kidneys
* does NOT usually cause derangement in calcium levels even if in excess/deficient
← NOT essential for calcium homeostasis
## Footnote
note: little to no effect on phosphate and vit D!
58
diagnostic criteria for DM:
* symptomatic vs asymptomatic
* tests (3)
* **symptomatic** patients:
**ONE** of the following
1. FPG: **≥ 7.0** mmol/L
2. RPG: **≥ 11.1** mmol/L
3. OGTT **≥ 11.1** mmol/L
* **asymptomatic** patients:
**BOTH** and on 2 **different occasions**
1. FPG: **≥ 7.0** mmol/L
2. OGTT **≥ 11.1** mmol/L
## Footnote
* if patients are in hyperglycaemic crisis, DM can be diagnosed w/o further testing
* FPG = Fasting Plasma Glucose
RPG = Random Plasma GLucose
OGTT = Oral Glucose Tolerance Test
(overnight fast, then glucose intake, then measurement 2hrs later)
* units are impt!
7.0 mmol/L = 126 mg/dL
11.1 mmol/L = 200 mg/dL
59
alternate diabetic screening test (other than plasma glucose):
* how they work
* levels in diabetes
HbA1C
* non-enzymatic **glycation** of Hb reflects **average** blood glucose levels **over past 3 months**
← lifespan of RBC = 100 - 120 days
* ≥ **7.0%** = DM
60
which of these hormones increase and decrease blood glucose respectively?
* Insulin
* Glucagon
* Growth hormone
* Epinephrine
* Cortisol
* decrease blood glucose: insulin
* increase blood glucose: glucagon, growth hormone, epinephrine, cortisol
61
What symptoms are common to BOTH hyperthyroidism and hypothyroidism
* **HEART FAILURE**
* proximal myopathy (in lower limbs)
## Footnote
other CVS symptoms differ:
* hyperthyroidism: tachycardia. HTN, atrial fibrillation
* hypothyroidism: bradycardia, pericardial effusion
62
facts about thyroid symptoms:
* Face:
1) why is lid lag and lid retraction seen in hyperthyroidism?
2) what type of skin is seen in face in hypothyroidism?
* Menstrual: similarities vs diff seen in hyper vs hypothyroidism
* MSK: is carpal tunnel syndrome seen in hyper or hypothyroidism?
* Face:
1) lid retraction and lig lag seen in HYPERthyroidism **sympathetic overactivity**
2) **"peaches and cream" skin** is seen in HYPOthyroidism
* Menstrual: oligo-amenorrhea (i.e. infrequent or no menstrual periods) may be seen in both hyper and hypothyroidism,
but **menorrhagia** (i.e. heavy bleeding) is seen only in HYPOthyroidism
* MSK: **carpal tunnel** syndrome is seen in HYPOthyroidism
## Footnote
* The **superior tarsal** muscle (Müller’s muscle), which is sympathetically innervated, becomes overactive → **pulls the upper eyelid** higher → lid retraction
* "**peaches**" = **yellow tint** = accumulation of** β-carotene**
due to slower conversion to vitamin A
"**cream**" = **soft and smooth** texture = soft, puffy and doughy skin
due to **accumulation of glycosaminoglycans** in dermis which **draws water**
NOTE:
Hypothyroidism: **metabolic slowing**
→ **diffuse** *GAG deposition* (systemic)
Graves’ disease (Hyperthyroidism): **autoimmune** fibroblast stimulation
→ **localized** *GAG deposition* (orbit, pretibial skin)
63
epidemiology of Hashimoto thyroiditis:
* predominantly affects (men/women) of (what age range)
* associated with certain autoimmune diseases and genes
(which ones)
* predominantly affects **women** who are **middle-aged** (45-65 y/o)
* associated with other **autoimmune** diseases like **Type 1 DM** and SLE
* associated with HLA-*DR* **3** and HLA-*DR* **5** genes
"*Dr* Hashimoto is **odd - 3, 5**"
64
features of hashimoto thyroiditis
(other than symptoms of hypothyroidism)
**goiter**
which is firm, **painless**
and has gross appearance of being **pale** with a yellow cut surface
## Footnote
pale due to lymphocytic infiltration
65
pathophysiology of Hashimoto
**breakdown of self-tolerance** to thyroid **ANTIGENS**
→ resulting in
1) **CD4+ Th** cells sensitised to thyroid Ag
→ release cytokines like **IFN-γ**
⇒ activation of **macrophages**
2) **CD8+ Th** cells **directly destroying** thyrocytes
3) **B cells** producing antibodies: anti-thyroid peroxidase (**anti-TPO**) and anti-thyroglobulin (**TgAb**)
→ immune-mediated cytotoxic destruction
⇒ **gradual thyroid failure**
66
investigations for Hashimoto
* Thyroid function test: decreased T3/T4, **high TSH**
* anti-TPO and anti-thyroglobulin
## Footnote
* note that there may be **transient hyperthyroidism** (= Hashitoxicosis) **at the start**
= increased T3/T4, low TSH
* possible to see all 3 antibodies (anti-TPO, anti-thyroglobulin and TRAb),
just that it is MOST LIKELY to be anti-TPO and anti-thyroglobulin for Hashimoto
67
complications of Hashimoto
* increased risk of other **autoimmune** conditions (e.g. **Type I DM**, SLE)
* thyroid **malignancies**
(e.g. primary thyroid lymphoma — marginal zone **B**-cell (aka MALT),
papillary thyroid carcinoma)
## Footnote
for thyroid malignancies,
**enlarging** thyroid in **elderly** is a RED FLAG
68
histological findings in Graves vs Hashimoto
* Graves:
follicular hyperplasia + irregularly shaped follicles,
pseudopapillae (i.e. intraluminal papillary tuftings),
**colloid scalloping**
* Hashimoto:
lymphocytic infiltration,
**germinal centers**,
**Hurthle cells**
## Footnote
Hurthle cells = follicular cells transforming from
small cuboidal → larger w/ abundant eosinophilic cytoplasm
69
main drugs used to treat HYPERthyroidism (3)
* thioamides
(PTU, CMZ)
* Lugol's solution / potassium iodide: high conc of iodone
* radioactive iodine
70
MOA of thioamides
* Both PTU and CMZ inhibits **TPO**
⇒ inhibit **coupling** of iodotyrosyl residues to form iodothyronines
* **PTU** also inhibits deiodination of **T4 to T3**
## Footnote
TPO = thyroid peroxidase enzyme
71
why may CMZ be prefered over PTU
* less **hepatotoxic**
* longer DOA
⇒ **once daily** dosing
(⇒ may thus result in better adherance)
72
which thioamide should be used during **pregnancy**
Both!
* 1st trimester: PTU
2nd and 3rd trimester: CMZ
* bcos **CMZ** is **teratogenic**
⇒ increased risk of **congenital malformations**
## Footnote
including aplasia cutis and esophageal atresia
73
adverse effects of thioamides
* **AGRANULOCYTOSIS**
* purpuric, urticarial papular **rash**
(most common)
* liver-related: jaundice, severe liver injury, acute liver failure
## Footnote
liver-related problems are for both,
but esp PTU
74
If patient experiences adverse effects of agranulocytosis in response to PTU, should we switch her over to CMZ?
NO!
* **cross-reactivity** between the 2 drugs
⇒ use of the other drug bears high risk of recurrence of agranulocytosis
* patients should switch to non-thioamide therapy (RAI, surgery)
75
MOA of Lugol's solution / potassium iodide
* suppress **iodination** and **coupling** of monoiodotyrosyl and diiodotyrosyl residues
<- **Wolff-Chaikoff** effect:
an **autoregulatory** phenomenon of thyroid in response to **high intrathyroidal iodide**,
where excess iodide temporarily **inhibits TPO** activity
* decrease thyroid gland size and vascularity
76
what can happen if Lugol's solution / potassium iodide is **stopped suddenly**
no block but still a lot of iodide around in gland
→ surge in thyroid hormone production
⇒ risk of **thyrotoxicosis** exacerbations
## Footnote
Thyrotoxicosis is a medical condition resulting from having **too much thyroid hormone in the body**
77
how should Lugol's soluton / potassium iodide be administered
| COMMONLY TESTED!!
* administer **thioamides FIRST**
=> **inhibition of TPO**,
preventing iodine from being used to produce **more thyroid hormones**
(Jod-Basedow effect)
* wait for at least **1 HOUR**
* administer iodine
78
MOA of radioactive iodine therapy
* RAI is rapidly and efficiently trapped into **follicular cells** by **thyroid-iodid transporter**,
from which it is slowly liberated
* **destructive BETA particles** originate from within the follicle and act on the follicular cells,
while **GAMMA radiation** passes through tissue and can be **quantified** by external detection
* **pyknosis and necrosis** of follicular cells occur,
followed by **disappearance of colloid**
and **fibrosis** of the gland
* properly selected doses will destroy thyroid gland **completely**
(after **4 months**)
while smaller doses will result in some follicles (usually in periphery) **retaining their function**
79
RAI:
* types
* adverse effect
* contraindicated in pregnant women?
* 2 types:
1) **123**I: used for **diagnostic** purposes
"taking a picture 1, 2, 3!"
2) **131**I: used for **destructive** purposes
* adverse effects:
**delayed HYPOthyroidism** (most likely),
worsen Graves' opthalmopathy, increase risk of CA
* YES! due to risk of **foetal radiation exposure** and concentration of isotope in detal thyroid
80
should RAI have the same administration procedure as Lugol's solution (potassium iodid) in relation to thioamides?
No!
RAI **CANNOT** be co-administered with thioamides
* bcos thioamides inhibit TPO and **decrease iodine uptake into thyroid follicles**
→ blunt thyroid uptake of radioactive iodine
⇒ RAI is **less effective** or even **ineffective**
* thioamides should be stopped
**3-5 DAYS** before RAI therapy
81
what is the diff bet thyrotoxicosis and thyroid storm
* thyrotoxicosis: clinical state of **excess circulating** thyroid hormones
* thyroid storm: **acute, life-threatening** complication of thyrotoxicosis,
often **triggered by** e.g. infections, stopping meds suddenly
82
management of thyroid storm
* Thioamides and Iodine:
block **synthesis of thyroid hormones**
* Beta blockers and Glucocorticoids:
both decrease **T4 to T3 conversion**,
AND beta blockers control **peripheral effects** of thyroid hormones
while glucocorticoids treat **potential concomitant adrenal insufficiency**
* **cholestyramine**:
enhance **faecal excretion** of thyroid hormone and thus reduce circulating T4 and T3
* **paracetamol**:
treats **fever**
83
histology of PTC
| seen on FNA (fine needle aspiration) cytology
"annie the hawaiian girl working at a coffee shop lost her parents and got trapped"
* gross:
1. psamomma bodies
("hawaiian"):
calcifications
* zoomed in:
1. orphan annie eye
("annie" "lost her parents"):
looks like **clearing of chromatin**
2. nuclear grooves
("coffee shop"):
coffee bean appearance
3. pseudoinclusions
("got trapped"):
a bit of cytoplasm pushes into nucleus, making it seem like there is a **round inclusion body inside nucleus**
84
how do you differentiate bet follicular thyroid adenoma and carcinoma
capsular and vascular **invasion**
* FT**A**: absent
* FT**C**: present
85
route of spread for follicular thyroid adenoma and carcinoma
haematogenous
86
route of spread for papillary thyroid carcinoma
lymphatic
87
what is the most common primary thyroid malignancy
PTC
88
characteristics of anaplastic carcinoma
* most **dangerous**
<- poor prognosis
* usually **elderly**
* presentation: **enlarges rapidly** within weeks, metastasis to lungs
89
pathogenesis of multinodular goitre
* **iodine deficiency** (CAUSE)
→ LOW **T3 and T4**
-> compensatory RISE in **TSH**
→ follicular cell **hypertrophy and hyperplasia**
⇒ **diffuse** goiter
* **recurrent cycles** of hyperplasia and involution
(some follicles proliferate, others regress)
→ **structural heterogeneity** over time
⇒ **nodular** enlargement
90
facts about MNG:
* description
* types (2)
* **enlarged** thyroid with MULTIPLE **nodules**
* can either be
1) **nontoxic**: nodules are REGULATED by TSH
2) **toxic**: nodules **produce T3 and T4** INDEPENDENTLY of TSH
91
what do the following investigations for MNG show:
* thyroid function tests
* ultrasound
* radioiodine scan
* TFTs:
TSH — suppressed,
T3/T4 — **normal** in **non-toxic**
but **high** in **toxic**
* ultrasound: **enlarged** thyroid
w/ multiple nodules of **varying echogenicity**
* radioiodine scan: **patchy** uptake (hot and cold areas)
## Footnote
about echogenicity:
* normal thyroid has medium-level echogenicity
* pathologies usually are **HYPOechoic** (i.e. **DARKER**)
← **denser** tissue
(e.g. due to proliferation in malignancies and Graves
or lymphocytic infiltration in Hashimoto;s)
92
Which of the following is a distinguishing feature of IgG4-related thyroiditis?
A) **Self-limited** course following a **viral infection** (URTI)
B) Extensive fibrosis of the thyroid and surrounding structures
C) **Painful** thyroid with **bruit on examination**
D) Mild hyperthyroidism followed by hypothyroidism
B) Extensive fibrosis of the thyroid and surrounding structures
A), C) and D) are all characteristic of subacute granulomatous thyroiditis (de Quervain)
* A) patient usually presents with history or recent **URTI**
* C) "de Quer**VAIN** is **PAIN**ful"
* D) starts with mild hyperthyroidism
due to follicular cell damage
→ followed by hypothyroidism
→ then eventual recovery to euthyroid state
## Footnote
initial mild hyperthyroidism (D) is due to
follicular cells **storing thyroid hormones** (T3 and T4) in colloid
⇒ thus when **damaged**, the stored hormone **leaks out** into the bloodstream
93
approach to neck lump
that moves on swallowing
arise from THYROID gland
1. **thyroid function** test
=> determines if lump is normal (euthyroid), hyperthyroid or hypothyroid
2. **ultrasound** neck
=> look for suspicious features
3. **Fine Needle Aspiration Cytology**
(done if US has features suggestive of malignancy)
=> invasive but gold standard for diagnosis of suspicious nodules
## Footnote
general approach to investigations:
1. bloods
2. imaging (modality, what area)
3. others - things like FNAC, uptake scan
94
facts about Type 1 DM (T1DM):
* epidemiology: usually (...), peak in (...)
* risk factors: associated with (...) genes
* epidemiology: usually < 30 y/o, peak in **childhood/adolescence**
* risk factors: associated with **HLA-DR3** and **HLA-DR4** genes
"If you buy **4** *D*ia*M*onds and only pay for **3**, you get *1* for free"
95
facts about Type 2 DM (T2DM):
* epidemiology: usually (...),
associated with (...) and (...)
* risk factors:
1. modifiable: (4)
2. non-modifiable: (...)
3. secondary causes: (CHAP)
* epidemiology: usually > 40 y/o,
associated with obesity and **metabolic syndrome**
* risk factors:
1. modifiable: obesity, sedentary lifestyle, HTN, HLD
2. non-modifiable: genetics, family history (1st-degree relative)
3. secondary causes: **Cushing's, Hyperthyroidism, Acromegaly, Pheochromocytoma**
## Footnote
recall that **catabolic** hormones,
which promote energy release (i.e. **increase blood glucose**), are
* Cortisol (= Cushing's)
* Growth hormone (= Acromegaly)
* Epinephrine (= Pheochromocytoma)
for hyperthyroidism, also makes sense since thyroid hormones stimulate GH
which is a catabolic hormone!
96
clinical presentation of DM:
* acute/subacute
* chronic:
1. microvascular
2. macrovascular
3. others
* acute/subacute:
classic triad (**polyuria, polydipsia, polyphagia**),
T1DM: DKA
while T2DM: **hyperosmolar hyperglycaemic** state
* chronic:
1. microvascular:
retinopathy, nephropathy, neuropathy
2. macrovascular:
**CAD leading to AMI**,
stroke,
peripheral arterial disease
3. others:
cataracts, erectile dysfunction, poor wound healing
## Footnote
* polyphagia is cos glucose cannot enter cells without functioning insulin
→ cells are starved
⇒ brain signals hunger
* NO DKA in T2DM as presence of insulin prevents ketosis,
instead hyperglycaemia → osmotic diuresis → increased plasma osmolarity
⇒ hyperosmolar hyperglycaemic state
* for chronic clinical presentation,
retinopathy occurs **BEFORE** nephropathy
97
types of insulin (+ examples)
* rapid-acting
"**G**irls **A**nd **L**ads":
**G**lulisine, **A**spart, **L**ispro
* short-acting: **regular** human insulin
* intermediate-acting: neutral protamine hagedorn (**NPH**)
* long-acting
"**D**on't **G**o":
**D**etemir, **G**largine
98
adverse effects of insulin therapy
1. Hypoglycaemia
* most significant with **NPH**
* include dizziness, shaky hands, sweating, etc
* treatment: **glucose** tablets/drinking fruit juice
AND **glucagon (severe cases)**
2. Lipodystrophy (**lipohypertrophy** more common due to **lipogenic** action of insulin)
* treatment: **rotate** site of injection, **avoid hypertrophic** areas
(as they affect absorption)
99
contraindications for insulin therapy
**HYPOkalaemic** patients
as insulin **drives K+ INTO cells**
→ worsens hypokalaemia
⇒ can even trigger cardiac arrhythmias
## Footnote
note: other than glucose, K+ also increases after a meal
=> insulin clears K+ to prevent post-meal hyperkalaemia
100
more about fast-acting insulins:
* structure
* administration
* hypoglycaemia risk
* structure: **analogs** of endogenous human insulin but with **AA substitutions**
→ **prevent hexamer** formation
⇒ absorbed **quickly**
* administration: injected **JUST BEFORE meals**
* hypoglycaemia risk: LOW
101
more about short-acting insulins:
* structure
* administration
* hypoglycaemia risk
* structure: **similar** to endogenous human insulin
(but still NO C-peptide)
→ **hexamer** formation
⇒ slower absorption and thus onset of action (than rapid-acting)
* administration: injected **20-30 MINS BEFORE meals**
* higher hypoglycaemia risk than rapid-acting
← slower onset of action and longer DOA
102
more about intermediate-acting insulins:
* structure
* dosing
* hypoglycaemia risk
* structure: binds to **protamine**
→ **slows** absorption
* dosing: **2 times** per DAY
* **hypoglycaemia** risk: **highest**
← high intra and inter patient variability
AND **long peak effect**
103
more about long-acting insulins:
* structure
* dosing
* hypoglycaemia risk
* precaution
* structure: modified to **precipitate** (glargine) or bind to **albumin** (determir)
→ **very slow** release
* dosing: acts for **18-24 hours**, **ONCE** daily
⇒ acts as **basal** insulin
* **hypoglycaemia** risk: **lowest**
* discontinue **2-3 days prior** to operation
## Footnote
should discontinue before operation bcos
* risk of **hypoglycemia** if fasting before procedure
* **better perioperative control** with short-acting insulin
104
physiological endogenous insulin release
* uptake of glucose into cell via **GLUT2** receptors
* increased production of **ATP** and **ATP/ADP** ratio
* CLOSURE of **K+ channels** and **depolarization** of the cell membrane
* OPENING of **Ca2+ channels**
* exocytosis of insulin containing vesicles
105
Which of the insulins are commonly used in hyperglycaemic crisis to rapidly lower blood glucose levels?
**short**-acting
(regular human insulin),
given **IV**
106
Which of the insulins has a **cloudy** appearance
**intermediate** acting
(NPH)
| rest have a **clear** appearanc
107
which of the insulins CANNOT be mixed with other insulins
**long**-acting
(Detemir, Glargine)
← incompatible **pH**
## Footnote
allowed combinations:
* NPH + regular
* NPH + rapid-acting
108
dosing regimen for insulin therapy
(mixed, intermediate-acting)
* 1st dose (morning): NPH + rapid-acting insulin
1) RAPID-ACTING covers **post-*breakfast* glucose spike**
2) NPH provides **basal** until lunch,
and its peak covers reduces **post-*lunch* glucose spike**
* 2nd dose (evening): NPH + rapid-acting insulin
1) RAPID-ACTING covers **post-*dinner* glucose spike**
2) NPH provides **basal** overnight,
but peak means that **must consume *supper***
## Footnote
thus means that there is a HIGHER risk of **hypoglycaemia**
(e.g. if meal is missed)
109
What factors affect the absorption of insulin?
* Site of injection
* Depth of injection
* Volume and concentration of the dose injected
* exercise
* heat (e.g. sitting in a sauna)
* massage of insulin site
## Footnote
* site and depth of injection could affect due to **vascularity**
* **larger** vol can **delay** absorption
* exercise, heat and massage could affect due to **increased blood flow**
110
What circumstances would insulin demands be increased
(and this higher dosing in insulin therapy be required)?
* **stressful** situations
→ activate stress response
→ increase in catecholamines, cortisol, GH and glucagon
⇒ hyperglycaemia
* steroids
⇒ directly induce insulin resistance
111
Biguanides:
* examples
* MOA
* A/Es (including hypoglycaemia risk)
* weight changes
* renal/cardio effects
* glucose-dependence
* example: **metformin**
* MOA:
1. decrease **hepatic** glucose production
⇒ decreased **production**
2. decrease **intestinal** glucose **absorption**
⇒ decreased absorption
3. increase density of **insulin receptors** at tissues
⇒ increased **uptake** into cells
4. improves **muscular** glucose absorption
⇒ increased **uptake** into cells
* A/Es: good **safety** profile,
w/ **minimal hypoglycaemia** risk,
but could result in **lactic acidosis**
* weight changes: modest **weight LOSS**
* glucose-**independent**
## Footnote
think! glucose levels can be affected by:
* production
* absorption
* uptake into cells
* reabsorption
112
sulfonylureas:
* examples
* MOA
* A/Es (including hypoglycaemia risk)
* weight changes
* renal/cardio effects
* glucose-dependence
* drugs with "*gli-*" at front
(e.g. *gli*pizide, *gli*clazide, *gli*benclamide)
* MOA: binds to **sulfonylurea receptor** proteins
(part of K+ channels)
-> INHIBIT **K+ efflux**
(by closing those K+ channels)
-> depolarisation of cell
-> ...
=> secretion of insulin
* A/E: **hypoglycaemia**
(**glibenclamide** has highest risk),
**weight GAIN**
* **contraindicated** in **renal** and **hepatic** impairment
* glucose-**independent**
113
dipeptidyl peptidase 4 (DPP-4)
inhibitors:
* examples
* MOA
* A/Es (including hypoglycaemia risk)
* weight changes
* renal/hepatic/cardio effects
* glucose-dependence
* drugs with "*-gliptin*" at back
(e.g. sita*gliptin*, vilda*gliptin*, lina*gliptin*)
* MOA: **inhibit** DPP-4
-> **prolong action** of endogenous incretins
(by preventing their **inactivation**)
=> stimulate pancreatc B cells to **release insulin**
AND SUPPRESS A cell mediated **glucagon release**
* A/E: nasopharyngitis, **headache**,
pancreatitis
* **linagliptin** CAN be used in **CKD** patients,
vildagliptin CANNOT be used in **CLD** patients
* glucose-**dependent**
=> LOW risk of hypoglycaemia
## Footnote
mainly used for **post-prandial** glucose
<- incretins only release when glucose lvls are high after consumption of food
114
glucagon-like peptide 1 receptor (GLP-1) agonists:
* examples
* MOA
* A/Es (including hypoglycaemia risk)
* weight changes
* renal/hepatic/cardio effects
* glucose-dependence
* drugs with "*-glutide*" at back
(e.g. sema*glutide*, lira*glutide*)
* MOA: **activation** of GLP-1 receptor which
1) increases **insulin release** AND delay **gastric emptying**
=> slower **glucose absorption**
2) delay gastric emptying also
=> promotes **satiety**
3) **reduces appetite**
* A/Es: **GI**,
nasopharyngitis, pancreatitis,
**suicidal attempts/ideation**,
**worsen diabetic retinopathy**
* weight changes: HELPS with **weight loss** and obesity management
* **renoPROTECTIVE**, **cardioPROTECTIVE**
* glucose-**dependent**
=> LOW risk of hypoglycaemia
115
sodium-glucose co-transporter 2 (SGLT-2) inhibitors:
* examples
* MOA
* A/Es (including hypoglycaemia risk)
* weight changes
* renal/hepatic/cardio effects
* glucose-dependence
* drugs with "*-gliflozin*" at back
(e.g. empa*glifozin*, cana*glifozin*, dapa*glifozin*)
* MOA: **inhibition** of SGLT2 expressed in **proximal** renal tubule
-> decreases **reabsorption** of glucose
-> lowers **renal threshold** for glucose
=> increases **urinary glucose excretion**
* A/Es: **EUGLYCEMIC DKA**, vulvovaginal **candidiasis**, hypotension (due to osmotic diuresis),
canglifozin: increased risk of **LL amputaton**
* weight chainges: causes **weight LOSS**
* **renoPROTECTIVE**, **cardioPROTECTIVE**
* glucose-**independent**
116
thiaolidinediones:
* examples
* MOA
* A/Es
* weight changes
* drugs with "*-glitazone*" at the back
(e.g. pio*glitazone*, rosi*glitazone*)
* MOA: **activation** of nuclear transcription factor **PPAR-gamma**, resulting in
1) increased production of **GLUT1 and GLUT4**
=> increase glucose **uptake**
(esp via GLUT4)
2) enhanced **tissue sensitivity** to insulin
* A/Es: **weight GAIN**,
peripheral **oedema**, increased risk of **HF**,
**bone fractures**
117
meglitinides:
* MOA
* A/E
* weight changes
* renal/hepatic/cardio effects
* e.g. repaglinide
* MOA: bind to **SUR1**
(part of K+ channels)
-> closure of K+ channels
-> ...
=> release of **insulin**
* A/Es: **hypoglycaemia**, mild **weight GAIN**
* use with **caution** in patients with **hepatic impairment**
* glucose-**dependent**
-> BUT still force insulin release even w/o glucose
=> higher hypoglycaemic risk than other glucose-dependent drugs
118
Why are meglitinides commonly used at meal times?
**rapid** onset
AND **short** duration of action
=> better for **post-prandial** levels
119
alpha-glucosidase inhibitor
* e.g. acarbose
* **REVERSIBLY inhibit** membrane-bound alpha-glucosidase in **intestinal brush borders**
-> SLOW DOWN glucose **absorption**
=> and thus rise in glucose levels
* A/Es: gaseous distension, flatulence
* **contraindicated** in **renal** and **hepatic** disease
* also **contraindicated** in **GI** diseases (e.g. IBD)
## Footnote
note: must be administered **with food**,
taken with **first bite** of each main meal
basically everything comes down to food and GIT lol
120
which T2DM drug should be used in patients with **HF**
| reason it out!
SGLT2 inhibitors!
* both **SGLT2 inhibitors** and **GLP-1 agonists** have **cardioprotective** effects!
* **SGLT2 inhibitors** reduce preload and afterload
via **osmotic diuresis**
⇒ best for HF
## Footnote
* on the other hand, GLP-1 agonists,
via weight loss and improved lipid profile,
is better for **atherosclerotic CVD**
* but BOTH can be used for atherosclerotic CVD
121
which T2DM drug should be used in patients with CKD / albuminuria
SGLT2 inhibitors!
* both **SGLT2 inhibitors** and **GLP-1 agonists** have **renal protective** effects!
* while **GLP-1 agonists** has a more **indirect** protective effect,
**SGLT2 inhibitors** has a **direct** protective effect
via e.g. osmotic diuresis
→ less congestion, lower BP
⇒ reduces renal workload
med
flashcards
Decks in class (23)
# Cards
-
embryology30
-
biochem1
-
immunology16
-
cvs pharm (DONT USE)9
-
blood86
-
cvs233
-
respi153
-
renal123
-
thorax anatomy181
-
lungs anatomy38
-
git355
-
foundation I10
-
biochem168
-
foundation II133
-
endocrine121
-
repro194
-
mskderm160
-
mskderm 2387
-
multisystem19
-
paediatrics24
-
PE42
-
approach to passing5
-
procedural skills4
