Endocrinology Flashcards
1
Q
What are endocrine hormones?
A
blood borne, acting at distant sites
2
Q
What are exocrine hormones?
A
glands that pour secretions through a duct to the site of action
3
Q
What are paracrine hormones?
A
hormones acting on adjacent cells
4
Q
What are autocrine hormones?
A
Feedback on the same cells that secretes the hormone
5
Q
Water soluble hormones
how is it transported, interacts with cell, half life, clearance, ex?
A
unbound, binds to surface receptor, short HL, fast clearance, peptides / monoamines
6
Q
Fat soluble hormones
how is it transported, interacts with cell, half life, clearance, ex?
A
Protein bound, diffuses into the cell, long HL, slow, thyroid hormones, steroids
7
Q
Name the 4 hormone classes?
A
peptides, amines, iodothyronine, steroids
8
Q
Nature of peptides as hormones & ex?
A
linear / ring / vary in length
ex insulin
- stored in secretory granules
- released in pulses or bursts
- cleared by tissue or circulating enzymes
9
Q
Nature of amines as hormones & ex?
A
ex adrenaline & noradrenaline
- water soluble
- binds to alpha & beta adrenoreceptors
- stored in secretory granules
- released in pulses or bursts
- rapid clearace
10
Q
Nature of iodothyronine as hormones & ex?
A
thyrosine, iodine
- basis of thyroid hormone synthesis
- not water soluble, 99% protein bound
- usually measure T3 & T4 not this
11
Q
How might iodothyronine be synthesised into thyroid hormones?
A
- thyroglobulin released into colloid - acts as base for thyroid hormone synthesis
- iodine + tyrosine → iodothyrosine
- conjugation of iodothyrosines give rise to T3 & T4 & stored in colloid bound to thyroglobulin
12
Q
Subtypes of steroids & cholesterol derivatives?
A
vitamin D, adrenocortical & gonadal steroids, steroid
13
Q
Nature of vitamin D?
A
it is a hormone!!
- fat soluble
- enters cell directly to nucleus to stimulate mRNA production
- Transported by vitamin D binding protein
14
Q
Nature of adrenocortical & gonadal steroids?
A
- protein bound - fat soluble
- usually bind to cytoplasmic receptor, pass to nucleus and induce a response
- altered to active metabolites
- inactivated in liver by reduction and oxidation or conjugation to glucoronide & sulphate groups
15
Q
Nature of pure steroids?
A
- diffuse through plasma membrane (lipid soluble!), binds to receptor
- binding occurs in cytoplasm, move to nucleus
- mimic transcription to form mRNA → exert steroid function
- (protein synthesis?)
16
Q
Where are hormone receptors found and what type of hormones bind to them respectively?
A
- Cell Membrane (peptide)
- Cytoplasm (steroids)
- Nucleus (thyroid, estrogen, vitamin D)
think about fat solubility!
17
Q
Types of hormone secretion patterns?
A
continuous or pulsatile
superadded rhythms - day/night cycles
18
Q
Define type 1 diabetes mellitus?
A
autoimmune condition where beta cells are damaged with genetic component
profound insulin deficiency
19
Q
Define type 2 diabetes mellitus?
A
chronic hyperglycaemia due to relative insulin deficiency, resistance or both
20
Q
Diagnostic criteria for DM!
A
- HbA1c ≥ 48 mmol / mol (6.5%)
- Fasting VBG ≥ 7 mmol/L
- Random VBG ≥ 11.1 mmol/L
- OG Tolerance T>11 mmol/L
21
Q
If someone is prediabetic, they would have
A
Impaired glucose tolerance
22
Q
Where is insulin produced?
A
pancreas
Beta cells in the pancreatic islet of Langerhans
INHIBITED by beta blockers
23
Q
How does insulin work?
A
acts on the liver to reduce its glucose output, inhibiting glycogenolysis and gluconeogenesis
promotion of glucose uptake in peripheral tissues
Decreases serum potassium through stimulation of Na/K ATPase pump
24
Q
Risk factors for type 1
A
- Northern European / Scandinavian
- Family History (less but is)
-
Other autoimmune disease as comorbidity
- Addison’s, coeliac, autoimmune thyroid
25
Risk factos for type 2
* sedentary lifestyle, diet high in calories, obseogenic environment
* overweight
* fam hx - gestational diabetes, hypertension / vascular disease
26
Pathophysio of type 1?
autoimmune
pancreas stops producing insulin. glucose is not taken up
level of glucose in blood keeps rising → hyperglycaemia
27
Pathophysio type 2?
* repeated exposure to glucose & insulin makes cells in the body resistant to insulin
* beta cells in pancreas fatigued & damaged therefore producing less
* or due to lipid depo in pancreatic islets, normal secretion cannot be
28
Differentiate type 1 / type 2 DM?
ketones
1 - increasing level // 2 - almost never excess
insulin
1 - deficiency // 2 - always detectable
both lead to profound skeletal muscle breakdown & unrestrained lipolysis
29
Presentations - T1DM?
4T’s: **toilet, thin, tired, thirsty**
* Short history, rapid onset
* Weight loss, fatigue → check if intentional
* lipid & muscle loss due to unrestrained gluconeogenesis
* Repeated infections? Blurred vision?
* Moderate or large urinary ketones
* _immediate_ tx with insulin!
30
Additional testing for type 1?
for other autoimmune diseases
and for antibodies related to T1DM
31
Antibodies associated with T1DM?
* Anti GAD
* Pancreatic islet cell antibodies
* Islet antigen-2 antibodies
* ZnT8
common in children, the more the better
32
Presentations - T2DM?
* Usually in **people over 30’**s
* **More obese children**
* **and obese now?**
* Onset is very **gradual**
* Stronger positive **family history**
* (less in type 1!!)
* identical twins, almost 100% concordance
33
Further typical presentations, T2DM
| (like if you misdiagnosed and seeing patient again…)
ketone breath
free fatty acid from impaired glucose uptake - lipolysis instead so produces ketone bodies
34
Differentiate T1 & T2 at presentation?
type **2** in **younger**, including childhood
but t1 can be obese, uncontrolled t2 can present with weight loss & ketonuria → **check hx, weight loss intentional?**
if in doubt treat with insulin
35
Goal of treatment - DM
if not on insulin = normal HbA1c 50 mmol/mol
if on insulin = fasting BG between 4-7mmol/L
36
Types of insulin & how they should be used?
**basal Insulin** - covers time between meals and especially during the night, given once or twice daily
**prandial or bolus (meal time) insulin** (rapid acting analogues) → adjusted according to glucose & carbohydrate content of meals
37
Typical insulin regime for type 1?
**intensive basal-bolus (both types)** used = best treatment
separate basal from bolus to mimic physiology
38
Typical insulin regime for type 2?
insulin usually given **later on in disease** course, or those with poor glycemic controls
usually _start with just_ **basal** → lowers nocturnal, may **add bolus later** (and is often required)
39
Ways insulin can be given (dosage)?
* **analogue insulin** - less risk of hypoglycemia
* **premix insulin** - (mixed quick acting & long acting) - better for people who don’t want to take 5 injections a day
* but risks of hyper / hypo as day goes by and higher target needed
40
GUIDELINE order for oral therapy T2DM
[2022]
1. metformin / metformin MR (Gi into)
if CVD with SGLT2 inhibitors
2. DPP4 inhibitor / pioglitazone / sulfonylurea
3. insulin and/or GLP-1
41
Mechanism of metformin?
* **decrease** hepatic glucose output (**gluconeogenesis**) & **increase** **peripheral** glucose **uptake** (+ insulin sensitivity!)
* **AMP kinase** activation - helps with **weight loss**
42
Metformin CI?
CA renal and hepatic impairment, reduce dose or avoid
acute alcohol intox & chronic alcohol abuse
withheld 48 hours after injecting IV contrast media (+ renal imapirment)
43
Metformin SE?
biggest is lactic acidosis & GI upset
anorexia / diarr / nausea / abdo pain
44
Mechanism of SGLT-2 inhibitors
| ('flozin's)
* **block** the **reabsorption** of glucose in the **kidney**, **increase** **glucose** **excretion** & lower blood glucose levels
* also helps with **weight loss**
* Specific benefit in **reducing CV mortality!**
45
Examples of SGLT-2 inhibitors?
‘flozin’s
Empaglifozin, Dapaglifozin, Canaglifozin, Ertugliflozin
46
CI SGLT-2 inhibitors?
CI ketoacidosis
CA in renal impairment, diuretics, low systolic BP & elderly
47
SE SGLT-2 inhibitors?
genital thrush
increased risk of euglycaemic ketoacidosis in T2
48
Incretins - what are they?
GLP-1 & GIP - glucose dependent, released by intestines to food, _inactivated by DPP-4_!
## Footnote
**promote insulin secretion & suppress glucagon release**
49
Mechanism of DPP-4 inhibitors
| ('gliptin's)
lowers blood glucose by competitively inhibiting the action of DPP-4 (enzyme) which destroys incretins
low risk of hypo, no effect on weight
50
Examples of DPP-4 inhibitors?
vidagliptin, sitagliptin
‘gliptin’s
51
CI DPP-4 inhibitors?
type 1, ketoacidosis
preg, breastfeed, elderly \>80, pancreatitis
moederate to severe renal impairment
52
SE DPP-4 inhibitors?
low risk, but still present, of hypoglycaemia
acute pancreatitis
53
Which type of medications may mask symptoms of hypoglycaemia?
beta blockers
54
Mechanism of pioglitazone?
improve insulin sensitivity, binds to peroxisome proliferator activated receptor
activate genes concerned with glucose uptake, utilisation & metabolism
→ **need insulin for a therapeutic effect**, so relatively rarely used
55
CI pioglitazone?
heart failure, macular haem or oedema, high risk of fractures
avoid in hepatic impairment
56
Mechanism of sulfonylureas?
* **stimulate pancreatic insulin release** by binding to beta cell receptors
* improve glycemic control, but at the expense of **weight fain**
* **can cause hypo**
## Footnote
**→ only in patients with residual pancreatic function**
57
CI & SE sulphonylureas?
renal & hepatic impairment
GI upset, hypoglycaemia
58
Complications for diabetes?
Retinopathy, nephorpathy, neuropathy
cardiovascular disease
acidosis
hypoglycaemia
59
Feature of diabetic ketoacidosis?
Must have all 3!!
* **Hyperglycaemia**: plasma gluc \> 50 mmol / l
* **Raised** plasma / urinary **ketones:** 3mmol/L or \> 2+ dipstick
* **Metabolic acidosis plasma bicarbonate** bicarbonate \< 15.0 mmol/L and/or venous pH \< 7.3
60
Which type of DM is more prone to DKA?
**type 1** (lots of ketones)
but _type 2_ incidences increasingly recognised - as _low insulin levels_ are sufficient to _suppress catabolism_ & _prevent ketogenesis_, but may occur when hormone rise to high lvl, e.g MI
61
How can ketones cause acidosis?
Lack of insulin = unable to utilise glucose
**Lipolysis instead**: products = **ketones** (acetone, beta-hydroxybutyrate and acetoacetate) → **_acidic_**
accumulates in blood = acidosis
62
Present - ketoacidosis
**Hyperventilation** - getting rid of Co2 & carbonic acid in blood
**dehydration -** might pres with **vomit / diarr**, **hypotention**, **tachycardia**, **coma**
63
Treatment of ketoacidosis?
1st line - **rehydration, 3l first 3 hours**
**_20ml /kg 0.9% NaCl_** over 15 mins
replace slowly or risk of cerebral oedema
**insulin** - reverse ketone production & fat breakdown
**replace electrolyte**s, esp K+ (drive in to cell)
64
Complications DKA?
Cerebral oedema = swelling of brain parenchyma
65
What are the counterregulatory hormones for insulin?
glucagon, adrenaline, cortisol, growth hormone
66
When might someone be at risk for hypoglycaemia?
* **Low HbA1c**, High pre-treatment HbA1c in type 2
* **long duration** of diabetes
* **_daily insulin dosage \> 0.85 U / kg / day_**
* **history** of previous hypo, recent episodes of severe hypo
* **impaired awareness** → checks if ability to **secrete adrenaline** is still intact
* → ask when do they get hypo symptoms! **if below 3.0 mmol / l = adrenaline no longer exists**, if above = adrenaline still there
* physically active
* impaired renal and or liver function
67
Hypoglycaemia - symptoms?
**Autonomic**: trembling, palpitations, sweating, anxiety, hunger
**Neuroglycopenic**: difficulty concentrating, confusion, weakness, drowsy / dizziness, vision changes & difficulty speaking
**Non**-**specific**: nausea & headache
\*\* may be **symptomless** if adrenaline secretion is gone too (**beta blocker!**)
68
Diagnostic criteria for hypoglycaemia?
If no known DM then Whipple's triad
* blood glucose concentration \< 4.0 mmol/L
* symptoms of hypoglycaemia
* Reversal of symptoms when BG normal
69
Which other conditions can cause hypoglycaemia?
* **Beta cell secretagogue ingestion** (e.g. ingestion of a medication that stimulates insulin release from beta cells)
* **Islet beta-cell tumour** (e.g. insulinoma)
* **Functional beta cell disorder** (e.g. high insulin secretion not due to an insulinoma)
* **Insulin autoimmune hypoglycaemia** (antibodies develop against insulin or its receptor)
70
Treatment for hypoglycaemia?
* **glucose load** - oral if alert, IV if coma
* retest and give more if needed
* if coma does not respond - **consider glucagon** but diff if poor glycogen stores; then IV glucose infusion if needed
71
How might one prevent hypoglycaemia?
* correct choice of therapy - sulfonylureas and insulin
* adjust targets, specialist support?
* discuss with patient - alcohol, exercise, consider sleep & age
72
What is diabetic neuropathy?
a collection of conditions that result from glucose-related damage to neurones of the somatic and autonomic nervous systems
73
Signs and symptoms, diabetic neuropathy?
**glove and stocking sensory loss**
**Pain** - burning, nocturnal exacerbation
like electrical shocks, walking on glass
**Extreme spectrum sensitivity** - hyper & paraesthesia, insensitivity
74
Consequences of diabetic neuropathy?
Diabetic foot ulceration, Charcot's joint
Peripheral neuropathy & peripheral vascular disease - nerves and circulation affected and damaged
75
Treatment for general diabetic neuropathy?
good glycaemic control
opioids, antidepressants etc,
Transcutaneous nerve stimulation / acupuncture / spinal cord stimulators / Psychological interventions
76
Screening tests for diabetic foot ulceration?
* Test sensation
* 10 gm monofilament
* neurotips
* Vibration perception
* tuning fork
* biothesiometer
* Ankle reflexes
77
Treatment for diabetic foot ulceration?
lower limb amputation
78
What is diabetic retinopathy?
**Persistent damage** **to retina** leads to ischaemia and angiogenic factors which promotes new formation of weak and friable vessels → **microaneurysms**, **haemorrhage, fibrosis retinal detachment**
79
Risk factors for diabetic retinopathy?
* long duration diabetes
* poor glycemic control
* hypertensive
* on insulin treatment
* pregnancy
80
How might one prevent diabetic retinopathy?
National Eye screening programme
81
Treatment for diabetic retinopathy?
* **Laser therapy**
* proven treatment for DR
* aim is to stabilise changes
* but treatment does not improve sight!!
82
What is diabetic nephropathy & pathophysiology?
Diabetic kidney disease
## Footnote
**High BG** → **damage to blood vessel clusters in kidney & kidney itself** → pressure increased on filtering system in the kidneys → glomerular changes/injury → **filtration rate endangered** → DN
83
Present diabetic nephropathy?
hallmark = **proteinuria** (**albuminuria**)
reduced calculated creatinine clearance, decreased glomerular filtration rate
84
How might one screen for diabetic nephropathy?
at least two **urine samples**, collected with 3-6 months
test for **urine albumin, albumin:creatine ratio, eGFR**
**→** can use CKD classify system
85
Consequences / complications - diabetic nephropathy?
major risk for CVD, kidney failure
this is more common in T2 and less in T1
86
What is peripheral vascular disease?
decreased perfusion to an area due to macrovascular disease
symptoms more likely to occur at more dital sites
= 15-40x more likely for amputation
87
Signs and symptoms of peripheral vascular disease?
_most common at more distal sites_
**intermittent claudication + rest pain** = key
* Diminished or absent pedal pulses
* Coolness of feet and toes
* Poor skin & nails
* Absence of hair on feet & legs
88
How might one diagnose peripheral vascular disease?
Doppler Pressure studies & Ankle Brachial Index!
Duplex arterial imaging / MRA
89
Treatment for peripheral vascular disease?
* quit smoking
* Pressure relieving footwear, podiatry, revascularisation, antibiotics
* surgical intervention
90
Preventive measures for peripheral vascular disease (& diabetic foot)?
* Screening
* Education, providing orthotic shoes
* MDT Foot clinic - treat the ulcer !!!!
* Pressure relieving footwear, podiatry, revascularisation, antibiotics
91
Which hormones are released by the anterior pituitary?
* Thyroid stimulating hormone (TSH) → Thyroid
* Adrenocorticotropic hormone (ACTH) → Adrenal cortex
* Follicle stimulating hormone (FSH) & Luteinising hormone (LH)
* Growth hormone (GH) → entire body & liver
* Prolactin → Mammary gland
92
Which hormones are released by the posterior pituitary?
Oxytocin, Antidiuretic Hormone (ADH)
93
Outline the thyroid axis?
= Hypothalamus stimulating (via anterior pituitary) thyroid, releases T3 & T4
1. Hypothalamus: Thyrotropin-releasing hormone (**TRH**)
2. Anterior Pituitary: Thyroid stimulating hormone (**TSH**)
3. Thyroid: triiodothyronine (**T3**) & Thyroxine (**T4**)
= Negative feedback cycle to control hormones
1. Hypo & AP: senses T3 & T4: Suppress TRH & TSH
2. Lower amount of T3 & T4 released
94
Function of thyroid hormones?
* accelerates and enhances food metabolism
* increase ventilation, heart rate & cardiac output
* growth rate accelerated & brain dev postnatal
95
How is thyroid hormone consumed by the body?
Thyroid gland produces thyroxine (T4) which is converted to triiodothyroxine (T3) in target tissues!
96
What is primary hyperthyroidism?
thyroid pathology → excessive Thyroid hormone
pathology = **thyroid**
97
Causes for primary hyperthyroidism?
* graves' disease (75-80%)
* toxic multinodular goitre
* toxic adenoma
* drug induced - AMIODARONE (high iodine)
98
What is secondary hyperthyroidism?
thyroid overstimulated by thyroid stimulating hormone → excessive TH
pathology = **hypothalamus or pituitary**
99
What is Grave's disease?
TSH receptor antibodies (abnormal) produced by immune system mimics TSH, overstimulate TSH receptors on thyroid → excessive TH
pathology = **autoimmune**
**→** associated with anti-TSH antibodies and anti-thyroglobulin (anti-tg)
→ may cross placenta! ophthalmopathy strongly associated
100
What is a goitre?
palpable & visible thyroid enlargement
* variety of causes
* commonly sporadic or autoimmune
* endemic in iodine deficient areas
101
3 mechanisms for increased levels of thyroid hormones (T3 or T4)?
* **overproduction** of thyroid hormones
* **leakage** of preformed hormone from (inflamed) thyroid
* **ingestion** **of** **excess** **thyroid** hormone (from overtreatment or overingestion of pharm)
102
General symptoms of hyperthyroidism?
**Goitre - may develop into facial swelling**
* tachycardia
* **lid-lag + stare** → suspect autoimmune
* anxiety, irritability, sweating, heat intolerance
* **Unintentional weight loss** but with increased appetite, diarrhoea
* **frequent loose stools**
* **Sexual dysfunction,** sub-fertility, menstrual disturbance (infrequent & light)
* **dry, brittle hair or thinning hair on your scalp and body - underactive thyroid**
* AF lol
103
Grave's specific symptoms of hyperthyroidism?
* **Diffused goitre - symmetrical**
* entire, smooth
* **Pretibial myxoedema** - waxy oedematous on tibia - **_specific to Grave's_**
* **Thyroid eye disease - 50% -** eyes & eyelids are swollen and red
* **Exophthalmos** - **bulging of the eyeball out of the socket (stare-y eyes)** (from swelling, inflam & hypertrophy of tissues behind eyes)
* **Acropachy - finger clubbing**
104
Differentiate between a diffused goitre vs a nodular goitre?
**Diffused** - entire thyroid gland swells and feels smooth to the touch
**Nodular** - lumpy to touch due to solid or fluid filled lumps
105
Biggest risk factor for autoimmune hyperthyroidism?
(single biggest) being female → very common postpartum
* during pregnancy: autoimmune activity goes down
* postpartum: rise in immunity
* autoimmune thyroiditis
* grave’s thyroiditis
106
Diseases associated with thyroid autoimmunity?
* T1DM
* Pernicious anaemia
* Vitiligo (skin discolouration
* Coeliac disease (1 in 3 with autoimmune hyperthyroidism have coeliac)
107
Testing for thyroid diseases?
* *_Thyroid function tests: free TSH & fT4/T3_**
* *primary** = **suppressed** TSH
* *secondary** = **inapp** **high** TSH
Thyroid antibodies & isotope uptake scan
urinary iodine secretion
Doppler ultrasound of thyroid for nodules etc
108
Pharmacological tx for hyperthyroidism?
**Antithyroid drugs** - for symptom control
= act as a preferred substrate for iodination by thyroid peroxidase (key enzyme in thyroid hormone production)
In order - Carbimazole, PTU, beta blockers
109
Carbimazole - mechanism
**prevents thyroid peroxidase enzyme (TPO)** from coupling and iodinating thyroglobulin (which degrades into T3 and T4) hence reducing production of TPO
110
Carbimazole indications & regime?
1st line, Successful even for Grave's
Normal thyroid function in 4-8 weeks, may serve as maintenance
Give as either
* **Titration-block**: dose is carefully titrated to maintain normal levels
* **Block and replace**: dose is sufficient and block all production → patient takes levothroxine titrated to effect
111
Propylthiouracil PTU mechanism and indications?
if carbi not tolerated, prepreg / 1st trimester, specialist for thyroid crisis
**inhibits conversion of T4 → T3**
small risk of liver injury so not 1st line
112
How might beta blockers be useful in hyperthyroidism?
**blocks adrenaline** related syndromes of hyperthyroidism = **controls symptoms** whilst the definitive treatment takes time to work
= propanolol = good choice, as non selective
= very useful in thyroid storm
113
SE antithyroid drugs?
common = rash
less common = arthralgia, hepatitis, neuritis, thrombocytopenia, vasculitis etc
but resolvable if stop drug
**agranulocytosis** → most serious!!
114
Signs of agranulocytosis
& how to prevent?
* sore throat, fever, mouth ulcers
* MUST warn patient before starting ATD
* STOP if patients develop symptoms & check FBC
115
Other tx options for hyperthyroidism?
radioactive iodine treatment
thyroid surgery
116
Mechanism for radioactive iodine treatment & indications?
1st line definitive for Grave's & toxic multi-nodular goitre
Uses iodine isotope (as iodine needed for TSH production) to **induces DNA damage → death of thyroid cells**, causing a decrease in thyroid function and / or reduction in thyroid size
117
Care & CI, radioactive iodine treatment for hyperthyroidism?
radioprotection after treatment - children & preggers
CI Grave's with active orbitopathy, pregnant / conceiving / breastfeeding women
118
Thyroid surgery - indications?
total or hemi or for single thyroid nodule
for intolerant to drug, recurrence, coexisting potential malignant, compression symp's
119
What is **Sporadic Non-toxic Goitre**
* commonest endocrine disorder
* 8.6% prevalence thyroid enlargement
* **Euthyroid** → thyroid function is normal
* Goitre - **diffuse**, **multinodular**, **solitary** **nodule**, **dominant** **nodule**
* differentiate benign from malignant
120
What is toxic multi-nodular goitre?
= Plummer's disease
nodules develop on the thyroid gland that **acts** **independently** **of** the normal feedback system
continuous production of **excessive** **TSH**
121
Features of toxic multi-nodular goitre?
* goitre with firm nodules
* Most patient’s aged over 50
* second most common cause of thyrotoxicosis (hyperthyroidism)
122
What is De Quervain's thyroiditis?
= Subacute thyroiditis
self limiting condition from viral infection
123
Features of Subacute thyroiditis?
Viral infection with fever, neck pain, dysphagia (swallowing problems)
Features of hyperthyroidism
Phases: viral infect - hyperthyroid - hypothyroid - euthyroid (normal!)
124
Treatment for De Quervain's thyroiditis?
self limiting
but can treat with NSAIDs for pain & inflam.
beta blockers for symptomatic relief of hyperthyroidism
125
What is a thyroid storm?
emergency, thyrotoxic crisis
rare presentation of hyperthyroidism
126
Features of a thyroid storm?
hyperthermia, tachycardia, arrhythmias, nausea, vomiting, seizures and cognitive decline.
127
Treatment for thyroid storm?
Admission, support with fluid
Pharm
Beta blockers, thionamides (PTU), steroids, Lugol's iodine
128
Hypothyroidism - define & types?
inadequately low output of thyroid hormones by the thyroid gland
Primary (thyroid pathology) or Secondary (pituitary pathology)
tingling of carpal tunnels
129
Features of primary hypothyroidism?
= 99% hypothyroidism
caused by **thyroid gland insufficiency**
**T3 & T4 will be low**
**TSH will be high**
(pit producing TSH to stimulate thyroid)
130
Features of secondary hypothyroidism?
caused by pituitary (or hypothalamic pathology)
TSH will be low → no production
131
How might you investigate hypothyroidism?
TSH = most sensitive marker
free T4 to confirm
antibodies - anti-TPO, anti-Tg, TSHR-Ab
132
What is Hashimoto's thyroiditis?
* **autoimmune** **inflammation** of the thyroid gland
* associated with antithyroid peroxidase **(anti-TPO - specific)** & antithyroglobulin **(anti-tg)** **antibodies** (also in Graves)
* Goitre → **_atrophy_** (shrinkage) of the thyroid gland
133
Causes of primary hypothyroidism?
Hashimoto's thyroiditis
iodine deficiency
tx for hy**_per_**thyroidism
medications - **lithium & amiodarone**
limits production of TSH, interfere with thyroid metabolism
134
Causes of secondary hypothyroidism?
hypopituitarism
may be caused by tumours, infection, vascular, radiation
135
Signs and symptoms, hypothyroidism?
* weight gain, fatigue
* **dry skin**
* **coarse hair and hair loss**
* **fluid retention** (oedema, pleural effusions, ascites)
* heavy or irregular periods
* constipation
* muscle - delayed reflexes, cramps
136
Tx for hypothyroidism?
Thyroid hormone replacement
oral levothyroxine = T4,
leothyroxine = T3 = shorter half life so for emergency
137
CI thyroid hormone replacements?
coronary heart disease, hypopituitarism
138
Interactions for thyroid hormone replacements?
increase dose if taking CYP450 inducers e.g. carbamazepine
can increase effects of insulin & warfarin
139
What is the adrenal axis?
Hypothalamus stimulating (via **anterior** **pituitary**) the **adrenal** glands (above each kidney), releasing **cortisol**
140
Effect of cortisol?
major metabolic & stress hormone
diurnal variation
* inhibits immune system & bone formation
* raises blood glucose
* increases alertness & metabolism
141
Briefly outline the adrenal axis?
1. Hypothalamus: corticotrophin release hormone (**CRH**)
2. Anterior pituitary: adrenocorticotrophic hormone (**ACTH**)
3. Adrenal gland: **cortisol**
= Negative feedback cycle to control hormones
Hypo & AP senses cortisol: suppress release of CRH & ACTH
142
What is Cushing's - differentiate between syndrome & disease?
**Syndrome** = symptoms that develop after prolonged abnormal elevation of cortisol
**Disease** = specific condition with excess glucocorticoids resulting from **inappropriate** **ACTH** **secretion** from a **pituitary adenoma**
→ **Disease** causes **syndrome**, but **syndrome** is not always caused by **disease**
143
Where is cortisol released from and by?
zona glomerulosa of the adrenal cortex above the kidneys
144
3 mechanisms which will give you excess cortisol?
either result from **excess ACTH** (antpit) or from **neoplasms** in **adrenals** stimulating z.reticu to release more
also from **ingesting excess glucocorticoids,** e.g. prednisolone
145
Symptoms, cushing's
= round in the middle (trunk, abdomen and neck) with thin limbs!
* round ‘moon’ face
* central obesity
* abdominal striae
* buffalo hump = neck
* osteoporosis
* **easy bruising** and **poor skin healing**
* **failure for children to grow tall despite excess weight**
146
Signs of cushing's
High level of stress hormone
* hypertension
* cardiac hypertrophy
* hyperglycaemia (DM2)
* depression, mood change - irritability
* proximal weakness
* gonadal dysfunction
147
Causes of Cushing's
* **pituitary adenoma** releasing excess ACTH (can be benign), peak 30-50 yrs
* **adrenal adenoma** = 80%
* **ectopic ACTH** = small cell lung cancer / carcinoid tumours
* **exogenous steroids** - long term high dose
* **alcohol pseudo-Cushing's**, obese, preg
148
Differentials - Cushing's
* alcohol pseudo-Cushing's = caused by alcohol excess, resolve 1-3 wks after abstinence
* asthma patients on ACTH
* obesity, pregnancy
149
How might you investigate Cushing's
**Dexamethasone suppression test,** 24hr & 48 hr, if positive then
**plasma ACTH**, if positive then
High dose dexameth supp / corticotropin releasing hormone (CRH) test
150
Outline Dexamethasone Suppression Test?
should in a healthy patient, send neg feedback to pit&hypo → decreased ACTH & cortisol
low dose given to patient at **midnight** & cotisol & **ACTH** measured in the **morning**
if cortisol suppression \< 50nmol, then Cushing's can be excluded
**high / normal cortisol** = further invest for type
151
How might high dose dexamethasone suppression test differentiate between diff types of abnormalities
High dose = 8mg = further invest
Cushing's = cortisol suppressed
Adrenal adenoma = cortisol unsuppressed, ACTH suppressed
Ectopic ACTH = neither cortisol nor ACTH suppressed
152
How might a 48h dexamethasone confirm the diagnosis?
Oral dex x4/day for 2 days, measure cortisol at 0 & 48hr
in Cushing's there will be no suppression of cortisol
153
If dex suppression tests are positive, how might you further confirm diagnosis of Cushing's?
Plasma ACTH
if ACTH **_detectable_** then distinguish pituitary cause from ectopic ACTH production → high dose dexa or CRH test
if ACTH **_undetectable_** then **adrenal tumour**. **Image** to confirm; if no mass then adrenal vein sampling
154
What is a Corticotropin releasing hormone (CRH) test?
* **Human IV CRH** given - activates and release ACTH
* Measure **cortisol** at **120 mins**
* **Cortisol** will **rise** with **pituitary disease** but **NOT** with **ectopic ACTH production**
* if positive cortisol response to CRH → cushing’s disease, pit MRI to confirm
* if negative cortisol response to CR → hunt for ectopic source of ACTH
155
Alternative to dexamethasone test?
24 hour urinary free cortisol
but cumbersome to carry out and does not indicate underlying cause
**Take \> 2 measurements (cortisol is bound to albumin, when capacity is reached then will spill out to urine)**
156
Tx for Cushing's?
Surgical & pharma to inhibit cortisone synthesis
157
Surgical options for Cushing's?
remove **pituitary adenoma**
go with trans sphenoidal
if impossible or **adrenal adenoma**
bilateral adrenalectomy & replacement hormones for life
if adrenal carcinoma = radiotherapy & adsrenolytic drugs - e.g. mitotane
158
If source unlocatable or recurrence post op - syndrome?
present?
Nelson's syndrome
present as increased skin pigmentation from enlarged pit tumour
will respond to pit radiotherapy
159
Pharma options for Cushing's
Drugs to inhibit cortisol synthesi
esp ectopic ACTH, post op or awaiting radiation
= METYRAPONE, KETOCONAZOLE and FLUCONAZOLE
160
What is acromegaly
multi-system disorder characterised by excessive growth hormone
mean age of diag = 44!
161
Cause of acromegaly?
**benign pituitary GH producing adenoma**
in almost all cases
expansion of the tumour in the pituitary can result in **compression** of surrounding structures resulting in **headaches** & **visual field loss**
**hyperplasia** e.g. **ectopic** **GH** releasing hormone from a **carcinoid** **tumour**
in rare cases
162
Action of growth hormone?
* **indirectly** through **induction** of **insulin**-**like growth factor (IGF-I)** which is synthesised in the liver & other tissues
* **directly onto tissues** such as the liver, muscle bone, or fat to induce metabolic changes
163
GH secretion monitoring?
inhibited by? stimulated by?
inhibited by **somatostatin** & **high glucose**!
stimulated by **ghrelin** - synthesised in stomach, also stimulates GH secretion
164
Classification of acromegaly?
* **gigantism** = excessive GH production in _children_ _before_ fusion of the epiphytes of the long bones
* **acromegaly** = excess GH in _adults_
165
Presentation - acromegaly?
* large hands = ‘**acral enlargement**’ - tight rings, carpal tunnel in 50%
* **maxillofacial changes**
* coarsening of facial features
* wide nose, skin darkening
* mandibular prognathism (地包天 or 天包地)
* arthralgia (joint stiff), bony and soft tissue overgrowth = sleep apnoea
* headache, hypogonadal, microglossia (- size tongue)
166
Complications for acromegaly?
* **cardiomegaly & hypertension**
* a very big risk factor!
* increased risk of **cerebrovascular** **events** and **headaches**
* MSK - bony / soft tissue overgrowth / arthritis
* **insulin resistant diabetes** or exacerbation of type 2
* **sleep apnea**
167
Key investigations for acromegaly?
IGF-1 test
Glucose tolerance test
168
Mechanism & diagnostic of growth hormone test for acromegaly
In normal patients, GH falls as glucose wears off, in acromegaly = opposite = GH peaks as glucose wears off
diagnostic if there is **no suppression of glucose**, since normally **glucose should inhibit GH release**
169
Relevance of IGF-1 in acromegaly testing?
secreted by **liver** in response to **growth hormones**
almost always raised in acromegaly & fluctuate less than GH
this is **diagnostic** if high (if not → OGTT)
170
How might you further assess / confirm acromegaly?
Glucose tolerance test (GTT)
Imaging - ECG / ECHO for cardio disease
check for pituitary adenoma
171
How would you check for a pituitary adenoma?
* **visual field exam** - can be bilateral temporal hemianopia due to pituitary adenoma
* **MRI** scan of pituitary fossa
* **serum lactin** will be raised if pituitary adenoma
172
1st line treatment for acromegaly?
* *pituitary surgery** - transsphenoidal
* *remove tumour**, correct & prevent tumour compression of surrounding struc
difficult if large size & invasive, most needs lifelong monitoring
173
if surgery fails, pharmacological therapy options for acromegaly?
**dopamine agonists** - **cabergoline**
fair amt wont respond
**somatostatin analogues** - **IM octerotide or lanreotide**
bound & inhibit multitude of hormones
SE GI cramps, flatulence, loose stools
**growth hormone receptor antagonist** - **SC Pegvisomant**
blocks IGF-I action, GH analogue
174
Option besides surgery and pharma?
radiotherapy - lots of options
175
What is prolactinoma?
excessive prolactin secretion by the lactotroph cell tumour of the pituitary
176
What is prolactin?
secreted by? inhibited by?
**secreted** - anterior pit
**tonic inhibited** - dopamine
= if dopa stops, prolac will rise
**function** (and a rise leads to)
lactation
reduced sex hormones
177
Hyperprolactin - besides prolactinoma,
can be caused by?
pituitary stalk damage
drugs - metoclopramid or ectasy
physiological - preggers, breastfeed, stress
178
Presentation for prolactinoma?
**menstrual dysfunction** (often initial!), infertility, **galactorrhoea**, low libido, erectile dysfunc / low testosterone, reduced facial hair
tumour - headache, bitem hemia, CSF leak from skull base erosion
179
Galactorrhoea can also be caused by
liver disease!! - associated with impaired oestrogen metabolism, which can cause breast tissue growth
Antipsychotics, antidepressants (SSRIs), Cimetidine, beta-blockers
180
Investigation for hyperprolactimea?
blood test
for basal prolactin levels
181
Differentials for hyperprolactimea
non functioning pituitary tumour - compression will interfere, but even then prolactin will be low
antidopaminergic drugs
macro / micro (\<1cm) prolactinoma
182
Management of prolactinoma?
Pharma only - use **dopamine agonists**
e.g. *carbergoline, bromocriptine, quinagolide*
usually remarkable shrinkage in a day/two
* *macro** - usually sight change will improve!
* *micro** - respond to carbergoline once / twice / week
183
What is vasopressin?
= AVP = ADH Anti diuretic hormone
184
Function of vasopressin?
act on **collecting ducts by inserting aquaporin 2 channels** therefore
**allow kidney to reabsorp water** → **concentrates urine**: increase H2O permeability in kidney, due to concentration gradient in the glomerular nephron
also causes **vasoconstriction on vasculature** = restore arterial BP
185
Vasopressin - controls?
secreted by? controlled by?
made in **paraventriculae nuclei** in hypothalamus
secreted by **_posterior pituitary_**
(other one is oxytocin)
release controlled by
* *osmoreceptors** in **hypothalamus** = d2d
* *baroreceptors** in **brainstem** & **great vessels** = emergency
186
What is diabetes insipidus?
**passage of large volume** (\>3 L / day) of **dilute** **urine** due to _impaired water reabsorption_ in the kidney either due to
lack of vasopressin secretion or vaso resistence
plasma osmolality will be high, urine osmolality will be low
187
Differentiate cranial DI from nephrogenic DI?
Cranial = lack of vasopressin secretion, congenital defect in ADH gene
Nephrogenic = resistance to action of vasopressin by kidneys, acquired or congenital
188
Causes of cranial DI?
tumour - never anterior pituitary though
severe head injury → damage to hypothalamus or pit gland
complications from neuro or pit surg
189
Causes of Nephrogenic DI?
Congenital - AVPR2 or AQP2 mutations
Acquired - lithium (BPD), +Ca, -K, kidney infect
190
Presentation DI?
* *polyuria** = excessive urine, 15L in 24 hours
* *hypernatraemia** = water loss \> Na loss
**polydipsia** = excessive thirst
can **dehydration**
**_NO glycosuria_**
191
How might you diagnose DI?
urine volume measure to confirm polyuria
Water deprivation then vasopressin test
| (must be \> 3L / day)
192
Briefly outline the water deprivation test?
morning = osmolality measure, stop patient from drinking.
see if osmolality increases, if so is it matched in urinary osmolality?
* normal individuals = **urine concentration gets darker** (**_higher_**) as no water
* DI = osmolality **not matched in urine**, does not get concentrated
193
How can the vasopressin test be used to differentiate between cranial and nephrogenic DI?
Give **IM Synthetic vasopressin** (= desmopressin) & water at 4pm
[vasopressin concentrates urine]
**_cranial_** = give both = plasma osmolality falls, urine osmolality increases (will be more concentrated)
**_nephrogenic_** = urine stays the same as resistant to vasopressin
194
What is hypertonic saline infusion and measurement of vasopressin used for?
measures copeptin, a part of the same protein that vasopressin is made
able to distinguish primary polydipsia from two DI's
195
Management for cranial DI?
TUC
desmopressin - works at V2 receptor, maintain sodium and symptomatic relief
196
Management for nephrogenic ID?
TUC, avoid precipitation drugs
free access to water, very high dose desmopressin
can try **thiazide diuretics** → encourage kidney Na+ uptake or **NSAID** - inhibit prostaglandin which locally inhibit action of ADH
197
What is SIADH?
Syndrome of anti-diuretic hormone secretion
= continuous & excess secretion of vasopressin despite plasma being very dilute → hyponatraemia
= opposite of DI
urine osmolality will be high, plasma osmolality will be low
198
Cause of SIADH?
Proton Pump Inhibitor!!!!!
Tumours - pituitary tumour, carcinoma of lung, other
Respiratory causes
199
Signs and symptoms - SIADH
reduction in GCS and confusion with drowsiness, fits and coma - occurs later
**water retention** - lose salt in urine, can’t switch on urino angiotensin, no aldesterone
but clinically no oedema
increased GRF, less Na reabsorption in PCT
normal thyroid and adrenal func
200
How might you distinguish SIADH from salt & water depletion?
test with 1-2l of 0.9% saline
SIADH will not respond, sodium depletion will respond!
201
Treatment options for SIADH?
TUC, fluid restriction, U&E replacement
202
If giving U&E, must be careful of?
**Reperfusion injury - osmolality demyelination syndrome**
can demyelinate the brain and irreversible (if chronic) - may take up to 2 weeks to manifest
LIMIT is **\<8 mmol / l** whereas normal **\< 10-12 mmol/l** in any 24 hour period
203
Pharmacological options for SIADH?
Selective V2 receptor oral antagonist = tolvaptan
* **competitive antagonist to vasopressin**
* cause a **profound** ‘**aquaresis**’
* collecting duct impervious to water, water is able to pass out
Salt and loop diuretic = furosemide to prevent circulatory overload
204
Presentation thyroid cancer
* Thyroid nodule/mass
* Hoarseness/change in voice
* difficulty swallowing & breathing
* Cervical lymphadenopathy
* Stridor (a harsh, high pitched sound, normally heard on inspiration, indicative of upper airway obstruction)
205
Types of thyroid cancer and specific features
Thyroid follicular epithelial-derived cancer
FEMALE ELDERLY risk
Papillary - (commonest) younger, lymph node mets (separate from gland)
Follicullar- womenn
Anaplastic - 65 female high aggressive poor prog
Medullary = neuroendocrine, secretes calcitonin!
MEN II, RET gene
Primary thyroid lymphoma = with Hashimoto's
206
Free card for break
207
Parathyroid hormone
released from?
by **_chief cells_** in four parathyroid glands in each corner of thyroid gland
208
Parathyroid hormone
released in response to? controlled by?
_low_ serum calcium
low magnesium and & high serum phosphate
controlled through **_negative feedback_** by serum sodium! (increase Ca = suppress)
209
Where is does PTH act on and what is its function?
increase serum calcium to 1.1 mmol/l by
increasing activity of osteoclast
= reabsorption of Ca from bone
increasing calcium reabsorp in kidneys
in _distal convoluted tubule_
and in the GI tract
stimulate kidney to convert vitamin D3 to calcitrol = active form = promotes Ca absorption form food in small intestine
210
Function of vitamin D in Ca physiology
converted by PTH to active form
act on all three of processes
therefore **_acts along PTH to increase Ca reabsorption_**
211
Epidemiology of hyperparathyroidism?
* esp in **elderly women**
* primary hyperparathyroidism & **malignancies** = most common causes of hypercalcaemia
* but hypercalcaemia is rarely the first presenting symptom of malignancy
212
Types of hyperparathyroidism?
Primary
Secondary
Tertiary - as extension of secondary
213
Outline pathophysio of primary hyperparathyroidism?
uncontrolled PTH production by **tumour of parathyroid gland**
80% due to single benign adenoma (out of 4 parathyroid), 15-20 due to gland hyperplasia, \< 0.5% malignant
mostly asymptomatic. surgical removal
214
Outline pathophysio of secondary parathyroidism?
**insufficient vitamin D** or **chronic kidney disease** = low Ca → compensatory PTH → hyperplasia / hypertrophy of gland
215
Outline pathophysio of tertiary hyperthyroidism?
secondary continues for years
hyperplasia of gland after secondary, baseline PTH increases dramatically but long term ⇒ **_autonomous gland_** even after tx
surgical removal partial
216
Disease pictures of the three types of hyperthyroidism?
**Primary** - high PTH, high Ca
normal phos / alk phos
```
**Secondary** - high PTH, low Ca
high phos (renal disease) / alk phos
```
**Tertiary** - high PTH, high/norm Ca
217
What is malignancy hyperparathyroidism?
**fake PTH secreted by carcinomas → mimic**
**=** parathyroid related protein
squamous cell lung, breast, renal
so high Ca, normal PTH
calcium mobilisation, secondary mets in bone
218
Signs and symptoms of hyperparathyroidism?
Bones, stones, groans and moans
* **Bones** - from excessive bone resorption
* pain & fractures
* osteoporosis / osteopenia / osteomalacia
* osteitis fibrosa cystica
* Kidney **stones** - from excessive calcium = renal colic or biliary stone
* Psychic **moans**
* confusion, depression, anxiety, insomnia
* Abdominal **groans**
* abdo pain
* constipation
* acute pancreatitis
* polyuria & nocturia - if ca2+ deposit in renal tubules
* high ca2+ also dehydration, confusion and risk of cardiac arrest
219
How would you investigate the parathyroid in hyperparathyroidism?
* **PTH measure**
* **renal function measure** - if low then secondary or tertiary?
* **Albumin-adjusted serum calcium**
* **24 hour urinary calcium**
* high in hypercalcaemia
* where excess reabsorp despite hypercalcaemia, urinary will be low
220
What imaging would you use for hyperparathyroidism
* doppler ultrasound / CT / MRI - malignancy // radioisotope scanning will be 90% sensitive for adenomas
* DXA bone scan - bone effects
221
How would you treat hyperparathyroidism
primary & tertiary - surgery
secondary - TUC replace vit D or renal transplant in those with renal failure
222
Pharmacological tx for hyperparathyroidism post surgery!
* hypocalcaemia after surgery
* if surgery CI **= calcimimetic** - increase sensitivity of parathyroid cells to ca2+ thereby causing less PTH secretion - e.g. oral cinacalcet
* **avoid thiazide diuretics** and high ca2+ and vitamin D intake
223
What is an acute severe hyperglycaemia & tx?
= emergency!
* **rehydrate** IV 0.9% saline **fluids** to prevent stones
* **bisphosphonates** after **rehydration** IV pamidronate to prevent bone resorption
* measure serum UE and serum ca2+ 48hrs post tx
* **glucocorticoid steroids** ORAL prednisolone in myeloma, sarcoidosis and vit D excess
224
How might hypercalcaemia present?
rarely first sign of hyperparathyroidism! but
* renal stones
* ECG: _short_ QT
* thirst: polyuria (diluted)
* nausea, constipation, confuse, coma
225
Causes of hypercalcaemia?
malignancy - mets, PTH related peptides
primary hyperparathyroidism
226
When looking at high / low Ca results, always question if ‘true’ or ‘pseudo’ - think these
tourniquet damage
sample is old and haemolysis
if low - hypoalbuminaemia?
227
How would you correct calcium from albumin
(40 - serum albumin ) \*0.02 + total serum calcium
for every gram that serum albumin is below 40, + 0.02
228
Epidemiology of hypoparathyroidism?
* all ages and both sexes
* extremely common in hospitalised patients and correlates with severity of illness - in 88% of intensive care patients
229
Causes of hypoparathyroidism?
secondary to increased serum phosphate
**chronic kidney disease** - most common cause
severe vitamin D deficiency
**malabsorption**, **crohn's**, **anti-epileptic drugs**
**reduced PTH function**
230
Define primary hypoparathyroidism?
= gland failure
PTH low, Ca+ is low, Phosphate high
**autoimmune** causes - DiGeorge or idiopathic
231
Define secondary hypoparathyroidism
post- surgical or radiation
232
Define secondary hypoparathyroidism
post- surgical or radiation
233
Define functional hypoparathyroidism?
caused by **Magnesium deficiency**
* present with **low PTH & low Ca**
* need magnesium to excrete PTH! (carry vesicle to cell surface)
* caused by alcoholic, drugs etc
234
Presentation of **hypocalcaemia**?
**_SPASMODIC_**
Spasms - **Trousseu's** **sign** (how much)
Periodical paraesthesia
Anxious, irritable, irrational
Seizures
Muscle tone +
wheeze + longer QT
Orientation impaired & confusion
Dermatitis
Impetigo herpetiformis - reduced Ca and pustules in preggers
**Chvostek's sign**, Cataract, Cardiomyopathy
235
What is the Trusseau's sign?
sign of muscle spasm in the hands
inflate BP cuff to 20 mmhg above systolic for five minutes
_positive_ if hand elicit ‘how much’ sign
236
What is the Chvostek's sign?
sign of muscle spasm
tap over facial nerve and twitch of facial muscles
sign of hypocalcaemia
237
Define pseudohypoparathyroidism?
organs resistant to PTH
mutation in GNAS1 receptor
low Ca, high PTH
inherited from father
238
Presentation pseudohypoparathyroidism
* short stature, obesity, round facies, mild learning difficulties
* subcutaneous calcification
* !! **short fourth metacarpals**
* make a fist & fourth metacarpal won’t be there → just a dimple
* 4th and 5th may be same length
* other hormone resistance
239
Diagnostics for hypoparathyroidism?
* usually history is enough
* bloods
* **low serum calcium** - used to confirm history
* **_remember to correct for albumin abnormality_**
* urea:creatinine for eGFR for renal disease
* **serum PTH**
* absent / low in hypo
* high in other causes of hypocalcaemia
* **parathyroid antibodies** - for idiopathic
* **serum 25-hydroxyvitamin D** - low in vit D deficiency
* **Mg2+ level** - severe hypomagnesaemia - functional hypoparathyroidism
240
How would you treat hypoparathyroidism / hypocalcaemia generally?
* **calcitonin**
* decreases plasma Ca2+ and phosphate
* **bisphosphonates** - reduce osteoclast activity therefore stop ca2+ declining
* **calcium supplements + calcitrol** (active vit D)
241
How would you treat an acute episode of hypocalcemia?
* **tetany**
* IV **calcium gluconate** over 30 min with ECG monitoring
* **vitamin D deficiency**
* oral **colecalciferol** (D3) or oral **Adcal** (calcium + D3) (**calcitrol**?)
* ineffective for those with hypoparathyroidism as PTH is needed to convert D3 to 1, 25 dihydroxyvitaminD
242
Aldosterone is secreted by?
Zona glomerulosa of the adrenal gland
243
Aldosterone is a part of which system?
Renin-angiotensin-aldosterone
increases BP
244
Briefly outline the renin-angiotensin-aldosterone system?
renin (kidney) on angiotensinogen (liver) → angio I → ACE → angio II → stimulates release of aldosterone
raises BP by both angiotensin II & aldosterone
245
What cells monitors the BP in kidneys
& where is it located?
**juxtaglomerular cells**
monitors kidney BP
in the **afferent arteriole**
246
Aldosterone acts on which part of the body and what effects does it have?
on the distal tubules
* *sodium reabsorption**
* *potassium secretion**
on the collecting ducts
**hydrogren secretion**
247
Nature of aldosterone?
Minerocorticoid steroid hormone
248
Overall effects of aldosterone?
**increase sodium reabsorption** into blood
= water also reabsorped (**retain H2O**)
blood volume is increased, systemic vascular resistance changed,
**_blood pressure is increased_**
249
Biggest linked condition with hyperaldosteronism?
most common cause of secondary hypertension
consider **_hyperaldosteronism_** if patient not responding to hypertension treatments!
→ screen with renin aldosterone ratio blood test, clue can be low potassium in blood
250
Presentation for hyperaldosteronism?
**hypertension** &
**hypokalaemia** (often absent)
but may present as:
* muscle weakness, paraesthesia, mood disturbance
* **polyuria / nocturia** as potential diuresis
251
What is Primary hyperaldosteronism
= Conn's syndrome
## Footnote
= when **adrenal glands** secretes too much aldosterone
= **serum renin is low** (renin is only secreted when BP is high!) → suppressed by high BP entering kidneys
252
Causes of primary hyperaldosteronism?
adrenal adenoma = 30-40%
bilateral adrenal hyperplasia = 60-70%
familial hyperaldosteronism
adrenal carcinoma (rare)
253
What is secondary hyperaldosteronism?
= when **excessive renin** is **stimulating** the adrenal gland to produce more aldosterone
= serum renin will be high → cause!
254
Causes of secondary hyperaldosteronism?
principle = juxtaglomerular cells, which senses kidney BP, keep sensing low → lots of renin → adrenal stimulated but kidney will not feel high BP
**renal artery stenosis**
= narrowing of artery supplying the kidney
= atherosclerosis (plaque)
**renal artery obstruction**
255
How would you confirm hyperaldosteronism & differentiate?
renin : aldosterone ratio in blood
low / normal renin = primary
high renin = secondary
256
How would you investigate for causes of hyperaldosteronism?
Imaging
CT / MRI
for **adrenal tumour**
Renal doppler ultrasound, CT angiogram or MRA
for **renal artery stenosis or obstruction**
257
3 classic investigative findings for hyperaldosteronism?
BP - hypertension
Serum electrolytes - hypokalaemia
Blood gas - alkalosis
258
What is hyperaldosteronism typically associated with?
Heart failure
259
How would you pharmacologically manage hyperaldosteronism?
aldosterone receptor antagonists
* eplerenone - no gynaecomastia
* spironolactone - gynaecomastia
* if not tolerated - ENaC inhibitor = amiloride
antihypertensives if needed
260
Which aldosterone receptor antagonist could potentially cause gynaecomastia?
spinocolactone
261
How would you surgically treat hyperaldosteronism?
surgically remove adrenal adenoma
percutaneous angioplasty for renal artery stenosis
262
What is adrenal insufficiency?
= adrenal glands do not produce enough steroid hormones, particularly **cortisol & aldosterone**.
primary = Addison's
263
Briefly outline the adrenal axis?
**Hypothalamus = CRH**
Corticotrophin releasing hormone
**Anterior pituitary = ACTH**
adrenocorticotrophic hormone
**Adrenal gland = cortisol**
Cortisol inhibits CRH & ACTH throgh negative feedback
264
Function of cortisol?
= major metabolic & stress hormone
* inhibits immune system & bone formation
* raises blood glucose
* increases alertness & metabolism
265
Key signs of adrenal insufficiency!
= **bronze hyperpigmentation** to skin
particularly in skin creases like **hands**
* *= hypotension,** particularly
* *postural hypotension**
**=** _low_ Na, **high** potassium
hyponatraemia, hyperkalaemia
266
Symptoms of adrenal insufficiency?
HYPOTENSION, low Na high K
* dehydration
* reduced libido, hair loss in axilla / pubic region !! **esp in women**
* weight loss, muscle wasting
* mood disturbance
* cramps, abdo pain, fatigue, nausea, vomit
267
What is primary adrenal insufficiency?
= Addison's disease
## Footnote
= **damage of the adrenal glands**, resulting in a reduction of cortisol & aldosterone secretion
= **high ACTH**, trying to stimulate but no response or neg feedback (no cortisol production)
268
What are the causes of primary adrenal insufficiency?
* most common = **_autoimmune_** → esp in women
* **infective**
* **tuberculosis** (most common worldwide)
* HIV, fungal, syphilis
* other
* haemorrhage
* malignancy
269
What is secondary adrenal insufficiency?
= inadequate (low) ACTH stimulating the adrenal glands
270
Causes of secondary adrenal insufficiency?
* **loss or damage to the pituitary gland**
* injury, surgery, radiotherapy
* infection
* loss of blood flow
* pituitary gland necrosis from massive blood loss during childbirth - **Sheehan’s syndrome**
271
What is tertiary adrenal insufficiency?
= inadequate CRH release by hypothalamus
272
Causes of adrenal insufficiency?
= **steroids not being tapered off properly**
long term exogenous steroid being suddenly withdrawn, hypothalamus doesn't wake up fast enough & no replacement
= taper slowly for adrenal axis to regain normal function
273
How might you investigate adrenal insufficiency?
**_Short Synacthen_** = test of choice!
**Plasma ACTH** = primary / secondary
**adrenal autoantibodies**
= adrenal cortex antibodies & 21 hydroxylase antibodies
Imaging if suspecting tumour, haemorr or other structural pathology
274
How might plasma ACTH differentiate between primary & secondary adrenal insufficiency?
primary = high ACTH
trying to get adrenal to work
secondary = low ACTH
loss of injury to pit
275
What are the autoantibodies associated with Addison's?
adrenal cortex antibodies & 21 hydroxylase antibodies
276
Outline the short synacthen test?
give synacthen = synthetic ACTH
(IV 250 mcg of tetracosactide)
in the morning
measure blood cortisol at baseline, 30 & 60 minutes after administration
277
How might you interpret the results of the short synacthen test?
if blood cortisol
double of baseline = pituitary issue
(secondary) as adrenals responsive
less than double of baseline = adrenal issue
(primary) = Addison's as not responsive
278
How might you treat someone with adrenal crisis?
= **_replacement steroids_** titrated to signs, symptoms and electrolytes
**hydrocortisone** for **cortisol**
**fludrocortisone** for **aldosterone**
steroid card and tag, double dose in acute illness
279
What is an Addisonian crisis?
= adrenal crisis, acute Addison's
**_emergency_**
can be first presentation of Addisons
or triggered by **infection**, **trauma**, or other **acute illness** in someone with est. Addie's or **steroid** **withdrawal**!
280
Presentation of an acute adrenal crisis?
HYPOtension
low glucose, low Na, high K
reduced consciousness, patient very unwell
281
How might you treat an acute adrenal crisis?
**parenteral steroids** - **IV** **hydrocortisone** 100mg stat then 100mg every 6 hours
* IV fluid resus
* correct hypoglycaemia
* careful monitoring of electrolytes and fluid balance
282
What is serotonin syndrome?
due to **increased** serotonergic activity in CNS which can be induced by a range of medications that **increase** serotonergic transmission by **altering neurotransmitter serotonin**
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Risk factors of serotonin syndrome?
within several hours of taking a new drug
increasing the dose of a drug you're already taking
Overdose
in all ages, esp young adults
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Function of serotonin?
= monoamine neurotransmitter derived from tryptophan
CNS = theromoregulation, behavior, attention
PNS - vasoconstriction, bronchoconstriction, GI motility, uterine contraction
**Promotes platelet aggregation** = risk
haemorrhagic + if used with antiplatelet
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Drugs implicated in serotonin syndrome?
serotonin inhibitors, receptor agonists,
impaired serotonin reuptakes, increased
SSRI's, SNRI's. TCA, MAOI
MDMA (ectasy), cocaine, lithium!
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Outline pathophysiology of SS?
serotonin reuptake is inhibited from synaptic cleft into presynaptic neuron
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Presentation of serotonin syndrome?
* **altered** **mental** **status**
* anxiety, restless, disorientation, or agitation
* **autonomic** **hyperactivity** = HYPER tension, thermia, TACHYCARDIA
* flushed skin, diaphoresis (sweating lol)
* **neuromuscular abnormalities**
* dilated pupils
* clonus (repeat rhythmic), myoclonus (sudden)
* **positive babinski**! bilateral upgoing plantars
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How might you investigate serotonin syndrome?
**Hunter criteria**
patient is taking a serotonergic agent and presents with _ONE_ of the following
spontaneous clonus
Inducible/ocular clonus and agitation or diaphoresis
tremor / hyperreflexia
hyperthermia, hypertonia, ocular / inducible clonus
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differentials for serotonin syndrome?
MDMA / cocaine use
neuroleptic malignant syndrome
broad as it is with confusion - encephalitis, drug intox, phaechromocytoma
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What is the general tx for serotonin syndrome?
observation, supportive care if needed
cardiac monitoring, electrolyte, acute kidney, rhabdomyolysis
iv fluids, antipyretics
specific antihypertensive for profound hypertension
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Specific antihypertensive for serotonin syndrome?
cyproheptadine, and propofol
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Mechanism of cyproheptadine
histamine receptor antagonist with action against serotonin receptors
293
Complications of serotonin syndrome?
* Cardiac arrest
* Cardiac arrhythmias
* Acute kidney injury
* Rhabdomyolysis
* Disseminated intravascular coagulation
* Seizures
* Respiratory failure
* Venous thromboembolism
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What is rhabdomyolysis?
clinical syndrome characterised by skeletal muscle necrosis due to release of toxic intracellular contents including **myoglobin** and **electrolytes**
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Aetiology of rhadomyolysis?
(3)
**Muscle compression** from crush injury
compartment syndrome, surgical operation, electrical injury, prolonged immbo
**Non traumatic, exertional**
**Non traumatic, non exertional**
statins & colchicine, cocaine, opioids, benzodiazepines, amphetamine, toxins
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What leaks out of the muscles during rhabdomyolysis?
creatinine kinase and myoglobin
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High risk of which disease is linked to rhabdomyolysis?
AKI as creatinine kinase inceases
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Pathophysio of rhabdomyolysis
**myocyte injury**
= as a cause or as a step in process
depletes ATP = everything foes
releases creatinine kinase & myoglobin
**myocyte** damages **kidney** - renal rubular obstruct, intrarenal vasoconstrict
**creatinine** also increase **risk of AKI**
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Rhabdomylysis presentation & trigger?
suspect when _unexplained AKI_ = following immobile, crush, muscle tender or meh U&E
**myalgia**, **muscle weakness, dark urine (coca cola)**
aches, calves & lower, from myoglobin
others - soft tissue swelling, altered mental status // skin changes, limb deformity
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investigations for serum creatine kinase?
**_serum creatine kinase - KEY_**
= marker of skeletal breakdown
= rhabdo if CK \> 5x upper limit of normal
will rise within 12 hrs of injure & peak 24-72
**Myoglobin in urine**
= 50% patients as excreted quickly
= will show on dipstick as ‘blood’
**Renal function - stat!**
= 15-50% will have AKI
= risk increases with higher CK
**ECG** = risk of UE abnormality
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Management for rhabdo?
fluid resus aggressive and early
dialysis if needed
loop diuretics, IV bicarb
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What is carcinoid syndrome
syndrome which arise when a **neuroendocrine tumour** (aka **carcinoid** syndrome) begins secreting hormones
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What is a carcinoid tumour?
Tumour of the neuroendocrine cells
releases hormones into blood
e.g. serotonin, histamine, bradykinin (vdilate), prostaglandins (vdilate)
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When do symptoms usually arise?
when tumour has spread to the **_liver**_ and releasing hormones e.g. _**serotonin_** into bloodstream
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Symptoms of carcinoid syndrome?
abdo - RUQ, diarr, const, poo blood
cough - blood, wheeze, short breath, pain
general cancer stuff
**flushing of the skin!** particularly the face _bluish red_ - caused by bradykinin
fast heart rate, breathlessness, wheezing, **carcinoid heart disease** - heart valve thicken and stop working properly
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What is a carcinoid crisis?
when tumour outgrows its blood supply or is handled too much during surgery - mediators flow out
vasodilate, bronchoconstrict = bradykinin
tachycardia = serotonin
hypotension = ACTH
hyperglycaemia = glucagon and ACTH
exacerbated by alcohol and stress!!
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How might you diagnose a carcinoid tumour?
urinalysis = will show
increased 5 hydroxyindoleacetic acid
imaging = ct, mri scan
otreoscan / gallium 68 pet scan
blood test = niacin deficiency!
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How might you treat carcinoid syndrome?
surgical removal of tumor
pharmacology
lifestyle - avoid ALCOHOL & stress
as symptoms exacerbated
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Surgical options to remove carcinoid tumor?
removal, radiotherapy,
block blood supply to the tumour esp if in liver = hepatic artery embolisation
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pharmacological options to treat carcinoid tumor?
somatostatin analogues
= octreotide and lanreotide - slows growth of the tumour, receptor antagonist
311
Lifestyle advice for carcinoid syndrome?
avoid alcohol and stress
avoid food with tyramine = in aged cheese, salted or pickled meats,
avoid spicy food
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What is a pheochromocytoma?
tumour of the **chromaffin cells** in **adrenal** **glands** which secretes unregulated and excessive amounts of **adrenaline**
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What is phaeochromocytoma linked to?
Linked to **multiple endocrine neoplasia type 2 (MEN2)!!, Von Hippel Lindae syndrome**
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Adrenaline is secreted by?
Chromaffin cells in adrenal medulla of adrenal glands
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Effects of the tumour?
* **alpha-adrenergic** - + BP, increased cardiac contract, increased glycogenolysis / gluconeogenesis (glucose utilise)
* **beta-adrenergic** - increased heart rate and contractility
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Where might you find a phaeochromocytoma?
abdomen \>95%
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Symptoms of a phaeochromocytoma?
PAROXYSMAL
**episodic** **headache**
**sweating**
**tachycardia**, palpitations, paroxysmal atrial fibrillation
→ resembles panic attack
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What is a phaeochromocytoma crisis?
= hypertensive crisis, if severe could lead to circulatory collapse
= hypertension, hyperthermia, confusion
end organ dysfunction - cardiomyopathy, pulmonary oedema
319
How might you diagnose phaeochromocytoma?
24 hour urine catecholamines
plasma free metanephrines
= breakdown product of adrenaline
CT / MRI cross section
alt MIBG scintigraphy - MIBG substance taken up by adrenergic tissue
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How might you manage a phaeochromocytoma?
BP control
= **phenoxybenzamine**, alpha blocker
irreversible, long acting
alt CCB, and beta blocker once established on alpha blockers
**Metyrosine** - inhibit catecholamine synthesis
High sodium diet to replace with excessive catecholamines
**adrenalectomy** = removes the tumour = GOLD
