Endocrinology Flashcards
1
Q
Define endocrinology
A
The study of hormones (and their gland of origin), their receptors, IC signalling pathways & associated diseases
2
Q
Function of endocrine glands
A
Release hormones DIRECTLY into BLOOD
ductLESS
3
Q
Why are endocrine glands useful?
A
- allows rapid adaptive changes
- integration of whole body physiology
- maintenance of metabolic environment
- communication for multi-cellular organisms
4
Q
Examples of endocrine glands
A
- thyroid
- adrenal
- beta cells of pancreas
5
Q
Function of exocrine glands
A
Pour secretions through a duct to the site of action
6
Q
Examples of exocrine glands
A
- submandibular
- parotid
- pancreas
7
Q
Endocrine hormone action
A
- blood borne
- acting on distant sites
8
Q
Paracrine hormone action
A
Acting on nearby adjacent cells
9
Q
Autocrine hormone action
A
Feedback on same cell that secreted hormone - acts on itself
10
Q
Characteristics of water-soluble hormones
A
- transported unbound
- bind to surface receptor
- short half life
- fast clearance
11
Q
Examples of water-soluble hormones
A
- peptides
- monoamines
(both stored in vesicles before secretion)
12
Q
Characteristics of fat-soluble hormones
A
- transported bound to protein
- diffuse into cells
- long half life
- slow clearance
13
Q
Examples of fat-soluble hormones
A
- thyroid hormones
- steroids
(synthesised on demand)
14
Q
Example of peptide hormone
A
Insulin (MAIN EXAMPLE)
15
Q
Properties of insulin
A
- hydrophilic
- water soluble
- stored in secretory granules
16
Q
How is insulin released?
A
In pulses or bursts
17
Q
How is insulin cleared?
A
By tissue or circulating enzymes
18
Q
How is insulin activated?
A
1) Binds to insulin receptors
2) Phosphorylation of receptor
3) Secondary messenger activated - tyrosine kinase
4) Phosphorylation of signal molecules
5) Cascade effect
6) Glucose uptake
19
Q
Examples of amines
A
- dopamine
- adrenaline
- noradrenaline
20
Q
Sequence of amines
A
Phenylalanine > L-tyrosine > L-dopa > Dopamine > Noradrenaline > Adrenaline
21
Q
What is noradrenaline broken down by?
A
Catechol-O-methyl transferase (COMT)
22
Q
What is noradrenaline broken down into?
A
Normetanephrin
norepinephrine go into normetanephrines
23
Q
What is adrenaline broken down by?
A
COMT
24
Q
What is adrenaline broken down into?
A
Metanephrin
epinephrine go into metanephrines
25
How can normetanephrin and metanephrin be measured?
In serum
| - indicators of adrenaline and noradrenaline activity
26
What can amines bind to?
1) Alpha receptors
| 2) Beta receptors
27
What happens if amines bind to alpha receptors?
- vasoconstriction
- bowel muscle contraction
- sweating
- anxiety
28
What happens if amines bind to beta receptors?
- vasodilation
- increase in HR
- increase in force of contractility
- relaxation of bronchial smooth muscles
29
What are the iodothyronine hormones?
1) T3 - triiodothyronine
| 2) T4 - thyroxine
30
Which is more active: T3 or T4?
T3
| but more T4 produced
31
Are iodothyronines protein bound?
Yes
32
What protein do iodothyronines bind to?
Thyroid-Binding Globulin (TBG)
33
What gives rise to T3 and T4?
Conjugation of iodothyrosines
34
How are T3 and T4 stored?
In colloid bound to thyroglobulin
35
How are iodothyrosines formed?
Incorporation of iodine on tyrosine molecule on thyroglobulin
36
Examples of cholesterol derivatives and steroid hormones
1) Vitamin D
| 2) Adrenocortical & gonadal steroids
37
Properties/ Functions of vitamin D
- fat soluble
- enters cell directly
- binds to nucleus
- stimulates mRNA production
38
How is vitamin D transported?
By vitamin D binding protein
39
Examples of Adrenocortical & Gonadal steroids
1) Cortisol
2) Aldosterone
3) Testosterone
4) Oestrogen
5) Progesterone
40
What % of adrenocortical and gonadal steroids are protein bound?
95%
41
How does a steroid hormone work?
| cortisol/ aldosterone/ progesterone/ testosterone
- diffuses through plasma membrane
- binds to cytoplasm receptor
- receptor-hormone complex enters nucleus
- binds to glucocorticoid response element (GRE)
- this initiates transcription of gene to mRNA
- mRNA directs protein synthesis
42
What are the hormone receptor locations?
1) Cell membrane (peptides)
2) Cytoplasm (glucocorticoids, mineralocorticoids, androgens, progesterone)
3) Nucleus (thyroid hormones, oestrogen, vitamin D)
43
What are the different hormone secretion patterns?
1) Continuous release
2) Pulsatile
3) Circadian rhythms
44
Example of continuous release hormone
Prolactin
45
Example of pulsatile release hormone
Insulin
46
Examples of circadian rhythm release hormone
ACTH, prolactin, GH, TSH, cortisol
47
What are the different ways hormone action is controlled?
1) Hormone metabolism
2) Hormone receptor induction
3) Hormone receptor down regulation
4) Synergism
5) Antagonism
48
How does hormone metabolism work?
Increased metabolism = reduced function
49
Example of hormone receptor induction
Induction of LH receptors by FSH in follicle
50
How does hormone receptor down regulation work?
Hormone secreted in large quantities = down regulation of target receptor
51
How does synergism work?
Combined effects of 2 hormones amplified
| e.g glucagon & adrenaline released together when hypoglycaemic - increase sugar levels
52
How does antagonism work?
One hormone opposes other hormone
| e.g glucagon & insulin
53
What kind of hormones does the hypothalamus release?
Hypophysiotropic hormones
54
How do hypophysiotropic hormones reach the anterior pituitary?
Via the hypothalamo-hypophyseal portal vessel/vein
55
How many hormones in total does the anterior pituitary secrete?
6
56
What are the 5 hypophysiotropic hormones?
1) Corticotropin releasing hormone (CRH)
2) Growth hormone releasing hormone (GRHR)
3) Thyrotropin releasing hormone (TRH)
4) Gonadatropin releasing hormone (GnRH)
5) Dopamine
57
Function of CRH
Stimulates release of ACTH
58
Function of GRHR
Stimulates release of growth hormone
| - somatostatin INHIBITS release of GHRH
59
Function of TRH
Stimulates release of TSH
60
Function of GnRH
Stimulates release of FSH and LH
61
Function of Dopamine
```
Inhibits prolactin
(prolactin is under negative control by dopamine)
```
62
What are the 6 peptide hormone secreted by the anterior pituitary?
(FLATPIG)
1) FSH
2) LH
3) ACTH
4) TSH
5) Prolactin
I for ignore !!
6) Growth hormone
63
What is another name for the anterior pituitary?
| And what is the blood supply?
Adenophysis
- no arterial blood supply
- blood through portal venous circulation from the hypothalamus
64
What is another name for the posterior pituitary?
Neurohypophysis
65
What 2 hormones are stored and released by the posterior pituitary?
1) Vasopressin/ADH - synthesised in cell body of supraoptic nucleus
2) Oxytocin - synthesised in cell body of paraventricular nucleus
66
What stimulates vasopressin/ADH to be released?
- decreased blood volume
- trauma
- stress
- increase blood CO2
- decreased blood O2
- increased osmotic pressure of blood
67
What receptors do ALL pituitary and hypothalamic hormones act on?
G-protein coupled receptors
68
What are the 3 vital presentation of pituitary tumour?
1) Pressure on local structures
2) Pressure on normal pituitary - hypopituitarism
3) Functioning tumour - hyperpituitarism
69
What can pressure on local structures cause?
- optic chiasm pressrure = bitemporal hemianopia
- hydrocephalus
- can get CSF leak
70
What can hypopituitarism cause?
- cortisol deficiency
In males: pale, no body hair, central obesity, effeminate skin
In females: lose body hair, jaundiced complexion
71
What can hyperpituitarism cause?
- prolactinoma - increase prolactin
- acromegaly - increased GH
- Cushing's - increased CTH
72
What is the HPA axis?
Hypothalamo-Pituitary-Adrenal axis
73
What is the pituitary-thyroid axis?
- hypothalamus releases TRH
- stimulates secretion of TSH from pituitary
- stimulates release of T3 & T4 from thyroid
- T3 & T4 have -ve feedback on hypothalamus & pituitary
74
What is the pituitary-gonadal axis?
hypothalamus > pituitary > gonads - release testosterone > -ve feedback on HT & pituitary
75
What are the diseases of the pituitary?
- benign pituitary adenoma (pituitary produces less & presses on things e.g optic chiasm)
- craniopharyngioma
- trauma
- Sheehan's - pituitary infarction after labour
- sarcoid/ TB
76
What happens in prolactinoma?
- common in females
- increased prolactin = increased milk production
- galactorrhea - milk leaks
- reduced fertility
- menstruation stops = amenorrhea
77
How do you treat prolactinoma?
- use dopamine agonist
- inhibits prolactin production
e. g CABERGOLINE
78
What happens in acromegaly?
- increased GH
- thick, greasy, sweaty skin
- enlarged organs
e. g large heart = high risk of heart attack/ disease
79
What happens in Cushing's?
- increased CTH
- too much cortisol
- central obesity
- bruising, thin skin
- osteoporosis
- ulcers
- purple stretch marks
80
Calcium homeostasis: What happens in response to decreased serum calcium?
- increased parathyroid hormone
- increased bone resorption
- increased calcium reabsorption
- increased calcium absorption
81
What are the actions of the parathyroid hormone?
- increased Ca2+ reabsorption
- decreased phosphate reabsorption
- increased 1 α hydroxylation of 25-OH vit D
- increased bone remodelling
resorption>formation
- increased Ca2+ absorption (because of increased 1,25 (OH)2 vit D
82
Is calcium homeostasis +ve or -ve feedback?
Negative
83
What is the set point of serum ionised calcium?
1.1mmol/L
84
What percentage of total plasma calcium is ionised?
40% (only this is physiologically relevant)
| - rest is bound to albumin (unavailable)
85
What stimulates calcitriol release?
- low plasma Ca2+
- low plasma phosphate
- PTH
86
What are the roles of calcitriol?
- increased Ca2+ and phosphate absorption in the gut
- inhibits PTH release (-ve feedback)
- increases no. of osteoclasts
- increased Ca2+ & phosphate reabsorption in kidneys
87
Where is calcitonin made?
C-cells of thyroid
88
What does calcitonin do?
Decrease in plasma Ca2+ & phosphate
89
Definition of Diabetes Mellitus
Syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both
(can be thought of as vascular disease)
90
How much glucose is produced and utilised everyday?
200g
91
What percentages of glucose are derived from where?
- 90% from liver glycogen & hepatic gluconeogenesis
| - 10% from renal gluconeogenesis
92
Which organ is the main consumer of glucose?
The brain
93
Why does the brain use the most glucose?
- Cannot use free fatty acids to be converted to ketones (then acetal CoA & therefore Krebs)
- fatty acids can't cross BB barrier
94
Is glucose uptake by the brain obligatory?
Yes
95
Is glucose uptake in the brain dependent on insulin?
No
96
What is glucose oxidised to in the brain?
CO2 and H2O
97
What does fat use glucose for?
As a substrate for triglyceride synthesis
98
What does insulin do?
- suppresses hepatic glucose output
- decreases glycogenolysis and gluconeogenesis
- increases glucose uptake into muscle and fat
- suppresses lipolysis and breakdown of muscle
99
Biphasic insulin release
```
- B cells sense rising glucose levels
Phase 1) RAPID RELEASE of stored insulin
Phase 2) initiated if glucose levels remain high
- longer than 1st phase
- more insulin has to be synthesised
```
100
Which chromosome is insulin coded for on?
Chromosome 11
101
What is insulin produced by and where?
B cells in the Islets of Langerhans in pancreas
102
Function of FSH
Stimulates oestrogen release
103
Function of LH
Stimulates release of egg = stimulates progesterone release = increased thickening of uterine wall
104
Effect of LH in men
On Leydig cells = testosterone release
105
Function of growth hormone (GH)
- stimulates growth and protein synthesis
- stimulates gluconeogenesis
- inhibits insulin
(inc. glucose)
- lipolysis
- inc. protein synthesis in liver = stimulates IGF-1
106
What is measured to reflect GH levels?
Insulin-like growth factor 1 (IGF-1)
107
Function of ACTH
Stimulates release of cortisol, androgen and adrenaline
108
Where is cortisol secreted from?
Zona fasiculata
109
Where are androgens released from?
Zona reticularis
110
Where is adrenaline released from?
Adrenal medulla
111
Effects of cortisol
- regulates and breaks down proteins / fats / carbs
- anti-inflammatory effect
- lowered immune response
- overcomes stress
112
Name a disease where death would result from lack of cortisol
Addison's
113
Function of TSH
- stimulates release of thyroid hormone
| - prolactin release
114
Functions of thyroid hormone
- controls metabolic reactions
- inc. food metabolism
- inc. protein synthesis
- stim. carb metabolism
- inc. ventilation rate/ CO / HR
- growth rate acceleration
- brain development in foetus
115
Effect of thyrotropic releasing hormone (TRH)
TRH -> TSH -> inc. release of T3 and T4 from thyroid -> inc. metabolism
116
Effect of GnRH
GnRH -> LH & FSH -> targets gonads -> inc. oestrogen, progesterone and testosterone
117
Effect of GRHR
GHRH -> GH -> stimulates growth and protein synthesis
118
Effect of somatostatin
Somatostatin -> inhibits GH - > inhibits growth and protein synthesis
119
Which hormone inhibits growth hormone?
Somatostatin
120
Effect of CRH
CRH -> ACTH -> increases cortisol production in adrenal cortex from zone fasiculata
121
Effect of dopamine
Inhibits prolactin -> inhibits growth and milk production
122
What can hyperglycaemia result in?
Serious microvascular & microvascular problems
123
3 microvascular problems of diabetes mellitus
1. Retinopathy
2. Nephropathy
3. Neuropathy
124
4 microvascular problems of diabetes mellitus
1. Strokes
2. Renovascular disease
3. Limb ischaemia
4. Heart disease
125
Normal blood glucose levels
3.5-8.0mmol/L
126
Effect of glucagon
- increases hepatic glucose output
- reduces peripheral glucose uptake
- stim. peripheral release of gluconeogenic precursors
- stim. lipolysis & ketogenesis
127
Why is there a high level of C peptide in blood when insulin is released?
Because proinsulin is cleaved from C peptide
128
Difference between synthetic insulin and natural
Synthetic insulin has no C peptide
| - presence of it can determine whether insulin is natural or not
129
Name of transporters that carry goose across membranes
GLUT proteins - specialised glucose transporter
130
How many types of GLUT proteins are there?
4
131
Function of GLUT 1
Enables basal non-insulin stimulates glucose uptake
132
Characteristic and function of GLUT 2
- low affinity transporter (allows glucose in when glucose conc. is high)
- transports glucose into beta cells
133
What can GLUT2 beta cells detect?
High glucose levels
| - therefore release insulin in response
134
Where is GLUT 2 found?
In beta cells of pancreas
| - also found ion renal tubules and hepatocytes
135
Function of GLUT 3
Enables non-insulin mediated glucose uptake into brain neurones and placenta
136
Function of GLUT4
- Mediates peripheral action of insulin
- enables glucose uptake into muscle and adipose tissue
(following stimulation of insulin receptor)
137
What kind of protein is the insulin receptor?
Glycoprotein
138
Where is insulin receptor coded for?
Short arm of Chromosome 19
139
What results when insulin binds to receptor
- activation of tyrosine kinase
| - imitation of cascade response
140
Consequence of cascade response
Migration of GLUT4 to cell surface
| =increased transport of glucose into cell
141
What might diabetes be secondary to?
- pancreatic pathology
- endocrine disease (acromegaly / Cushing's)
- drug induced
- maturity onset diabetes of youth (MODY)
142
Drugs that may cause secondary diabetes
- thiazide diuretics
| - corticosteroids
143
Describe MODY
- autosomal dominant form of type 2
- single gene defect
- alters beta cell function
- presents <25 years with positive family history
144
Define type 1 diabetes mellitus (DM1)
Disease of insulin deficiency usually caused by autoimmune destruction of beta-cells in pancreas
145
What is insulitis?
Anti-bodies forming against insulin and islet beta cells
146
Genetic susceptibility to DM1
1. HLA-DR3-DQ2
| 2. HLA-DR4-DQ8
147
Other autoimmune diseases associated with DM1
- autoimmune thyroid
- coeliac disease
- Addison's
- pernicious anaemia
148
Environmental risk factors for DM1
- dietary constituents
- enteroviruses (Coxsackie B4)
- vit D deficiency
- cleaner environment
149
Symptoms of DM1
- glycosuria
- ketonuria
- impaired glucose clearance in skeletal muscles/fats
- polyuria
- polydipsia (excess thirst)
- thin
150
Define diabetes mellitus type 2
Combination of increased insulin resistance and less severe decreased insulin deficiency
151
Risk factors for DM2
- obesity
- family history
- inc. age
- ethnicity (Middle Eastern/ sE Asian)
- environment
152
What is DM2 associated with?
- central obesity
- hypertension
- hypertriglycerideaemia
- decreased HDL
- inc. in number of pro-inflammatory markers
- inc. CV risk
153
Where does insulin resistance develop?
Post insulin receptor
| - so DM2 is not a problem with insulin binding
154
Beta cell mass at time of diagnosis of DM2
50% of the normal
155
What do DM2 patients show at autopsy?
Amyloid deposition in islets of the pancreas
156
Early sign of DM2
Loss of first phase of biphasic response to insulin
157
Describe the Starling curve of the pancreas
- circulating inulin levels are high
- increase further
- decline again after months / years (due to secretory failure)
158
What does DM2 typically progress from?
Preliminary phase of impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
159
Fasting plasma glucose level in IGT
<7mmol/L
160
Fasting plasma glucose level in IFG
>6.1mmol/L
<7mmol/L
(6.1-7)
161
Oral glucose tolerance of 2 hours glucose
>7.8mmol/L
| < 11 mmol/L
162
Clinical presentation of DM2
- overweight in abdomen
- polydipsia
- polyuria
- weight loss
- ketosis (v advanced DM2 with absolute insulin deficiency)
163
Acute presentation of DM1 (2-6 weeks)
1. Polyuria & nocturia
2. Polydipsia
3. Weight loss
164
Reason for polyuria and nocturia in DM
- kidneys are at renal max reabsorptive capacity
- not enough glucose reabsorbed in kidneys
= high levels of glucose in tubule urine
165
Reason for polydipsia in DM
Loss of fluid and electrolytes from excess glucose & water in urine
166
Reason for weight loss in DM
Fluid depletion & accelerated breakdown of fat and muscle
- secondary to insulin deficiency
167
Subacute presentation of DM (months - years)
- polyuria
- polydipsia
- weight loss
- lack of energy
- visual blurring
- pruritus vulvae
168
Complications of DM as a presenting feature
- staphylococcal skin infection
- retinopathy
- polyneuropathy
- erectile dysfunction
- arterial disease (MI or peripheral gangrene)
169
Physical examination of DM
- weight loss / dehydration
- breath smells of ketones
- retinopathy
- acanthosis nigricans (in patients with severe insulin resistance) - black pigmentation at nape of neck & axillae
170
Diagnostic values for diabetes
1. Random plasma glucose >11.1mmol/L
2. Fasting plasma glucose >7mmol/L
3. HbA1c > 48mmol/L (>6.5%)
171
Is one abnormal test value diagnostic?
Yes - in symptomatic patients
| No - in asymptomatic patients (two abnormal values needed)
172
Diagnostic tests for diabetes
1. Screen urine (microalbuminaemia)
2. FBC / U&E / liver biochem / fasting blood for cholesterol /triglycerides
3. Raised blood pH = metabolic acidosis
173
Describe a good glycaemic control in a good diet
- low in sugar
- high in starchy carbs (low glycemic index - pasta)
- high in fibre
- low in fat
174
Treatment of DM 1 and 2
- maintain lean weight
- stop smoking / alcohol
- regular physical activity
- ACEI to treat hypertension
- statins to treat hyperlipidaemia
175
Treatment of DM1
- synthetic human insulin (SC injection)
- change injection site (prevent lipohypertrophy)
- finger pricking glucose before and after meal
176
What is the legal requirement for someone on insulin?
Inform DVLA
| - frequent hypoglycaemic events may be unfit to drive
177
How many types of insulin are there for DM1? What are they?
3:
- short acting (soluble) insulins
- short acting insulin analogues
- long acting insulins
178
How long does it take for short acting insulins to start working?
30-60 minutes
179
How long do short acting insulins last?
4-6 hours
180
When are short acting insulins given?
- 15-30 minutes before meals in patients on multiple dose regimens
- continuous IV in labour / medical emergencies / surgery / using insulin pumps
181
Examples of human insulin analogies
- insulin aspart
- insulin lispro
- insulin glulisine
182
Describe onset and duration of human insulin analogies
- fast onset
| - short duration
183
What kind of patients are given human insulin analogies? Why?
- those who are prone to nocturnal hypoglycaemia
| - have reduced carry-over effect compared to soluble insulin
184
What are longer acting insulins mixed with?
Retarding agents precipitate crystals
| e.g protamine / zinc)
185
How long do longer acting insulins work for?
Intermediate (12-24 hours)
| Long-acting ( >24 hours)
186
What are protamine insulins known as?
Isophane or NPH insulins
187
What are zinc insulins known as?
Lente insulins
188
What is insulin glargine? (long lasting insulins)
Structurally modified insulins that precipitates in tissues
| - slowly released from injection site
189
Complications of insulin treatment
- hypoglycaemia
- lipohypertrophy (injection site)
- insulin resistance
- weight gain (hunger)
190
First line treatment of DM2
- lifestyle & dietary changes
- nutrient load spread through day (3 main meals)
- BP control
- hyperlipidaemia control
- exercise / weight loss
- orlistat
191
What does orlistat do?
Intestinal lipase inhibitor
- reduces absorption of fat from diet
- promotes weight loss
192
Second line treatment of DM2
```
- oral metformin
If HbA1c > 53mmol/L 16 weeks later:
- add sulfonylurea (oral gliclazide)
If HbA1c > 57mmol/L after 6 months:
- insulin might be needed
- GLITAZONE
- glucagon like peptide analogues (GLP)
```
193
Effects of metformin
- reduces gluconeogensis in liver
- increases sensitivity of cells to insulin
- weight loss
- reduces CVS risk
194
Side effects of metformin
- anorexia
- diarrhoea
- nausea
- abdo pain
195
Contraindications of metformin
- heart failure
- liver disease
- renal disease
(can induce lactic acidosis)
196
Effects of gliclazide
- promotes insulin secretion
- avoided in pregnancy
- used with care in people with liver disease
197
When is gliclazide ineffective?
Without a functional beta-cell mass
| effect wears off as beta cell mass declines
198
Side effects of gliclazide
- Hypoglycaemia
- promote weight gain
(avoided in overweight patients)
199
Effect of glitazones
Replaces metformin and sulfonylurea
| - increase insulin sensitivity
200
Side effects of glitazone
- hypoglycaemia
- fractures
- fluid retention
201
Contraindications of glitazone
- congestive heart failure
| - osteoporosis
