Endocrinology Flashcards
1
Q
Endocrine Hormones
A
Adrenaline - Fast Acting, GPCR
Growth Hormones - Slow TKLR
The same hormone can have different effects on different cells via specific receptors.
Have an effect on low concentrations
Action terminated via -ve feedback loop
2
Q
Autocrine Chemicals
A
Cytokines
Act within the same cell which they were synthesised
3
Q
Paracrine Chemicals
A
Histamine
Act local to the synthesis - Diffuse through ECF
4
Q
Exocrine Chemicals
A
Act through ducts of exocrine glands to external environment. eg. Glands
5
Q
Insulin
A
Increases/Decreases Gluconeogenesis in Liver
Increases uptake of Glucose in skeletal muscle/adipose
6
Q
Types of Endocrine Hormones
A
Peptide/Protein - Amino Acids
Steroids - Cholesterol
Amines - 2 AA Tyrosine, Tryptophan
7
Q
Peptide Hormone Synthesis
A
Preprohormone - Synthesised by Ribosomes
Cleaved in RER to Prohormone
Prohormones are packed into vesicles with proteolytic enzymes into Golgi Apparatus where broken into Hormones and fragments stored in Endocrine cells
Measuring inactive fragments in plasma can be useful clinically e.g. C-peptide (insulin) in diabetes
8
Q
Steroids Hormone Synthesis and transport
A
Highly Lipophilic - Synthesised When needed
Carried through ISF by binding to carrier proteins such as Albumin protects from enzymatic degradation. Carriers can also be specific
eg. corticosteroid binding to globulin
receptors are located inside cells (cytoplasmic or nuclear receptors) and trigger either activation or repression (inhibition) of gene function within the nucleus = genomic effect.
Increasing / Decreasing protein synthesis
9
Q
Permissive Effect of Hormones
A
Thyroid Hormone doesn’t have an effect on its own to lipolysis but it has an additive effect to the function of epinephrine. Together causing a greater effect than the one epinephrine would have by itself
10
Q
Short Half Life Hormones
A
Catecholamines and Peptide Hormones
Excreted through kidneys and liver
11
Q
Non-tropic hormones
Tropic hormones
A
Hormones directly stimulate target cells - PP - Blood
Act on another endocrine gland - AP - Capillaries
12
Q
Pituitary Hormones and their targets
A
Tropic
FSH + LH - Testes/Ovaries
TSH - Thyroid
ACTH - Adrenal Cortex
Non Tropic
MSH - Melanocytes
Prolactin - Mammary Glands
GH - Liver, Bones (Non Tropic + Tropic)
13
Q
How is the hypothalamus connected to posterior pituitary gland
A
Infundibulum
14
Q
Anterior Pituitary Hormones
All Tropic (control secretion of other endocrine glands) Except Prolactin
A
Thyroid Stimulating Hormone (TSH) - thyrotropin Adrenocorticotrophic Hormone (ACTH) - corticotropin
Gonadotropins Follicle Stimulating Hormone (FSH) Luteinising Hormone (LH) Growth Hormone (GH)
Prolactin directly stimulates milk production from the breast during lactation
15
Q
short Feedback loop
long Feedback loop
direct feedback from physiological response
A
anterior pituitary to hypothalamus
endocrine target cell upwards
PTH (independent of pituitary control).
16
Q
Leptin
A
Peptide hormone released by fat stores which depresses feeding activity
17
Q
Normal range of [BG] =
Hypoglycaemia =
A
4.2-6.3mM (80-120mg/dl)
[BG] < 3mM olic
18
Q
Enterokinase
A
converts trypsinogen to trypsin
19
Q
Proteases Nucleases Elastases Phospholipases Lipases α-Amylase
A
Cleave peptide bonds Hydrolyse DNA/RNA Collagen digestion Phospholipids to fatty acids Triglycerides to fatty acids+ glycerol Starch to maltose + glucose
20
Q
4 types of islet cells in Pancreas + Functions
A
A cells produce GLUCAGON
B cells produce INSULIN
Delta cells produce SOMATOSTATIN (slows down absorption to prevent exaggerated plasma peaks)
F cells produce pancreatic polypeptide
may help control of nutrient absorption from GIT
21
Q
Insulin
A
Increase Oxydation
Decrease BG - G taken up by cells
Increases Glycogen synthesis in muscle and liver. Stimulates glycogen synthase and inhibits glycogen phosphorylase.
Inhibits the enzymes of gluconeogenesis in the liver
Increases amino acid uptake into muscle, promoting protein synthesis. Inhibits proteolysis
Increases triacylglycerol synthesis in adipocytes and liver i.e. stimulates lipogenesis and inhibits lipolysis.
Has a permissive effect on Growth Hormone
Promotes K+ ion entry into cells by stimulating Na+/K+ ATPase.
22
Q
GLUT-1, GLUT-3
GLUT-2
GLUT-4
A
Basal glucose uptake in many tissues
eg. Brain, Kidney and RBC’s
B-cells of pancreas and liver (NOT insulin dependent)
*Glucose conv. to G6P by hexokinase keeping ICG low
Muscle and Adipose Tissue ONLY tissues which are insulin sensitive
23
Q
Stimuli which increase insulin release
A
- Increased [BG]
- Increased [amino acids] plasma
- Glucagon (stimulates insulin to take up glucose created via gluconeogenesis)
- Incretin hormones controlling GI secretion and motility eg. gastrin, secretin, CCK, GLP-1, GIP.
- Vagal nerve activity
24
Q
Stimuli which inhibit insulin release
A
- Low [BG]
- Somatostatin (GHIH)
- Sympathetic a2 effects
- Stress e.g. hypoxia
25
Stimuli that promote glucagon release
Low [BG]
*High [amino acids]. Prevents hypoglycaemia following insulin release in response to aa
Sympathetic and epinephrine, b2 effect, Cortisol
Stress e.g. exercise, infection
26
Stimuli that inhibit glucagon release
Glucose
Free fatty acids (FFA) (Lipolysis) and Ketones
Insulin
Somatostatin
27
DMT2 Treatment
Restore insulin sensitivity of tissues with exercise and dietary change
Oral hypoglycaemic drugs eg. Metformin (inhibits hepatic gluconeogenesis and antagonises glucagon)
Sulphonylureas act by closing the K ATP in b cells and
stimulating Ca2+ entry and insulin secretion
28
90 mg/dl to mM
900 mg/L
/180 mM = 5
90 mg/dl / 18 = 5
29
Development of Type 1 Diabetes
Genetic Predisposition plus
Trigger (Viral Infection) /
Auto-Immunity (HLA) - Auto-digestion
Autoimmune attack on islet cells – lymphocyte infiltration of islets (insulitis) – destruction of B cells
30
Insulin controls intracellular processes
ADIPOSE TISSUE - Reduced lipolysis
LIVER - Reduced glucose production
MUSCLE - Increased glucose uptake
31
Type 1 DM
Signs
```
Ketones on breath
Dehydration
Increased respiratory rate, tachycardia, hypotension.
Low grade infections, thrush / balanitis
Linked to other Autoimmune Diseases
```
32
Type 1 DM
Symptoms
```
Thirst
Tiredness
Polyuria / Nocturia
Weight loss
Blurred vision
Abdominal pain
```
33
Type 2 DM
Signs
Not ketotic, May have NO Symptoms
*Usually overweight but not always
Low grade infections, thrush / balanitis
*May have micro vascular or macrovascular Cx
34
DM Screening Risk Factors
Overweight
Family history
Over age 30 years if Maori ⁄ Asian
Over age 40 years if European
History of Gestational Diabetes
Had a big baby (more than 4 kg)
Inactive lifestyle, lack of exercise
Previous high blood glucose
35
MODY: Maturity Onset Diabetes in the Young
Autosomal dominant - single gene defect (5% diabetics)
Impaired beta-cell function
Glucokinase mutations
- Birth, Stable Hyperglycaemia, NO Cx
Transcription factor mutations
- Young, Progressive Hyperglycaemia, Cx Frequent
HNF-1a, HNF-1b, HNF-4a
36
Secondary Diabetes
Drug therapy e.g corticosteroids
Pancreatic destruction, Chronic pancreatitis, Pacreatectomy, Cystic fibrosis
Haemochromatosis- excess iron deposition
Rare endocrine disorders e.g. Cushings syndrome, Acromegaly, Pheochromocytoma
37
Gestational diabetes- Hyperglycaemia of pregnancy
Increasing insulin resistance in pregnancy
Develops 2nd / 3rd trimester
Associated with FH of Type 2 diabetes
More common if overweight and inactive
Increased risk of Type 2 diabetes later in life
Neonatal problems: macrosomia / respiratory distress / neonatal hypoglycaemia
38
Diagnosing Diabetes
ONE diagnostic lab glucose plus symptoms
TWO diagnostic lab glucose / HbA1c levels without symptoms (HbA1c ≥ 48 mmol/mol)
Glucose levels in venous plasma
- Fasting > 7.0 mmol/l, Random > 11.1 mmol/l
OGTT BG > 11.1 mmol/l 2h after 75g CHO
39
Steroid Hormone Action
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell
Steroid hormone receptors are in cytoplasm or nucleus.
Some bind to membrane receptors that use second messenger systems to create rapid cellular responses.
The receptor-hormone complex binds to DNA and activates or represses one or more genes.
Activated genes create new mRNA that moves back to the cytoplasm. Translation produces new proteins
for cell processes.
40
Amine Hormones derived from Tyrosine
| Catecholamines
Dopamine from the brain
Norepinephrine from neurons
Epinephrine from the adrenal medulla
Similar mechanism of action to peptide hormones (hydrophilic)
41
Amine Hormones derived from Tyrosine
| Thyroid hormones
Thyroxine T4
Triiodothyronine T3
Similar mechanism of action to steroid hormones (lipophilic)
42
Amine Hormones derived from Tryptophan
Melatonin which regulates circadian rhythm
43
Pathophysiology of Type 2 DM
Failure of the B cells to meet an increased demand for insulin in the body.
1) Reduced tissue sensitivity to insulin (insulin resistance caused by central adiposity) due to
Free Fatty Acids (more and more insulin is released to stimulate the receptors)
2) Inability to secrete very high levels of insulin due to genetic predisposition. Genes involved in causing inadequate ‘high level’ insulin secretion by B cells
44
DM Cx
Macrovascular
Coronary heart disease
Myocardial infarction
Atherothrombotic stroke
Microvascular
45
Human Leukocyte Antigen (HLA) molecules
Molecules that help T cells recognise self from non-self
46
Arteriolar Disease - Hyaline Change
Trapped molecules below endothelial wall thicken the basal lamina. Arteriole is thickened, lumen narrower.
Narrow arteriole - poor blood flow - ischaemia
47
Small vessel disease
Capillaries
Increased connective tissue around capillaries
eg. Glomerulus in kidney
Glucoses added to proteins = Glycosylation
- Non-enzymatic, Reversible at 1st
- Irreversible if covalent bonds = Advanced Glycosylation End-products = AGE’s
Albumin can sometimes get into subendothelial space
48
Peptide and catecholamine hormones:
Water soluble, transported in solution in the plasma.
Vulnerable to degradation before reaching target.
have a short half-life in the plasma, usually minutes.
Prolonged action therefore requires continued secretion.
49
Steroid (AND thyroid) hormones
Lipophilic, once made they diffuse across the cell membrane into the blood.
Circulate in plasma bound to specific transport plasma proteins (eg thryoxine-binding globulin, or albumin) so have longer half-life, usually hours to days.
Alter protein synthesis via modifying gene expression thus effect also persists for hours to days.
50
- ve Feedback Reflex in Endocrine
| eg. Parathyroid Hormone
Increased plasma Ca+
Parathyroid cells are stimulated releasing parathyroid hormone which stimulates
Bone resorption,
Calcitrol production - Ca intestinal reabsorption
Increased Kidney reabsorption
51
Surgical Weight Loss Techniques
Adjustable Gastric Bypass
Sleeve Gastrectomy
Laparoscopic Gastric Bypass
52
Glucose counter-regulatory control system
Includes epinephrine, cortisol and GH
G-protein coupled receptors
adenylate cyclase/cAMP
53
Growth Hormone action in cartilage formation through IGF-I/II
Insulin-like growth factor-I (IGF-1) aka somatomedin C; released by liver and controls GH release via -ve feed.
IGF-II also exists but limited to the foetus and neonate
```
Cell size (hypertrophy) and Cell division (hyperplasia)
GH stimulates chondrocyte precursor in the epiphyseal plates. Cells begin to secrete IGF-I.
```
Acts as an autocrine or paracrine agent
Produce cartilage, the foundation for bone growth.
Osteoblasts lay down bone on top of cartilage
54
GH Functions
Increases *muscle, liver and adipose tissue amino acid uptake and protein synthesis = anabolic effect (cortisol stimulates protein catabolism).
Increases gluconeogenesis by the liver
Reduces the ability of insulin to stimulate glucose uptake by muscle and adipose tissue. Brain and Bone are still able to absorb glucose since they are not insulin sensitive. Muscle grows through aa.
Makes adipocytes more sensitive to lipolytic stimuli.
It is having an “anti-insulin” effect and synergises with cortisol in this respect. GH is diabetogenic
Majority of GH released during first 2 hours of sleep (deep delta sleep)
55
Stimuli that increase GHRH secretion (Increase GH):
Actual or potential increase in energy supply to cells
Increased amounts of amino acids in the plasma
Stressful stimuli
Delta sleep
Oestrogen and androgens
56
Stimuli that increase GHIH (Somatostatin secretion)
| (Decrease GH):
Glucose
FFA
REM sleep (Subjects deprived of REM sleep have increased GH secretion)
Cortisol (although inhibitory effect on growth may be more to do with increase protein catabolism than stimulating GHIH release)
57
Thyroid Hormones
Development of nervous system in utero and early childhood.
Ossification of cartilage, teeth maturation, contours of the face and the proportions of the body.
58
Cretinism
Condition where children are hypothyroid from birth. Retain infantile facial features = hypothyroid dwarf
59
Hypersecretion of GH
| Endocrine tumours usually the cause
Gigantism: XS GH due to a pituitary tumour before epiphyseal plates of long bones close
Acromegaly: XS GH due to a pituitary tumour after epiphyseal plates have sealed. Characteristic features are enlarged hands and feet.
In adults feet should NOT get bigger - Surgery to remove tumour or somatostatin analogues to treat.
60
Hypocalcaemia
Hypo-osmolarity IC - Increases neuronal Na+ permeability leading to hyperexcitation of neurons.
TETANY / if in larynx + respiratory muscles-asphyxiation.
61
Hypercalcaemia
Decreases neuronal Na+ permeability which will reduce excitability and depress neuromuscular activity and trigger cardiac arrhythmias.
62
Secretion of PTH
Released in response to decrease in free [Ca2+] plasma Acts to increase free [Ca2+] plasma by:
1. Stimulating osteoclasts to increase resorption (release) of Ca2+ and phosphate in bone (effects seen within 12-24hrs)
2. Inhibiting osteoblasts to reduce Ca2+ deposition in bone.
3. Increasing reabsorption of Ca2+ from the kidney tubules, therefore decreasing its excretion in the urine.
4. Increasing renal excretion of phosphate. This elevates free [Ca2+ ] by preventing it from being deposited back into bone, a process that requires phosphate.
5. Stimulates the kidney to synthesise calcitriol from vitamin D which promotes calcium absorption at the gut and kidney.
63
Calcitriol
Complements action of PTH - increase [Ca2+ ]plasma
A steroid hormone produced in liver, kidneys from dietary vitamin D or from precursors activated by sunlight on skin. Also stimulated by prolactin in lactating women (increased demand for milk).
Active vitamin D3 is formed from cholesterol derivatives by the action of UV light on the skin and diet.
64
Calcitonin
Action: Decrease [Ca2+] plasma
Peptide hormone produced by the thyroid gland, its secretion is stimulated by increased [Ca2+] plasma
Bind to osteoclasts and inhibit bone resorption as well as increase renal excretion
XS calcitonin effect is overridden by PTH, no pathology
Used to treat Paget’s disease (overactive osteoclasts).
65
Cortisol
Insulin
Oestrogen
Growth Hormone
Prolactin
Inhibits osteoblasts, increases renal excretion of Ca2+ and phosphate and reduces intestinal absorption of Ca2+ This with the reduced bone formation -- osteoporosis
Increases bone formation, antagonises the action of cortisol. Diabetics may have significant bone loss.
Promotes bone formation via oestrogen receptors on osteoblasts. Post-menopausal osteoporosis.
Constant stimulus for bone formation.
Promotes calcium absorption from the gut by stimulating synthesis of calcitriol
66
DHEA dihydroepiandrosterone
pre-hormone of testosterone and oestrogen.
| Marked decline with age.
67
Cortisol Glucocorticoid Actions
Gluconeogenesis: Gluconeogenic enzymes in liver
Proteolysis: breakdown of muscle protein
Lipolysis: in adipose tissue which increases [FFA] plasma creating an alternative fuel supply that allows [BG] to be protected while also creating a substrate (glycerol) for gluconeogenesis.
Decreases insulin sensitivity of muscles, adipose tissue.
68
Cortisol non Glucocorticoid Actions
Negative effect on Ca2+ balance: decrease absorption from gut, increases excretion at kidney resulting in net Ca2+ loss. Increased bone resorption - osteoporosis
Impairment of mood and cognition: depression and impaired cognitive function are strongly associated with hypercortisolaemia.
Permissive effects on norepinephrine: particularly in vascular smooth muscle - vasoconstrictive
Cushings Disease (hypercortisolaemia) is strongly associated with hypertension. low levels - hypotension
Suppression of the Immune System: Cortisol reduces the circulating lymphocyte count, reduces Ab formation and inhibits the inflammatory response. Useful clinically e.g. asthma/ulcerative colitis/organ transplant.
69
Aldosterone Increase or Decrease
Increased aldosterone release stimulates Na+ (and H2O) retention and K+ depletion, resulting increased blood volume and increased blood pressure.
Decreased aldosterone leads to Na+ (and H2O) loss and increase [K+] plasma, resulting in diminished blood volume and decreased blood pressure.
70
Pheochromocytoma
Rare neuroendocrine tumour, found in adrenal medulla which results in XS catecholamines:
Increased HR - CO - BP
Diabetogenic due to adrenergic effect on glucose metabolism. Responds well to surgery.
71
Thyroid Hormone
Raises metabolic rate and promotes thermogenesis Increase hepatic gluconeogenesis
Net increase in proteolysis and lipolysis
Critical for growth (lack of TH results in retarded growth)
Anabolic, stimulates GH receptor expression
Foetal brain development
(deficiency = congenital hypothyroidism)
Caused by dietary iodine deficiency in the mother
72
Hyperthyroidism
Graves Disease - Abs mimic TSH
Thyroid Adenoma
1. Increased metabolic rate and heat production
weight loss/ heat intolerance
2. Increased protein catabolism - muscle weaknes
3. Altered nervous system function - hyperexcitable reflexes and psychological disturbances
4. Elevated cardiovascular function. TH is permissive to epinephrine, b receptors - increased HR/contractile force, high output, cardiac failure
73
Hypothyroidism
Hashimoto’s Disease - autoimmune thyroid gland
Deficiency in dietary iodine
Idiopathic - thyroiditis
1. Decreased metabolic rate and heat production
- weight gain/cold intolerance
2. Disrupted protein synthesis - brittle nails/thin skin
3. Altered nervous system - slow speech, reflexes
4. Reduced cardiovascular function - slow heart rate
74
Thyroid Hormone Dysfunction - Goitre
Increased trophic action of TSH on thyroid follicular cells (hypothyroidism) or over-activity as a result of autoimmune disease (Graves Disease)
Hypertrophy of thyroid gland - Goitre
75
Factitious hypoglycaemia
Insulinoma
– high insulin levels in absence of elevated C-peptide concentrations.
– elevated C-peptide level indicative of insulin-secreting tumour.
76
Atherosclerosis in Diabetes
Dyslipidaemia, Triglycerides are higher
HDL Cholesterol is lower
LDL cholesterol in form of small dense particles - worse
Oxidisation of these particles promotes plaque
Endothelial dysfunction, Hypercoagulability
Ischaemic Cerebrovascular/Heart Disease
(Stroke, MI, HA, Angina)
Peripheral Heart Disease (Lower Limb Ischaemia - ulcers and poor healing of these ulcers)
77
Non Proliferative Diabetic Retinopathy
Proliferative Diabetic Retinopathy
Treatment (Microvascular)
Retinal capillary dysfunction, platelet dysfunction, blood viscosity abnormality.
Retinal ischaemia, new blood vessel formation, vitreous haemorrhage, retinal tears/detachment.
Laser photocoagulation
78
HbAc1 Test for DMT2
Do not use for
Children and young people, Pregnancy
Suspected Type 1 diabetes
Symptoms <2 months
High risk patients who are acutely ill
Patients taking medication that may cause rapid glucose rise (e.g. steroids)
Acute pancreatic damage
Presence of genetic, haematological or illness-related factors that affect HbA1c and its measurement
79
DM Monitoring
URINE TESTING - GLYCOSURIA, KETONURIA
Glucose meter monitoring of capillary blood glucose
Beware of finger contamination
Sodium, Potassium, Electrolytes, Albumin, Bilirubin, ALT
Cortisol to exclude Addison disease, adrenal insufficiency – not enough cortisol to stimulate gluconeogenesis
80
Nephropathy
Microalbuminuria - leak of protein (albumin) starts
Glomerular basement membrane changes, mesangial tissue proliferation, “glomerular hypertension” all contribute to renal dysfunction and renal failure
Paresthesia, Poor macro-vasculature, Charcot Foot
Autonomic neuropathy can cause GI effects (stomach, intestines), cardiovascular system (tachycardia, BP),
Tx: ACE inhibition, Angiotensin receptor blockade,
Renin Inhibition
81
Main substrate for formation of adrenal cortical hormones?
Cholesterol
82
Hormones that can cause abnormalities in sodium levels
Cortisol Aldosterone, Insulin, Vasopressin
83
Screening for Hypercortisolism
Confirmation of Hypercortisolism
ACTH Dependent or Independent
ACTH: Pituitary / no Pituitary
Localization
Overnight Dex test
24 hr urine Free Cortisol
24 hr urine Free Cortisol
Low Dose Dex test
Paired Morn- Midnight ACTH Cortisol
High Dose Dex test
MRI Sella, CT adrenal, BIPSS, CT Chest
84
Posterior Pituitary gland hormones
Oxytocin - milk ejection and uterine contraction
Triggered by: labour (head against cervix), suckling
Site/mode of action: Milk duct smooth muscle
- Contracts muscle, ejecting milk
Uterine smooth muscle - child birth
Vasopressin (ADH) - Regulates water balance
Triggered by: Plasma osmolarity - volume/BP
Site/mode of action:
Kidney collecting ducts - Increases water reabsorption
Vascular smooth muscle - Increases blood pressure
85
2 Types of Peptide Hormones
Water soluble so are carried in bloodstream and activate targeted tissues via modulating
GPCR (G Protein Coupled receptor) modification of existing proteins. -- Rapid response
or Tyrosine Kinase linked signalling pathways
Alters gene expression -- Slower, longer lasting activity
86
Steroid Hormones are synthesised in?
Gonads - Sex Steroids
Adrenal Cortex - Corticosteroids
Kidneys - Vit D3
Placenta - hCG, sex steroids
