ENDOCRINE

SYSTEM
Self-made Notes

Chu Kim Long Matthew

Li Ka Shing Faculty of Medicine | MBBS3010

Overview
Introduction to Hormones

v Introduction
Definition of hormones
Chemical substances that are secreted by living cells, and upon delivery by the circulation to a
specific site, act to regulate reaction that elicits a typical response endocrine mode of action
Endocrine system
Consist of
An endocrine gland
Endocrine cells in GI tract do NOT form into glands
Blood
Target organs (receptors)
Structure/synthesis
Physiological effects
Regulation of synthesis & secretion
Disorders
Causes & aetiology
Signs & symptoms
Tachycardia, palpitation
Diagnoses
Treatment
Other modes of action include
Paracrine
Acting on adjacent cells of a different kind
E.g. somatostatin
Neurocrine
Secreted at nerve endings
Autocrine
Acting on the same cell or a different cell of the same type that secretes it
E.g. T4
Neuroendocrine
Neurocrine + endocrine
E.g. SRIF (somatotropin release-inhibiting factor = somatostatin) on GH secretion
Endocrine mode of action needs more secretion than paracrine mode
E.g. hCG from the placenta acting on ovary (endocrine) or placenta (autocrine, hCG & sex steroids
from syncytiotrophoblasts)
v Chemical structures of hormones
Peptides (e.g. glucagon) or proteins (e.g. insulin & prolactin)
Biosynthesis involves the formation of preprohormone prohormone mature hormones
which are packaged in the Golgi apparatus into secretory granules
Constitutively secreted not in granules
Steroids
E.g. cortisol
Not stored to any extent
Amines, derivatives of amino acids
E.g. adrenaline, thyroxine from tyrosine
Prostaglandins & cytokines (local hormones)
May also have endocrine actions
E.g. TNF- on RBC production

v Plasma levels and metabolic clearance
The concentration of a hormone in the blood is a function of BOTH
Rate of production/secretion
Rate of clearance/removal from the plasma
Inactivation by liver or target organ
Excretion by kidney
Metabolic Clearance Rate (MCR)
Definition
Volume of plasma completely cleared of a hormone per unit time
Related to
Half life
Adrenaline T4 Cortisol 25-(OH)-D3 Insulin Somatomedin C (IGF-1)
2 minutes 7 days 70-90 minutes 15 days < 10 minutes ~ 20 hours
Binding to blood proteins
Binding MCR half-life
Thyroid hormones & steroid hormones are bound to plasma proteins
Peptides & protein hormones are generally NOT bound to plasma proteins
EXCEPT somatomedin (insulin-like growth factor, IGF)
Duration for hormone action
Minute-to-minute regulation (homeostasis) & rapid actions short half-lives
E.g. adrenaline, vasopressin
Prolonged actions (e.g. growth and development) long half-lives
E.g. thyroxine
v Rhythms of secretion
Episodic secretion
Many hormones are not secreted continuously, but in pulses
Constitutive secretion
Stimulated secretion
Amount secreted depends on
Frequency of the pulses
Magnitude of the pulses
E.g. LHRH, insulin
Continuous exposure desensitization of receptors prevent down-regulation of receptors
Diurnal rhythm
E.g. cortisol secretion is highest in the morning and lowest in the evening
Cyclic secretion
Some are secreted in complicated cycles coinciding with reproductive events
E.g. LH, FSH and oestrogens
v Negative and positive feedbacks
Negative feedback
Output decreases input (change in opposite direction)
Keep the level more or less constant important for homeostasis
Positive feedback
Output increases input (change in the same direction)
Make the level deviate more & more from norm important for amplification of level for action
v Hormone-receptor relationship
The relationship between bound and free hormones
The Scatchard plot
Dissociation (Kd) constant
Association (Ka) constant
Maximum binding (Bmax)
v Mechanisms of hormones actions
Mobile receptor model
E.g. steroid hormones, thyroid hormones
Receptors in the cytosol or nucleus
Responses depend on genomes activated or inactivated
E.g. cortisol
Liver increase protein synthesis
Lymphocytes inhibit glucose uptake
Fixed receptor model
E.g. peptides, catecholamines
Receptors on plasma membrane
Responses depend on proteins phosphorylated
E.g. glucagon
Liver phosphorylase glycogenolysis
Fat lipase lipolysis
Mechanisms involved
Adenylyl cyclase cAMP (PKA)
Calcium binding to calmodulin
Diacylglyceride & inositol triphosphate (PKC)
Tyrosine kinase insulin
Janus kinase phosphorylation of STATs GH
Same hormone/different receptors, e.g. vasopressin (ADH)
V1 receptor diacylglyceride/IP3 vasoconstriction
V2 receptor cAMP renal water reabsorption
Multiple receptors
E.g. thyroid hormones
Receptors may be found in the nucleus, plasma membrane, and/or mitochondria
Dependent on target tissue
v Endocrine disorders
Classification
Hyposecretion VS hypersecretion
Primary VS secondary
Primary disorders
The gland that secretes the hormone is involved (either tissue destruction or tumour)
Secondary disorders
The cause lies outside the gland that secretes the hormone usually of pituitary origin
E.g. abnormal pituitary ACTH secretion for the adrenal cortex
EXCEPT
Secondary hyperaldosteronism (due to blood volume)
Secondary hyperparathyroidism (due to vitamin D)
Effect SMALLER than primary disorders
Causes
Hyposecretion
Autoimmune diseases (thyroid, adrenal, pancreas, parathyroid) e.g. hypoparathyroidism
Hypersecretion
Tumour (pituitary, thyroid, adrenal, parathyroid) e.g. acromegaly
Ectopic (ACTH) e.g. ectopic ACTH syndrome
Iatrogenic
E.g. Cushing syndrome
Examples of multiple endocrine deficiencies Examples of multiple endocrine neoplasia (MEN) Type I
Parathyroid, thyroid & pancreatic islets Parathyroid, -pancreatic islets, pituitary & adrenal cortex
 Clinical features (signs & symptoms related to effects of too much or too little hormone secretion)
E.g. Thyrotoxicosis
Signs
Objective, as perceived by the doctor
E.g. tachycardia
Symptoms
Subjective, as perceived by the patient
E.g. palpitation
NOT ALL clinical features of an endocrine disorder are found in all patients suffering from that
disorder depends on
Severity of disorder (extent of hyposecretion or hypersecretion)
Compensatory mechanism (response from other systems)
Sometimes only a small percentage of the patients will have the clinical feature as a result
of compensatory mechanisms, e.g.
Hyperglycaemia in acromegaly (compensation by an increase in insulin secretion)
Congenital adrenal hyperplasia (CAH) 21-hydroxylase & aldosterone deficiency
loss of water & sodium (compensation by an increase in ACTH secretion, renin etc.)
Different endocrine disorders may lead to similar clinical features
E.g. hyperglycaemia, muscle weakness, polyuria
Same clinical feature may be due to different mechanisms
E.g. muscle weakness may be due to
Electrolyte disturbance
E.g. K+ in hyperaldosteronism, Ca2+ in primary hyperparathyroidism
Breakdown of muscle proteins
E.g. thyrotoxicosis, Cushings syndrome
Hypersecretion and hyposecretion of the same hormone may lead to similar symptoms
Too much cortisol causes muscle weakness by breaking down muscle protein
Too little cortisol by decreasing the release of acetylcholine at the neuromuscular junction
Nor the actions of the same hormones the same at all levels for some hormones
E.g. T4, adrenaline
Diagnoses
Physical examination
Biochemical tests
Stimulation test for hyposecretion
E.g. insulin hypoglycaemia
glucose GH (not or not so much in hypopituitarism) (normal > 20 ng/mL)
Suppression test for hypersecretion
E.g. glucose tolerance test
glucose GH (not or not so much in acromegaly) (normal < 0.5 ng/mL)
Other tests (radiological) X-ray, CT scan, MRI, ultrasound
Treatment
Hyposecretion
Replacement therapy
E.g. T4, insulin
Hypersecretion
Removal of tumour (glands)
Blockade of
Hormone synthesis
E.g. methimazole for T4
Hormone action
E.g. spironolactone for aldosterone
Physiological Actions of Hormones

v Introduction
BOTH secretion and level of a hormone are important
Receptor
Affect response by up or down-regulation of receptors
Receptor defect
Lack of action (e.g. ADH nehrogenic diabetes insipidus)
Peripheral resistance (e.g. T4)
The action of a hormone is only exerted by the free hormone and the bound hormone only act
as a reserve. When the free hormone is removed, more bound hormone dissociates to form the
free hormone
Thyroxine is bound to thyroxine-binding globulin
Cortisol is bound to corticosteroid-binding globulin
Sex steroids is bound to sex steroid-binding globulin
Conversion to active form is important, e.g.
T4 to T3 (liver)
25(OH) vitamin D into 1,25(OH)2 vitamin D (kidney)
Testosterone into dihydrotestosterone (prostate)
Synergistic effects
2 or more hormones act in the same direction
E.g. PTH & vitamin D on blood calcium
Antagonistic effects
2 or more hormones act in opposite directions
E.g. PTH & calcitonin on blood calcium
A hormone may be converted into an inactive form in the target organ, with the result that another
hormone may exert its action
Glucocorticoid receptors (GR)
Type I (MR)
Type II
Cortisol is converted by 11-hydroxysteroid dehydrogenase (11-HSD) to cortisone in the
kidney tubules & prevents its binding to MR loss of action allows aldosterone to become
the major mineralocorticosteroid
Mineralocorticoid activity of cortisol potency 1/500 of aldosterone
Total mineralocorticoid activity 30% due to cortisol
v Hormone-receptor relationship
Dissociation (Kd) (in pM or nM) & association (Ka) constants [ affinity of receptors] and maximum
binding (Bmax) (in fmol per mg protein) [ number of receptors] [HR]
= -KA x [HR] + KA x Ro
The Scatchard plot [H]
Increasing amounts of radioactive hormone are added to the tissue homogenate and the free
hormone (H) and bound hormone (HR) are separated by filtration or centrifugation
When [H] infinity
Y-axis ratios of bound to free hormone (HR/H)
X-axis corresponding values of bound hormone (HR) [HR]
Slope -Ka = 0 KA x [HR] = KA x Ro
[H] [HR] = Ro
Intercept on the X-axis value of Bmax
[H] + [R] [HR] Ka | [HR] [H] + [R] Kd (where H is the free hormone, [HR]
R is the free receptor and HR is the bound hormone) [H]
-KA
[HR] [HR]
= Ka = Ka x [R] = Ka x (Ro [HR]) = -Ka x [HR] + Ka x Ro (where Ro
H [R] H
is the total number of receptors) Ro
[HR] 0
When [H] infinity, = 0 Ka x [HR] = Ka x Ro [HR] = Ro
H HR
Up-regulation & down-regulation of receptors
v Some ways through which hormones act
Control of membrane permeability
Regulates the availability of substrates, ions, co-factors etc., e.g.
T4 & insulin affect glucose and amino acid transport & sodium-potassium flux
Aldosterone and vitamin D affect epithelial transport
Actions are rapid and protein synthesis is NOT involved
Nuclear regulation
Certain actions of steroid, thyroid and peptide hormones are brought about by increasing the
number of a few specific types of mRNA (polymerase II)
T4 also increases ribosomal RNA (polymerase I)
Control of protein synthesis
This can be exerted at the level of
RNA synthesis (steroids, GH and insulin)
Ribosomes (thyroxine, GH and insulin)
Cyclic AMP (cAMP) can also induce protein synthesis in some cells, either at the level of
Transcription (glucagon)
Ribosomes (ACTH)
Enzyme activation
Many effects of peptide hormones and catecholamines on intracellular enzymes involve
alternations in the activity of pre-existing enzymes by
Phosphorylation
E.g. glucagon, adrenaline cAMP activate lipase & phosphorylase
Dephosphorylation
E.g. insulin activate phosphofructokinase (glycolytic enzyme) & inactivate fructose-1,6-
bisphosphatase (gluconeogenic enzyme)
Decrease in phosphorylation may be through
Decrease in cAMP (GI protein inhibit adenylyl cyclase or stimulate phosphodiesterase)
Decrease in protein kinase A activity
Increase in phosphatase activity
Permissive action
In some cases a hormone (e.g. cortisol & T4 permissive role) has to be present for some other
hormones to work (e.g. glycogenolysis and lipolysis stimulated by glucagon and adrenaline), yet
the hormone itself does not stimulate the process may involves enzymes or receptors, e.g.
By inhibiting phosphodiesterase destroys cAMP (cortisol & T4 cannot generate cAMP)
By increasing the synthesis of adenylyl cyclase (inactive) (T4 action)
By increasing receptors for another hormone (T4 increases -adrenoceptors)
Some hormones have both direct and permissive actions
E.g. cortisol direct and permissive actions are opposite at different times
During feeding glycogenesis by increasing glycogen synthase
NO permissive action because high blood glucose level inhibits glucagon & adrenaline
secretion glucagon & adrenaline are low
In between meals (fasting) glycogenolytic effects of glucagon ( PKA) & adrenaline
via permissive action stimulate phosphorylase & inhibit glycogen synthase (push-pull)
NO direct action because the low blood glucose stimulates glucagon secretion & any
glucose-phosphate that is formed by gluconeogenesis by the action of cortisol is NOT
converted into glycogen but is released from the liver as glucose
Fast and slow actions
E.g. thyroxine and insulin
Fast actions by acting on existing molecules (transporters or enzymes)
Slow actions by increasing the numbers of molecules by protein synthesis

v Three ways to change the rate of a biochemical reaction
Change in the enzyme activity
E.g. insulin on glycolytic enzymes
Change in the level of the substrate
E.g. insulin on glycolysis by increasing glucose
Change in the level of the end-product, e.g.
Insulin stimulates glycolysis by removing acetyl CoA (remove the end-product)
Acetyl CoA malonyl CoA (1st step in FFA synthesis) [acetyl CoA FFA triglycerides]
FFA inhibits glycolysis through an increase in acetyl CoA (end-product inhibition)
ALL 3 ways can be found in the effects of T4 on oxidative phosphorylation (loose coupling)
v Increases the substrate (ADP) by stimulating the Na-K ATPase activity on the plasma membrane and
the transport of ADP (substrate) into the mitochondria
v Increases the activity of mitochondrial enzymes for oxidative phosphorylation
v Increases the transport of ATP (end-product) out of the mitochondria
v Principles of hormonal integration
Redundancy (safe-guard fine tuning)
Several hormones may affect a physiological process in the same way ensures a critical
process will take place and provides opportunity for flexibility
May have different range of actions
E.g. Adrenaline and glucagon on glycogenolysis
Glucagon on the liver ONLY, adrenaline on liver & muscle
Adrenaline increases glucagon & also directly stimulates liver glycogenolysis
May have different time constants
E.g. Adrenaline and GH on lipolysis
Adrenaline is rapid while GH is slow but long-lasting on increasing blood FFA
Reinforcement (different ways, same end)
A hormone may produce different responses in the same tissue or different tissues which
reinforce each other, e.g.
Cortisol on gluconeogenesis (different tissue)
Promotes the breakdown of proteins in muscles to release amino acids
Induces formation of liver gluconeogenic enzymes
Insulin on triglyceride storage in adipose tissue (same tissue)
Increases triglyceride uptake from blood
Increases lipogenesis from glucose
Decreases lipolysis
Push-pull mechanisms (opposite effects on antagonistic mechanisms) [one form of reinforcement]
Many critical processes are under dual control by agents that act antagonistically to either
stimulate or inhibit allows more precise regulation through negative feedback, e.g.
GRH & SRIF on GH secretion
On liver production of glucose (or sympathetic nervous system), noradrenaline & adrenaline
inhibit insulin secretion and at the same time stimulate glucagon secretion
Modulation of responding systems
Receptors hormones determine sensitivity of target tissues
Down-regulation
E.g. T4 on TRH receptor on pituitary cells
Upregulation
E.g. oestrogen on LH receptors of granulosa cells
Numbers & affinities
Sensitivity hormone level to give 50% maximal response
Post-receptor event (permissive actions)
E.g. through inhibiting cAMP destruction
v Biphasic actions of thyroid hormones
Thyroxine increases BOTH the synthesis/formation & breakdown of glycogen, proteins &
triglycerides (BIPHASIC) forms the basis for futile cycle energy is expended and heat is liberated
& oxygen consumption is increased
In the subnormal or normal range, the effects on synthesis are greater than on breakdown
E.g. Thyroxine increases protein synthesis
When the hormone is too high, the effects on breakdown are greater
E.g. Excess thyroxine increases lysosomal enzyme activity stimulates the breakdown of
muscle proteins
Actions of adrenaline (, )/noradrenaline (mainly )
Effects on cardiovascular system
Increase in cardiac output (1, heart rate & stroke volume) and blood pressure (,
vasoconstriction)
Adrenaline may also cause vasodilation (2)
Effects on metabolism ( & same direction)
Increase in glycogen breakdown in the liver and muscles
Muscle lactate
Increases gluconeogenesis
Increase in lipolysis
Effects on contraction of smooth muscle ( & opposite direction, same direction for the GI tract)
Muscle contraction ( effect)
Muscle relaxation ( effect)
v The specificity of a receptor may depend on a receptor-activity-modifying protein (RAMP)
An adrenomedullin (ADM) or calcitonin-gene related peptide (CGRP) receptor consists of 3 proteins
Calcitonin receptor-like receptor (CRLR)
Receptor-activity-modifying proteins (RAMPs)
Receptor component protein (RCP)
Co-expression of CRLR with RAMP1 terminally glycosylated mature glycoprotein & CGRP receptor
Co-expression of CRLR with RAMP2 & RAMP3 core-glycosylated immature ADM receptors






















Regulation of Endocrine Secretion

v Introduction.
Patterns of hormone secretion
Constitutive secretion
Stimulated secretion
Pulsatile secretion
Frequency & amplitude
E.g. insulin secretion
Intrinsic 15 minutes cycle
Virtually no secretion at <50 mg/100 mL plasma glucose
Stimulated secretion 3-6 minutes cycle
Modes of regulation
Humoral
Hormones, e.g.
Hypothalamic releasing factors/hormones cAMP, PKC
Anterior pituitary trophic hormones cAMP
Metabolites
E.g. glucose on insulin
Ions, e.g.
K+ depolarize opening of Ca2+ channel aldosterone (K+ on aldosterone)
Decrease in Ca2+ increase cAMP, decrease IP3 (& Ca2+) PTH (Ca2+ on PTH)
Neural
Neuroendocrine (hypothalamic hormones on posterior pituitary)
Depolarise Ca2+ influx
Autonomous nervous system (sympathetic system on adrenal medulla)
ACh depolarize Ca2+ influx
Physical
E.g. stretch of the atria increase in ANP secretion.
Negative feedback
Multiple modes of control, e.g.
Aldosterone
Potassium
Depolarise opens Ca2+ channels
Angiotensin
PLC
ACTH
cAMP PKA
Insulin
Humoral
Metabolites
E.g. glucose closes K+ channel opens Ca2+ channels
GI hormones, e.g.
Somatostatin
Glucagon, GLP-1 increase cAMP PKA
Neural
Sympathetic
-adrenergic decrease cAMP (inhibitory)
Parasympathetic
ACh CCK PKC

v General principles
Positive & negative feedback
E.g. up-regulation & down-regulation of receptors
Push & pull mechanisms
Under dual control by agents that either stimulate or inhibit more precise regulation through
negative feedback
E.g. control of GH by GRH and SRIF
GRH through Gs activates adenylyl cyclase & phospholipase (cleave phosphatidylinositol
to produce IP3 & DAG)
Somatostatin through Gi inhibits adenylyl cyclase
v Negative and positive feedback (CLOSE LOOP)
Negative feedback
The input leads to an output that results in a change in the input in the OPPOSITE direction, i.e.
decreases the input
Keep the level more or less constant important for homeostasis
E.g. blood glucose on insulin and glucagon secretion
glucose insulin glucose
glucose glucagon glucose
The set-point can be changed/adjusted or overridden, e.g. in stress
glucagon, adrenaline, cortisol & GH + insulin glucose though glucose is high
ACTH though cortisol is high (negative feedback by high cortisol dampens ACTH)
Intact 30 pg/mL Stress 100 pg/mL
ADX 100 pg/mL ADX + stress 1000 pg/mL
Positive feedback
The input leads to an output that results in a change in the input in the SAME direction, i.e.
increases the input
Make the level deviate more & more from norm important for amplification of level for action
E.g.
Haemorrhage
Loss of blood (1 L) BP BP towards normal (negative feedback)
Baroreceptor volume retention
Loss of blood (2 L) BP further BP (vicious cycle) (positive feedback)
Decrease in venous return decrease coronary blood flow toxic substances
LH
LH oestrogens LH oestrogens (negative feedback)
LH oestrogens LH oestrogens (positive feedback preovulatory LH
surge for ovulation
GnRH is omitted for simplicity GnRH or before LH or
Kisspeptin stimulates GnRH secretion (hypothalamus)
Negative feedback on the arcuate nucleus
Positive feedback on the anteroventral periventricular nucleus (at higher sex steroid
level, e.g. puberty, preovulatory LH surge)
Precocious puberty in congenital adrenal hyperplasia (CAH)
Oxytocin
Uterine contraction during labour (positive feedback)
Feedbacks are different from actions! negative actions mean that they are inhibitory while positive
actions are stimulatory
v Feed-forward control (anticipatory effect)
An anticipatory response to improve homeostasis, e.g.
glucose in GI tract secretion of GI hormone insulin secretion before blood glucose rise
Cephalic phase parasympathetic insulin secretion
v External and internal factors
External factors
The open loop (where output does not affect input)
E.g. lighting, stress, cold
Internal factors
The close loop (where output affect input)
Negative feedback, e.g. metabolites (e.g. glucose), blood pressure or volume
External factor with a feedback, e.g. suckling on oxytocin positive feedback
v Hypothalamic regulation of pituitary hormone secretion
In the pituitary, one can find examples of all kinds of control cyclic, diurnal, humoral or hormonal VS
neural, negative VS positive feedback, external VS internal factors etc.
Regulation of secretion of anterior pituitary hormones
Controlled by hypothalamic releasing and inhibiting hormones
Hypophyseal artery breaks up into capillaries that form the portal vein at median eminence
Hypothalamic releasing or inhibiting hormones released at the median eminence of the
hypothalamus into the portal blood vessels supplying the pituitary
Carried by portal blood to anterior pituitary
Secretion of hypothalamic factors controlled by neurotransmitters secreted by neurons,
which are controlled by other neuron from the CNS
The portal system is important to prevent the dilution of the hypothalamic hormones by the
peripheral circulation made possible by the proximity of the pituitary to the hypothalamus
The regulation of secretion of target gland hormones and the feedback of the latter hormones
on the hypothalamus and the pituitary are seen in
Hypothalamico-pituitary-gondal axis
Hypothalamico-pituitary-adrenal axis
Hypothalamico-pituitary-thyroid axis
Several feedback mechanisms are possible
Long-loop feedback
From target gland hormone or metabolite to pituitary/hypothalamus
E.g. cortisol on CRH (hypothalamus) & ACTH (pituitary) secretion, glucose on GH
Short-loop feedback
From anterior pituitary hormone to hypothalamus
E.g. ACTH on CRH secretion (hypothalamus), GH on somatostatin (SRIF)
Ultrashort-loop feedback
Within the anterior pituitary or the hypothalamus
E.g. GH decreases pituitary response to GRH GH secretion (somatotroph)
Positive feedback
E.g. oestrogen on LH secretion
Negative feedback changes in anterior pituitary hormone and its target gland hormone are
OPPOSITE direction in primary endocrine disorders
Deficiency target gland hormones are low while pituitary trophic hormones are high
(decrease in negative feedback), e.g. primary hypoadrenalism (cortisol , ACTH )
Excessive hormone production cortisol , ACTH
SAME direction in secondary endocrine disorders
Deficiency both pituitary tropic hormone & target gland hormone are low (low pituitary
hormone is the cause), e.g. secondary hypoadrenalism (cortisol , ACTH )
Excessive hormone production cortisol , ACTH
Regulation of secretion of posterior pituitary hormones
By action potentials travelling down the axon to the posterior pituitary
Negative feedback (long-loop), e.g. blood volume or osmolarity on ADH
Positive feedback, e.g. uterine contraction on oxytocin secretion
v The link between the environmental factors and anterior pituitary secretion
Environmental factors can act on different parts of the brain to bring about a change in the secretion
of hypothalamic releasing and inhibiting hormones via the release of neurotransmitters by neurons
that control peptidergic neurons which produce these hormones
E.g. stress via the brainstem or hippocampus secretion of acetylcholine that CRH secretion
at the median eminence carried by the portal blood anterior pituitary ACTH secretion
v Peripheral resistance
Peripheral resistance (e.g. decrease in receptors in target tissue) increase in hormone secretion
2 main mechanism
Negative feedback
Control by receptors
E.g.
Thyroid resistance
T4 receptors in the pituitary T4 action TRH receptors (T4 TRH receptors in the
anterior pituitary) ( negative feedback by T4) pituitary sensitivity to TRH TSH
secretion T4 secretion
T4 level compensates for the in receptor activity hormone levels are hyperthyroid,
but euthyroid (normal) state (no symptoms) may be maintained
Global receptor defect
Decrease in action increases hormone level to restore action to normal hyperthyroid
level but euthyroid state
Pituitary receptor defect ONLY
Hyperthyroid level and state
Insulin resistance (i.e. decrease in response to insulin)
Abnormal insulin receptors
Antagonistic hormone, e.g. cortisol blood glucose level while insulin blood glucose level
glucose uptake
gluconeogenesis
lipolysis fatty acid-glucose cycle (FFA-glucose cycle)
glucose uptake (e.g. GH, adrenaline, cortisol & T4) FFA glycolysis (mainly
muscle) blood glucose
FFA metabolism acetyl-CoA & citrate phosphofructokinase, pyruvate
dehydrogenase & hexokinase
FFA gluconeogenesis (liver) glucose output
FFA metabolism acetyl-CoA pyruvate carboxylase PEP
(phosphoenolpyruvate) gluconeogenesis from amino acids
FFA inhibit insulin signalling
Phosphorylation of insulin receptor substrate glucose uptake into muscle +
FFA uptake into muscle
Primary hyperaldosteronism
serum K+ insulin secretion










Mechanism of Action of Peptide Hormones

v Peptide hormones
Made up of amino acids
Soluble alone or in association with carrier proteins (e.g. albumin)
Enable communication between organs/tissues
Coordinate organ activities
Form a hierarchical functional network
E.g. calcitonin, glucagon, oxytocin, endorphin, adrenocorticotropic hormone & antidiuretic hormone
v How do peptide hormones regulate cellular activities? signal transduction mechanisms
The core machinery for the controlled production of an intracellular signal
Peptide hormone are charged cannot penetrate the plasma membrane (phospholipid bilayer)
interact with and bind to specific cell surface receptors
Divided into 3 domains
Extracellular domain recognize & respond to a specific peptide hormone
Transmembrane domain
Cytosolic domain production of intracellular signals (or signalling molecules)
E.g.
Seven-transmembrane receptor (G-protein coupled receptors)
Receptor with a single transmembrane region
Formation of hormone/cell surface receptor complex
Conformational change of the receptor
Activation of coupling protein
May or may not be a G-protein (an important example of coupling proteins)
Activation of effector protein (usually an enzyme)
E.g.
Adenylyl cyclase adenosine 3,5-cyclic monophosphate (cAMP)
Guanylyl cyclase guanosine 3,5-cyclic monophosphate (cGMP)
Phospholipase C Inositol 1,4,5-triphosphate (IP3) & diacylglycerol (DAG)
Production of intracellular signal
Peptide hormone rely on the production of intracellular signals (or signalling molecules)
Inactive protein + signalling molecule active protein cellular response
The more signalling molecules are produced the greater the cellular response
Uncontrolled production of signalling molecules (e.g. cancer) over response
E.g.
cAMP
cGMP The core machinery for the controlled production
IP3 & DAG of an intracellular signal
Hormonal response
Peptide hormone

Hormone/cell surface
Cell surface receptor complex
receptor

Plasma membrane

Effector protein
(usually an enzyme)

Coupling protein
Intracellular signal

Hormonal response
 G-protein coupled receptors (seven-transmembrane receptor)
G-protein mechanism is utilised by the seven-transmembrane receptors
Cytosolic domain interacts with G-protein
Mechanisms
cAMP dependent signalling pathway Phosphatidylinositol signalling pathway
Stage v G-proteins are made up of , , and subunits heterotrimeric
1 v GDP is bound to the subunit subunit remains bound to the - complex (inactive)
v Binding of the hormone molecule to the cell surface receptor formation of hormone/cell
Stage surface receptor complex conformational change of the receptor capable of acting as a
2 guanine nucleotide exchange factor (GEF) promote the exchange of GDP for GTP on G
subunit dissociation of G-protein into the subunit-GTP complex (active) and -subunits
v -subunit (GTP-bound) activates v -subunit (GTP-bound) (& -subunits in some
adenylyl cyclase (transmembrane cases) activates phospholipase-C spontaneously
enzyme) spontaneously catalyses catalyzes the cleavage of phosphatidylinositol 4,5-
Stage
the production of adenosine 3,5- bisphosphate into inositol 1,4,5-triphosphate (IP3) &
3
cyclic monophosphate (cAMP) diacylglycerol (DAG) (second messenger)
(second messenger) from adenosine IP3 releases Ca2+ from endoplasmic reticulum
triphosphate (ATP) DAG activates protein kinase C
Signal increases continuously with time overproduction of signal
G-protein mechanism on-off cycle of G-protein activity
GTPase accelerating protein (GAP) (regulator of G-protein signaling, RAS) promote
intrinsic GTPase activity of G subunit (-subunit has enzyme activity!) hydrolysis of
GTP to GDP disables the functional activity of the -subunit adenylyl cyclase
dissociates from GDP/-subunit (inactive) cAMP levels
- subunits serve to stabilize the association of GDP with G re-association of the
GDP/-subunit & - subunits and binding to GPCR
Hormone receptor complex starts another cycle of activity still NOT very helpful!!!!
Degradation of second messengers control is achieved by a careful balance between
synthesis & degradation of signalling molecules (e.g. cAMP)
Synthesis (effector protein on)
Hormone-receptor complex G-protein/adenylyl cyclase cAMP levels
Degradation (effector protein off)
cAMP phosphodiesterase catalyses hydrolysis of cAMP to AMP cAMP levels
Control time average of signal level of cAMP by altering BOTH frequency & amplitude
Receptor with a single transmembrane region
Usually possess protein-tyrosine kinase activity at cytosolic domain receptor tyrosine kinases
(RTKs)
Mechanisms
Binding of hormone dimerization receptor activation formation of receptor signaling
complexes
Self-phosphorylation of tyrosine residue near the catalytic site in the cytosolic domain of
the receptor dimer by the tyrosine kinase of each receptor monomer (ATP ADP)
(transphosphorylation)
Phosphorylation other proteins in the cytosol
Adaptor proteins binds to the phosphorylated tyrosine residues in the activated RTKs
& to phospholipase C (production of IP3 & DAG), protein kinase, protein phosphatase,
monomeric G-protein etc. production of intracellular signals
For some receptors, second messengers (IP3 & DAG) are also produced
Changes in activities of proteins in the cytosol & expression of new genes in the nucleus
bring about changes in cellular activities
Receptor activity can be regulated by dephosphorylation of phosphoproteins
 receptor signaling complexes
ligand

Adaptor proteins

PLC,
Protein kinase,
Protein phosphatase,
Ligand binding Monomeric G-protein, etc

dimerisation

P P
Production of
intracellular signals
P P

Receptor signaling complex

Regulation of intracellular signals produced by hormone receptors self-limiting
The G-protein mechanism
Degradation of second messengers
Dephosphorylation of phosphoproteins
Modulation by another receptor
Inhibition of adenylyl cyclase
Inhibitory ligand (e.g. PGE1 & adenosine) bind to receptor for inhibitory hormone
activation of inhibitory G-protein complex (Gi)
Activation of phosphodiesterase
Antagonize the actions of those receptors-induced elevation of intracellular cAMP level

v Regulation of receptor abundance
Receptor desensitisation
Binding of hormone to Gs-protein coupled receptor (GPCR) dissociation of G-protein into the
subunit-GTP complex (active) and -subunits
subunit-GTP complex (active) activation of adenylyl cyclase hormone-induced increase
in cAMP activation of cAMP-dependent protein kinase (cAPK)
-subunits (NOT cAMP) activation of -adrenergic receptor kinase (ARK) (G-protein
coupled receptor kinase (GRK))
cAPK & ARK (GRK) phosphorylated & desensitized receptor
Down-regulation of receptor by GRK-arrestin pathway
GRK phosphorylation of GPCR recruitment and binding of -arrestin
Uncouple receptors from heterotrimeric G proteins prevents G-protein-dependent
signalling even if an agonist is still present (GPCR desensitisation)
Act as adapter proteins that target GPCRs to clathrin-coated vesicles for receptor-mediated
endocytosis (GPCR sequestration) attenuation of GPCR signalling in continuous presence
of agonist (GPCR desensitisation), receptor re-sensitization & downregulation
After internalization in endosome 2 fates of GPCR
Degradation (after fusion with lysosome) receptor down-regulation
Dephosphorylation and recycling receptor re-sensitization
Receptor endocytosis
Hormone/cell surface receptor complex patching coated-pit for receptor-mediated
endocytosis formation of receptosome fusion of receptosome & lysosome degradation

v Control of hormone level
Control of synthesis & secretion of peptide hormones
Processes Occurs in/when Description
Transcription Nucleus Gene messenger RNA (mRNA)
mRNA + amino acids nascent polypeptide
Translation Ribosomes
(preprohormone)
Post-translational modification rER Preprohormone prohormone
Packaging Golgi complex Prohormone secretory vesicles
Activation Secretory vesicles Prohormone hormone
Hormone stored in the secretory vesicles are
Secretion intracellular Ca2+
secreted into bloodstream by exocytosis

v Control of cellular response towards hormones
Response with magnitude and duration determined by
Level of hormone
Control of synthesis & secretion
Intracellular signals
G-protein mechanism
Metabolism of second messengers
Receptor abundance
Modulation by other hormones
E.g. GnRH on FSH and LH release by intracellular Ca2+



Mechanism of Action of Steroid Hormones

v Key question
How steroid hormones as small hydrophobic signal molecules with subtle structural differences can
mediate diverse effects on cell differentiation and body physiology?
v Regulation of gene expression at the transcriptional level by steroid hormones
Regulation of puffing of insect salivary polytene chromosomes by ecdysone (in fruitfly Drosophila
melanogaster)
Study performed by Clever and Ashburner in ~1950s
Egg larva pupa fly
3 moltings in larva coordinated by ecdysone (steroid hormone)
Large cells in salivary glands
DNA replicated many times without cell division or segregation of chromatids
210 = 1024 copies of each genes
4 pairs of tightly paired homologous chromosomes with visible bands and interbands
(landmarks) large polytene chromosomes
Bands (85% DNA, ~5,000) darker on electron micrograph (EM)
Interbands (less condensed, 15% DNA, ~5,000) lighter on EM
Salivary gland isolation decondensation of bands (puffings) by ecdysone, which later
become re-condensed
Characteristic puffing patterns following precise temporal sequence
Newly synthesized RNAs labelled by 3H-uridine localized to puffs ecdysone coordinates
specific programs of gene expression (conclusion)
Ashburner hypothesis
Primary responses
Steroid hormone + steroid hormone receptor steroid hormone-receptor complexes
activates primary response genes induced synthesis of a few different proteins
in the primary response protein (early puff)
Delayed secondary responses
A primary response protein shuts off primary response gene turns on secondary
response genes induced synthesis of a secondary response protein (late puff)
Use of radiolabelled ligands to detect steroid hormone receptors and their association with high-
affinity binding sites in chromatin (~early to mid 1970s)
Radiolabelled ligands
3H glucocorticoid hepatic and lymphoid cells
3H estrogen uteri tissues
Labels seen under microscope to move from cytoplasm to nucleus suggesting effect on gene
expression
Specific sites labelled on chromatin (~50-100/cell = # of genes regulated)
Different specific sites in different cells acted on by different hormones

v Biochemical analysis and purification of hormone-receptor complexes
Availability of 3H labelled hormones and high affinity analogs e.g. dexamethasone allows detection
of hormone-binding proteins (intracellular receptors)
Receptor preparation (lysate containing glucocorticoid + 3H-dexamethasone receptor)
4oC no binding to chromatin on filter & low mobility in ion-exchange column
37oC binding to chromatin on filter & increased mobility in column
Model of steroid hormone action proposed
Most hydrophobic steroid hormones are bound to plasma protein carriers. Only unbound
steroid hormones can freely diffuse across cell membrane into the target cell
Steroid hormone receptor are in the cytoplasm OR nucleus (intracellular receptor) cytosolic
receptor (e.g. glucocorticoid receptor) & nuclear receptor (e.g. estrogen receptor)
Some steroid hormones also bind to cell-surface receptors that the second messenger
systems to create rapid cellular responses
Steroid hormone receptor undergo transformation/conformational change upon hormone
steroid binding (biochemical idea) (dimer) receptor-hormone complex translocation to
nucleus binds to hormone response element (HRE) on DNA in nucleus recruitment of
co-activators/co-repressors activates/represses one or more genes
Activated genes create new mRNA that moves back to the cytoplasm
Translation produces new proteins for cell processes
Early 1980s, purification of glucocorticoid receptor with the help of radiolabelled binding analogues
103 to 104/cell (trace amounts) requires 105 to 106-fold enrichment to achieve homogeneity
SDS-Polyacrylamide Gel Electrophoresis
Crude extract (many bands) purified GR (single band)
v Identification of glucocorticoid-responsive genes and cis-acting sequences required for hormonal
activation of transcription hormone responsive elements (HREs)
Viral (e.g. MMTV) genes first identified as being glucocorticoid-responsive region of MMTV
genome containing the binding sites for the glucocorticoid receptor within the regulatory sequences
(promoters) of responsive genes & the start site for hormone-dependent RNA synthesis
Direct binding of glucocorticoid receptor (GR)-hormone complexes to MMTV DNA demonstrated in
EM studies
Binding region defined by deletion analysis, e.g.
-84 to -305 of MMTV transcription-control region
Region sufficient to specify glucocorticoid responsiveness
HRE further defined by DNase I footprinting analysis & sequence comparison
Fact a protein (GR) bound to DNA protect DNA from enzymatic
cleavage locate a protein (GR) binding site on particular DNA molecule
The DNA fragment of interest (GR receptor binding region) is amplified
by PCR using a 32P 5' labelled primer DNA molecules with a radioactive
label on one end of one strand of each double stranded molecule
Cleavage of DNA by [DNase I] random 1 cut/DNA uniform ladder
If the protein (GR) binds DNA regions bound protected from DNase I
digestion 4 gaps on gel ("footprint") 4 binding sites
Same HRE for glucocorticoid receptor (GR), aldosterone receptor (MR),
androgen receptor (AR) & progesterone receptor (PR)
5- AGAACA (N)3 TGTTCT - 3
3- TCTTGT (N)3 ACAAGA - 5
HRE for estrogen receptor (ER)
5- AGGTCA (N)3 TGACCT - 3
3- TCCAGT (N)3 ACTGGA - 5
Dyad (rotational) symmetry receptors bind as dimers
HREs can be placed in front of other genes to make them hormone-responsive

v Cloning and functional analysis of steroid hormone receptors
In ~1985, GR (dimeric 94 kD) cDNA isolated by expression cloning
Purified GR antibodies raised against specific GR epitopes (colony formed by GR expression
bacteria GR blotted onto nitrocellulose filter) screening of expression cDNA library
All steroid hormone receptors cloned similarly or by low stringency hybridization
cDNA sequences allow prediction of protein structure and function
Conserved domains defined based on sequence homology
C (DNA binding domain) (~68 amino acids) 42 to 94% identical
Centrally located
Exhibits considerable sequence homology among different receptors (42 to 94% identical)
correlates with HRE recognition
GR, MR, PR have the same HRE > or = 94%
GR and ER recognize different HRE ~54%
Contains two copies of the C4 zinc-finger motif
E (ligand- or hormone-binding domains) (~225-285
amino acids)
C-terminal
Exhibits somewhat less homology less
conserved (15-57% identical)
A/B (variable regions) (100 to 500 amino acids)
N-terminal
Vary in length, have unique sequences
not conserved
Contain one or more transactivation domain transcriptional activation & specificity
D, F ?
Action model
Inhibitory protein complex (e.g. heat shock protein) binds to DNA-binding domain in the absence
Steroid hormone receptors
of steroid hormone prevents folding into the active conformation (dimer) of the receptor
[illustrated by glucocorticoid receptor (GR) as most studied example]

Steroid hormone (e.g. glucocorticoids) diffuse readily

(binding of HSP:
across the cell membrane bind to ligand- or heat-shock proteins)

hormone-binding domain of steroid hormone

receptor (GR) dissociation of heat shock protein
from the DNA binding domain allowing conversion
to the active configuration (dimer), translocation of GR
to the nucleus & exposure the DNA binding domain for
interaction with and binding to HRE in the nucleus
recruitment of co-activators and basal transcription
complex bind to TATA box gene transcription
v Traditional versus non-genotropic pathways, e.g. estrogen
Traditional
Estrogen diffuse readily across the cell membrane bind to ligand-binding domain of the
estrogen receptor in the nucleus gene transcription
Non-genotropic
Estrogen diffuse readily across the cell membrane bind to ligand-binding domain of the
estrogen receptor in the cytoplasm (extranuclear localization) activation of kinase diffusion
of kinase into the nucleus activation of transcription factor gene transcription
v Antiapoptotic signalling pathways stimulated by PTH, sex steroids, and BPs in osteoblasts and osteocytes
Through protein kinase, e.g. Akt, ERKs & RSKs by
Direct phosphorylation (e.g. inactivating Bad)
Activating transcription of some target genes via Elk-1/CREB


Pathology of Endocrine Disorders I & II

v Introduction
Endocrine system
A set of glands to maintain homeostasis by secreting hormones directly into the blood to reach
target organs
Endocrine glands
Similar normal histology nests of endocrine cells setting among a rich vasculature
Endocrine disorders
Functional VS non-functional hyperfunction or hypofunction
Neoplastic VS non-neoplastic benign or malignant
Difficult to tell definitely benign or malignant by histology ALONE
Constellation of clinical and pathological findings in deriving the diagnosis
v Pituitary
General
Anterior lobe (adenohypophysis)
Positive-acting releasing factors from hypothalamus
EXCEPT for prolactin
Posterior lobe (neurohypophysis)
Modified glial cells (pituicytes) and axonal processes Anterior pituitary

from the hypothalamus to the posterior lobe

Histology
Acidophil eosinophilic cytoplasm
Basophil basophilic cytoplasm Posterior pituitary

Chromophobe poorly staining cytoplasm

Pituitary disorders
Hyperpituitarism ( secretion of adenohypophyseal trophic hormones) or hypopituitarism
Endocrine effects & local mass effects
Pituitary adenoma
In adults 35-60 years
Classification
Size macroadenoma (>1 cm) & microadenoma (<1 cm)
Histological cell type
v Gigantism in children
Somatotrophs Acidophilic Growth hormone (GH)
v Acromegaly in adults
v Galactorrhoea
Lactotrophs Acidophilic Prolactin (PRL)
v Menstrual disturbances
Corticotrophs Basophilic Adrenocorticotropic hormone (ACTH) v Cushings disease
Thyrotrophs Pituitary
Pituitary
Basophilic gland
gland
Thyroid-stimulating hormone (TSH)
Gonadotrophs
Pituitaryadenoma
Pituitary
Basophilic
adenoma
Follicle stimulating hormone (FSH) &

Grossly:
Grossly: Luteinizing hormone (LH)
located
located in the
in the sella
sella turcica,
turcica, usually
usually wellwell
Grossly circumscribed
circumscribed
Located in the sella turcica, usually well circumscribed
Histologically:
Histologically: relatively
relatively uniform
uniform polygonal
polygonal cells
cells arranged
arranged in in
Histologically sheets
sheets or or cords,
cords, rare
rare mitosis
mitosis andand little
little pleomorphism
pleomorphism
Relatively uniform polygonal cell arranged in sheets/cords, rare mitosis & little pleomorphism

H&E section
H&E section Immunostain: synaptophysin
Immunostain: synaptophysin

 Hypopituitarism
Causes
Tumour or mass lesion
Surgery or radiation
Trauma
Ischemic necrosis & Sheehan syndrome
Infection/inflammation
Neurohypophysis
Oxytocin and antidiuretic hormone (ADH)
Oxytocin
Contraction of uterine smooth muscle at pregnancy
Acts on the smooth muscles around lactiferous ducts of the mammary glands at lactation
Antidiuretic hormone/ADH (= vasopressin)
Pancreas
Conserve water by restricting diuresis
General
Increases the permeability of renal collecting ducts
blood pressure or plasma osmotic pressure release of ADH
Deficiency of ADH diabetes insipidus islets
Produced by the hypothalamus
Stored in the axon terminals in the posterior pituitary
Exocrine and endocrine
v Pancreas components
General
Exocrine and endocrine components Endocrine component
Endocrine components
Islets of Langerhans
Islets of Langerhans
, , , and PP
, , , and PP (pancreatic polypeptide) cells
(pancreatic
Hypofunction diabetes mellitus
polypeptide) cells
Hyperfunction islet cell tumour
Diabetes mellitus acini
Abnormal metabolic state characterized by glucose intolerance due to inadequate insulin action
Biochemical features
Inability to utilise and overproduction of glucose
Decreased protein synthesis
Lipolysis resulting in hyperlipidaemia
Type I Type II
Present in childhood Middle age onset
Inadequate insulin secretion Decreased sensitivity to insulin
Histology
Reduction in the number and size of islets
Leukocytic infiltrates in the islets (insulitis)
T lymphocytes
Eosinophils
Amyloid deposition within islets in type II diabetes
Around capillaries
Between cells
Islet cell tumours
Functional or non-functional
Functional
Insulinoma Hypoglycaemia
Gastrinoma Severe peptic ulcer (Zollinger-Ellison Syndrome)
Glucagonoma Secondary diabetes
VIPoma Watery diarrhoea
 Histology

v Round nuclei
v Arranged in ribbons & anastomosing trabeculae
v Fine chromatin
v A richly vascularized background
v Eosinophilic cytoplasm
v Adrenal gland
General
Cortex derived from mesoderm
Zona glomerulosa (mineralocorticoids)
Zona fasciculate (glucocorticoids) [makes up ~75% of the cortex]
Adrenal gland
Zona reticularis (sex steroids)
Medulla neural crest embryological origin, part of sympathetic nervous system
General
Composed of chromaffin cells and sympathetic nerve endings
Synthesize and secrete catecholamines, mainly epinephrine

cortex

medulla

Hypofunctions
Cortex
Classification
Zona glomerulosa (mineralocorticoids)
Primary or secondary
Zona fasciculata (glucocorticoids), makes up ~ 75% of the cortex
Primary
Aetiology resides in the adrenal gland itself
Zona reticularis (sex steroids)
Secondary
Aetiology resides higher up in the axis
Medulla
Acute or chronic
Waterhouse-Friderichsen Syndrome (acute primary insufficiency)
composed of chromaffin cells and sympathetic nerve endings
Overwhelming bacterial infection
synthesize and secrete catecholamines, mainly epinephrine
Rapid progression to hypotension and shock
Disseminated intravascular coagulation
Adrenocortical insufficiency, with massive adrenal haemorrhage
Addison Disease (chronic primary adrenocortical insufficiency)
Causes
Autoimmune adrenalitis
Tuberculosis & infections
Amyloidosis
Metastatic cancers
 Hyperfunctions
Hyperplasia (cortical or medullary)
Cortical adenomas (e.g. hyperaldosteronism and Cushing syndrome)
Glucocorticoids (Cushings syndrome)
Clinically
Central obesity, hirsutism, hypertension, diabetes & osteoporosis
Causes
Excess ACTH secretion by pituitary gland
Adrenal cortical neoplasm
Iatrogenic effects (ACTH or steroid administration)
Mineralocorticoids (Conns syndrome)
Autonomous secretion of excess aldosterone (primary)
Usually caused by cortical adenoma
Renal retention of sodium & loss of potassium
Secondary aldosteronism Adrenal gland
Cortical neoplasms
glomerular perfusion stimulate renin-angiotensin system aldosterone secretion
Pheochromocytoma
Neoplasms
Primary
Cortical adenoma & carcinoma
Epidemiology adenoma

In adults adenomas & carcinomas

In children carcinoma PREDOMINATES
Histology of adenoma
Arranged in packets in a vascularized background
Central regular nuclei & pale to clear cytoplasm
Medullary
Pheochromocytoma
Peak at 40-60 years
Clinically
Hypertension, tachycardia, palpitations, headache, sweating, tremor & sense of
apprehension
Increased urine catecholamines & vanillylmandelic acid
Complication myocardial infarct due to vasoconstriction
Grossly
Pale grey or brown
Haemorrhage, necrosis & cystic change
Microscopically
Zellballen, trabecular or solid pattern vague packet
Polygonal or spindle cells in rich vascular network
Finely granular basophilic or amphophilic cytoplasm dirty-blue cytoplasm
10% tumour
10% extra-adrenal
10% sporadic tumours are bilateral
10% biological malignant (defined by presence of metastasis)
10% NOT associated with hypertension
Neuroblastoma (often metastasize MALIGNANT)
In infants and children, most before the age of 3
Grossly soft & lobulated
Histologically small blue round cell tumour
Secondary
v Thyroid gland
Normal histology
Lobules divided by thin fibrous septa
Each lobule consists of about 20 to 40 follicles
Follicles are lined by a cuboidal to low columnar epithelium
Parafollicular cells (C-cells) which secrete calcitonin
General
Common tumour & tumour-like lesions
Hyperplasia (diffuse or nodular goitre)
Adenoma
Carcinoma
Approach to thyroid nodules
Solitary or multiple?
Age of patient?
Male or female patient?
Any history of radiation treatment to the head and neck region?
Functional nodules?
Neoplasms
> 90% are adenomas
Simple goitre
Diffuse nontoxic (simple) goitre
Involves entire gland
Occurrence
Endemic due to compensatory increase in TSH
Sporadic due to ingestion of goitrogens or hereditary defect in enzyme synthesis
2 stages
Hyperplastic stage (enlarged follicles filled with colloid)
Colloid involution
Multinodular goitre
Some long-standing simple goitre convert into multinodular goitre
Clinical symptoms
Toxic or non-toxic
Most patients are euthyroid or with subclinical
hyperthyroidism
Pressure symptoms
Cosmetic effects
Histology
Variably sized colloid-filled follicles nodular
hyperplasia
Follicular adenoma Thyroid gland
Discrete solitary mass Follicular adenoma
Derived from follicular cells
MOST are non-functional capsule

Benign
Histology capsule
Capsule
Colloid-filled follicles
Hrthle cell change


Colloid-filled follicles
Hurthle cell change
 Carcinoma
Major histology subtypes of thyroid carcinoma
Papillary carcinoma (>85%)
Age of presentation 25-50 years
Risk factor
Ionizing radiation exposure
Clinical symptoms
Asymptomatic thyroid nodules
Mass in cervical lymph nodes
Hoarseness, dysphagia, cough, dyspnoea in advanced disease
Other characteristics
Appears as multifocal tumours
Prone to lymphatic permeation
Excellent prognosis with a 10 year survival rate over 95%
Prognostic factors
Age
Stage/metastasis
Extrathyroidal extension
Histological features
Nuclear inclusions
Nuclear grooves
Overlapping ground-glass nuclei
Psammoma bodies
Thyroid gland Thyroid gland
Multinucleated giant cells
Thyroid gland
Papillary carcinoma Papillary structures
Papillary carcinoma Papillary carcinoma

Nuclear grooves

Papillary architecture
Overlapping ground-glass nuclei
Nuclear inclusions

Follicular carcinoma (5% 15%) Other histological features include psammoma bodies & multinucleated giant cells

F:M = 3:1
Peak at 40-60 years
Thyroid
Thyroid glandgland
Prone to haematogenous metastasis (bone, liver, lungs)
Histologically
Follicular
Follicular
Encapsulated
carcinoma
carcinoma
Malignancy defined by capsular invasion and/or vascular invasion

Follicular cells
Follicular cells
Capsular Capsular
invasion invasion

 Medullarycarcinoma
Medullary carcinoma
Anaplastic (undifferentiated) carcinoma (<5%)
Mortality rate approaching 100%
Medullary
Medullary carcinoma
carcinoma
Mean age 65 years
Derived
Derived fromfrom parafollicular
parafollicular CC cells
cells
Preceding or concurrent well-differentiated thyroid carcinoma
Histologically
70%
70%
sporadic
sporadic andand remaining
remaining asas MEN MEN
Markedly pleomorphic cells/spindle cells/squamoid cells syndrome
syndrome
Medullary carcinoma (5%)
Derived from parafollicular C cells
70% sporadic and remaining as MEN syndrome

H&E
H&E calcitonin
calcitonin

Management
Surgical
Hormone replacement
Radioactive ablation of residual disease
Monitoring for recurrence with serum thyroglobulin level
v Multiple Endocrine Neoplasia (MEN) Syndromes
A group of genetically inherited diseases resulting in proliferative lesions (hyperplasia, adenomas
and carcinomas) of multiple endocrine organs
Significance
Occurs at younger age group
Diagnosis possible with molecular technologies
Surgical intervention can prevent development of malignancies
Characteristics
Younger age of onset
Multiple organs
Multifocal
Preceded by asymptomatic stage of hyperplasia
More aggressive and recur
Defective gene Comprises
v Parathyroid hyperplasia or adenoma
MEN 1 (Wermer MEN 1 encoding
v Pancreas endocrine tumour
Syndrome) MENIN
v Pituitary tumour, frequently prolactinoma
v Medullary thyroid carcinoma
MEN 2A* RET v Pheochromocytoma
v Parathyroid hyperplasia
v Medullary thyroid carcinoma
v Pheochromocytoma
MEN 2B RET
v Neuromas or ganglioneuromas involving the skin, oral mucosa,
eyes, respiratory tract and gastrointestinal tract
*Prophylactic thyroidectomy is generally recommended
v Case studies
Case 1 (pituitary adenoma)
Clinical history
F/40
Past medical history of endometriosis and haemorrhoids
Referred from GOPC for acromegalic features for 2 years
Presents with coarsening of facial features and increase in shoe size
Investigations
P/E
Large nose & spade-like hands
Anterior pituitary hormones
GH
Normal TSH, prolactin, LH, FSH & cortisol
Skull X-ray
Enlarged pituitary fossa
MRI brain
1.2 cm hypoenhancing nodule in right side of pituitary gland pituitary adenoma
Transsphenoidal resection of pituitary tumour with intra-operative frozen section are arranged
Role of pathologist
To ensure adequate and the right tissue obtained at surgery at frozen section
To make correct diagnosis and subtyping the tumour
Examples
Smear stained with Toludine Blue
Frozen section with H&E stain
Growth Hormone, immunostain (brown colour)
Case 2 (adrenal cortical adenoma)
Clinical history
F/48, teacher
History of hypertension and hyperlipidaemia
Presents with incidental finding of right adrenal mass (2 cm)
Investigations
BP 130/90
BMI 26
24-hour urinary free cortisol
Overnight dexamethasone suppression test (ONDST) non-suppressive
Normal aldosterone
Right adrenalectomy was done and grossly
It weights 15.6 g & measures 5 x 4 x 2 cm
Cut sections show a 2 cm nodule with golden yellow surface
Case 3 (multinodular goitre & papillary carcinoma)
Clinical history
F/59
Clear cell carcinoma of ovary, stage IIIc, with operation and adjuvant chemotherapy done
Presents with multinodular goitre
Serum TSH and free T4 were normal
Total thyroidectomy was done
Gross specimen
Multiple colloid nodules
Largest one measures 1.5 cm located in the left lower pole
A separate 0.5 cm well circumscribed nodule with tan cut surface is noted in left middle pole
Pituitary Gland
Development and Structure of the Pituitary

v Overview of pituitary gland and hypothalamus

Where nervous and endocrine systems interact
Hypothalamus regulates secretions of anterior pituitary
Posterior pituitary is an extension of the hypothalamus
Anterior pituitary produces 9 major hormones that
Regulate body functions
Regulate the secretions of other endocrine glands
v Pituitary hormones
Anterior pituitary hormones
Thyroid-stimulating hormone (TSH) tropic hormone
Adrenocorticotropic hormone (ACTH) tropic hormone
Luteinizing hormone (LH) tropic hormone
Follicle-stimulating hormone (FSH) tropic hormone
Growth hormone (GH) or somatotropin
Melanocyte-stimulating hormone (MSH)
-endorphin
Lipotropin
Prolactin
Posterior pituitary hormones
Antidiuretic hormone (ADH)
Oxytocin
v Pituitary or hypophysis
Location
Lie in a cavity of the sphenoid sella turcica
Anterior tuberculum sellae
Hypophysial (pituitary) fossa accommodates the hypophysis or pituitary gland
Posterior dorsum sellae
Development
Neural component
Evaginates from the floor of the diencephalon and grows caudally
Oral component
Arises as an out-pocket from the roof of the primitive mouth, forming the Rathkes pouch

 Structure

Posterior pituitary (neurohypophysis/pars nervosa)
Extension of the nervous system via the infundibulum
Composed of unmyelinated neurosecretory fibres in the hypothalamo-hypophyseal tract
Neurosecretions (stored as membrane-bound granules) accumulate at the end of the fibres
to form Herring bodies (large axon swelling, 100-200 nm)
Secretes 2 types of neurohormones
Vasopressin (or antidiuretic hormone)
Oxytocin
Each hormone is bound to a specific binding protein neurophysin
Pituicyte (a specific type of glial cell) serves a supporting role

 Anterior pituitary (adenohypophysis)
Consists of 3 areas with indistinct boundaries
Pars distalis
Main components cords of epithelial cells interspersed with capillaries
Chromophobes
Do NOT stain intensely
2 types of chromophils
Acidophils (-cell) [orange yellow]
Basophils (-cell) [magenta]
Hypothalamic
Staining
Cell type Hormone produced Releasing Inhibiting
affinity
hormones hormones
Somatotrope Acidophilic Somatotropin (or Growth hormone, GH) SRH Somatostatin
Lactotrope Acidophilic Prolactin (PRL) PRH PIH (dopamine)
Follicle stimulating hormone (FSH),
Gonadotrope Basophilic GnRH
Luteinizing hormone (LH)
Thyrotrope Basophilic Thyrotropin (TSH) TRH
Corticotrope Basophilic Corticotropin (ACTH) CRH

Pars intermedia
Develops from dorsal part of the Rathkes pouch
In human, made up of cords and different-sized follicles of weakly basophilic cells
containing basophilic granules and colloid. The function of these cells are unknown

Pars tuberalis
A funnel shaped region surrounding infundibulum
Most cells of this region secrete gonadotrophins
Arranged in cords alongside with blood vessels
 Blood supply
Derives from the internal carotid artery
Right and left superior hypophyseal arteries
Supplies the median eminence and the neural stalk forming the primary capillary plexus
Median eminence
In the wall of infundibulum
Neuro-haemal region where the neurohormones pass into the capillaries
Surrounded by extended perivascular connective tissue spaces
Axons endings of neurohormonal nerve cells open into them & release hormones
into the perivascular space pass into the blood stream through the portal veins
Re-join to form veins that develop secondary capillary plexus in the adenohypophysis
2 plexuses form the hypophyseal portal system
Fenestrated capillaries facilitate rapid exchange between hypothalamus and pituitary
Right and left inferior hypophyseal arteries
Provide blood for the neurohypophysis and a small supply to the stalk
3 groups of hormone production in the 3 sites of the hypothalamo-hypophyseal system
Peptides produced by aggregates of neurons in the supraoptic and paraventricular nuclei of the
hypothalamus
Hormones are transported along axons, accumulated at the end of axons in the
neurohypophysis released into the blood capillaries and distributed systemically
Peptides produced by neurons of the dorsal medial, ventral medial and infundibular nuclei of
hypothalamus
Hormones are carried along axons ending in median eminence where they are stored and
secreted enter the capillaries of the median eminence and transported to the
adenohypophysis via the hypophyseal portal system
Proteins & glycoproteins of the pars distalis
Liberated into the secondary capillary plexus of the portal system and are distributed to the
general circulation

Physiology of Pituitary Hormones

v Overview of hypothalamus & pituitary gland

Hypothalamus
A region of the brain composed of many small nuclei with diverse functions
By synthesizing and secreting neurohormones, the nuclei of the hypothalamus act as a conduit
between the nervous and endocrine systems via the pituitary gland
Pituitary gland
Looks like a protrusion off the bottom of the hypothalamus at the base of brain
2 parts
Anterior pituitary (AP)
Derived from an upward growth of the oral ectoderm
Anatomically distinct from the hypothalamus
Consists of a collection of endocrine cells
Posterior pituitary (PP)
Derived from a down growth of the neuroectoderm
Embryological and anatomically an extension of the hypothalamus
Connected with hypothalamus via the pituitary stalk (infundibulum)
v 2 different connections between the hypothalamus & pituitary gland
Anterior pituitary
By portal blood system
Portal vein is very short distance allows blood-borne molecules from the hypothalamus to
act on the anterior pituitary before they are diluted with the blood in larger vessels
Posterior pituitary
By neurons that form the hypothalamo-hypophyseal tract
The axons of the neurosecretory cells in supraoptic nucleus & paraventricular nucleus extend
directly to the posterior pituitary, where the hormones are stored inside the axonal terminal
Hormones)from)The)Hypothalamus)&)The)Pituitary
v Hormones from the hypothalamus & pituitary gland
Arcuate Nucleus PVN Magnocellular neurons
Hypothalamus

In$PVN$and$ SON

GH-releasing$ Gonadotropin- Corticotropin Thyrotropin-

hormone$ (GHRH) releasing$ Dopamine releasing-factor$ releasing$
hormone$ (GnRH)$ (CRH) hormone$ (TRH)$

Posterior$pituitary
+ + - + +
Pituitary

50% 10% 20% 15% 5%

Somatotrophs Gonadotrophs Lactotrophs Corticotrophs Thyrotrophs Vasopressin Oxytocin

Growth$hormone$ Gonadotropins: Prolactin Adrenocorticotropic$ Thyroid-

(GH) Follicle-stimulating$ (PRL) hormone stimulating$
hormone$(FSH)
Target$Tissues

(ACTH) hormone
Luteinizing$ (TSH)
hormone$(LH) Mammary
glands

Mammary
Adrenal
All$kind$of$tissues glands
cortex Thyroid$gland Kidney

Gonads Uterus

 Growth hormone (also known as somatotropin)
Synthesis & secretion
Stimulated by growth hormone-releasing hormone (GHRH) from arcuate nucleus
GH act via a short negative feedback loop to inhibit secretion of GH from GHRH neuron
Inhibited by somatostatin (SS) from periventricular nucleus
High blood levels of IGF-1 decreases secretion of GH
Suppressing the somatotrophs
Stimulating release of SS from the periventricular nucleus
2 distinct types of physiological effects
Direct effects
Result of GH binding to its receptor (G protein-coupled receptors) on target cells, e.g.
adipose & muscle
Indirect effects
Mediated by insulin-like growth factor I (IGF-I)
A hormone that is secreted from the liver in response to growth hormone
Bind to IGF-1 receptor on cartilage & bone multiple signalling pathways & effects
Functions
Increase protein synthesis in muscle
Increase lipolysis in adipose tissues to provide the energy necessary for tissue growth
Antagonizes the action of insulin decreases glucose uptake by different tissues and
increases blood glucose level insulin resistance
Stimulates body growth via IGF-1, e.g. proliferation of chondrocytes that leads to bone growth
Disorders
Hypersecretion of GH acromegaly and giantism
Usually caused by a tumour of the somatotrophs in the anterior pituitary
Associated with enlargement of other organs, cardiovascular diseases and hypertension,
diabetes mellitus etc.
GH deficiency dwarfism
Resulted primary from damage to the hypothalamus or to the pituitary gland, or
mutations in genes that regulate its synthesis and secretion
Growth retardation usually becomes evident within the first two years of life
Associated with hypoglycaemia, decreased energy, decreased muscle strength, decreased
bone density, delayed puberty
Treatment administration of GH
Irresponsiveness to GH Laron Syndrome
An autosomal recessive disorder characterized by an insensitivity to GH, usually caused
by a mutant growth hormone receptor GH but IGF-1
Treatment administration of IGF-1













 Gonadotropins
Synthesis & secretion
Secretion of gonadotropins, mainly follicle-stimulating hormone (FSH) & luteinizing hormone
(LH), is stimulated by gonadotropin-releasing hormone (GnRH) from arcuate nucleus
GnRH is released in a pulsatile manner after puberty. It is the frequency of the pulses that
controls LH or FSH secretion from the gonadotropes
Low frequency (1 pulse per 3 hours) FSH synthesis and secretion
High frequency (1 pulse per hour) LH synthesis and secretion
Physiological effects
Receptors for gonadotropins (i.e. FSH and LH) are expressed in the gonads
In both sexes, LH stimulates synthesis & secretion of sex steroids (steroidogenesis) from the
gonads, whereas FSH stimulates gametogenesis, i.e. spermatogenesis & oogenesis
Male Female
v Induce spermatogenesis
v Cause production of inhibin v Stimulate the maturation of ovarian follicles
FSH
v Stimulate testosterone-binding v Cause production of inhibin
protein in Sertoli cells
v Cause production of testosterone in theca cells of ovary
v Cause production of testosterone converted by adjacent granulosa cells into oestrogen
LH
in Leydig cells of testis v Terminate 1st meiosis formation of secondary oocyte
v Cause ovulation and formation of corpus luteum
Leydig cell sperm capillary Developing$ follicle

Male Female
Theca$cell

Granulosa$
Seminiferous$ tubule cell

Disorders
Hypergonadotropism
Occurs when there is
Pituitary tumour
Ectopic hormone-producing tumours of the lung, liver and germinal cell lines
Elevated GnRH level
Gonadotropin deficiency
Occurs when there is
Hyperprolactinemia
Genetic problems
Mutations that leads to developmental problem of GnRH neurons
Mutations in GnRH receptor or -subunit of gonadotropin gene
Associated with hypogonadism (diminished functional activity of gonads)
E.g. Kallmann syndrome (X-linked recessive or autosomal recessive)
GnRH-secreting neurons are congenitally absent affected individual does not
go through puberty and is infertile + loss of smell
 Prolactin:)Synthesis)&)Secretion
Prolactin
In contrast to other anterior pituitary hormones, production and secretion of prolactin
Synthesis & secretion
are predominantly under inhibitory control (dopamine) by the hypothalamus
In contrast to other anterior pituitary hormones, production and secretion of prolactin are
predominant under INHIBITORY control (dopamine) by the hypothalamus
Stimulus that triggers prolactin release is by reducing the tonic inhibitory effect of the
hypothalamus,
Stimulus thus freeing
that triggers the lactotrophs
prolactin to is
release express its inherentthe
by reducing capacity
tonic toinhibitory
secrete effect of the
prolactin at a very high rate
hypothalamus (e.g. breast-feeding) freeing the lactotrophs to express its inherent capacity
to secrete prolactin at a very high rate

Physiological effects
The biological effects or prolactin are mediated by interaction with its receptor, which is a
member of the cytokine family coupled to the JAK/STAT signalling pathways
Prolactin binding to its receptor causes receptor dimerization and activation of associated JAK
STAT5 phosphorylation induces transcription of target genes that
Stimulates growth and development of the mammary gland required or lactation
Simulated milk PRODUCTION by alveolar epithelial cells in the mammary gland
Prolactin receptors are also expressed in afferent neurons of hypothalamic GnRH neurons
Binding to its receptor reduces stimulating input to the hypothalamic GnRH neurons
decreasing GnRH secretion to prevent fertility protecting lactating women from a
premature pregnancy
Disorders
Hyperprolactinemia too much prolactin circulating in the blood
Causes
Pathological
Prolactinomas and mixed secreting adenomas
Hypothalamic and pituitary stalk disorders
E.g. compressive macroadenoma, hypophysitis
Ectopic prolactin secretion from other tumours
Medication
Dopamine antagonists (anti-hypertensive)
Associated with abnormal lactation (galactorrhoea)
Associated with hypogonadism and infertility because prolactin inhibits GnRH secretion
In female
Anovulation
Amenorrhea
In male
Lack of sex desire and erectile dysfunction due to low testosterone level
Enlargement of breast tissue
May associated with headaches and/or vision problems
Hypoprolactinemia too little prolactin circulating in the blood
Occurs as a result of general pituitary hormone deficiency (hypopituitarism)
E.g. Sheehan syndrome
Postpartum pituitary necrosis due to blood loss and hypovolemic shock during and
after childbirth inability to breast-feed
 Adrenocorticotropic hormone (ACTH)
Synthesis & secretion
Peptide hormone that is synthesized as a larger prohormone proopiomelanocortin (POMC)
Proopiomelanocortin -melanocyte-stimulating hormone (-MSH) (known to control
pigmentation in the skin) + ACTH + -lipotropin (-LPH) (NO physiological role in humans)
ACTH -MSH + corticotropin-like intermediate peptide (CLIP)
-LPH -LPH + endorphin (opioid peptides with pain-alleviation effects)
-LPH -MSH
Secreted from the corticotrophs in response to corticotropin-releasing hormone (CRH)
(released at median eminence) from the parvocellular neurons of the hypothalamic
paraventricular nucleus
CRH receptors (CRH-R1) activation PKA increases production of POMC & ACTH secretion
Physiological effects
ACTH receptors belongs to the subfamily of melanocortin receptors
5 melanocrotin receptors (MC1R MC5R) have been identified in human, and ONLY MC2R
binds ACTH with high affinity
MC2R is found primarily in adrenal cortex. Binding of ACTH (physiological levels) PKA
Activates transcription of a gene involved in cholesterol uptake by the adrenal cortical
cells adrenal cortex expansion
Activates transcription of several key steroidogenic enzymes steroidogenesis
(including cortisol and androgens)
Hormones produced from the adrenal cortex, especially cortisol, plays a critical role in
maintaining homeostasis in the hypothalamo-pituitary-adrenal axis
Elevated cortisol levels act via a long negative feedback loop to
Inhibit secretion of CRH from the hypothalamus
Suppress POMC production and ACTH release in the anterior pituitary
At extremely high plasma ACTH concentrations (supraphysiological levels), ACTH is able to
bind to MC1R expressed in the melanocytes of the skin and hair follicles PKA
Activation of it results in the production of brown/black melanin pigment
hyperpigmentation
Disorders
ACTH deficiency (secondary adrenal insufficiency)
Occurs when there is failure of the hypothalamus to stimulate pituitary ACTH production,
or there is mutation of MC2R gene
Symptoms are the same as for primary adrenal insufficiency (i.e. Addisons disease)
Over-production of ACTH
Occurs when there is adenoma of the pituitary or where there is ectopic CRH/ACTH
production in some fast-growing tumours (e.g. oat cell carcinoma of the lung)
E.g. Cushings disease (NOT Cushings syndrome)
Cushings disease describes the excessive secretion of ACTH from the anterior
pituitary gland. It is one of the causes of Cushings syndrome
Cushings syndrome describes the symptoms that occur when a persons cortisol
levels are too high, i.e. adrenal disorder








 Thyroid-stimulating hormone (TSH)
Synthesis & secretion
One of 3 pituitary glycoprotein hormones (TSH, FSH & LH) 1 subunit & 1 subunit
subunit is common to TSH, FSH & LH whereas subunit confer specificity to each hormone
TSH is released from the pituitary thyrotropes when stimulated by thyrotropin-releasing
hormone (TRH), the SMALLEST known peptide hormone (ONLY 3 amino acids in length), from
the parvocellular subdivision of the hypothalamic paraventricular nucleus
Physiological effects
TSH receptor is mainly found on the thyroid follicular cells. Binding of TSH leads to modulation
of thyroidal gene expression
TSH functions
Stimulates thyroid cell growth and differentiation
Stimulates the thyroid gland to produce thyroid hormones, thyroxine (T4) and
triiodothyronine (T3), which regulates bodys metabolic activities
Thyroid hormones (T3) exert strong negative regulation on the hypothalamus and pituitary
In the pituitary, it decreases the synthesis of TSH subunit and TSH secretion
In the hypothalamus, it decreases TRH synthesis
Disorders
Thyrotropin deficiency
Symptoms are similar to those in patients with primary hypothyroidism
Excess thyrotropin
Symptoms are similar to those in patients with hyperthyroidism
Occurs when pituitary adenomas causes overproduction of TSH, or when pituitary
developed resistance to negative feedback by thyroid hormones
Associated with weight lost
E.g. Graves disease
Immune system produces abnormal antibodies (stimulating antibodies) that mimic
TSH function TSH receptor is continuous activated
Vasopressin (also known as ant-diuretic hormone, ADH) & oxytocin
Synthesis & secretion
9-aminio acid peptide hormone that are very similar in structure, differing only 2 amino acids
ADH Oxytocin
Cys-try-phe-gln-asn-cys-pro-arg-gly-NH2 Cys-try-ile-gln-asn-cys-pro-leu-gly-NH2
Synthesized in the magnocellular neurons of paraventricular nucleus and supraoptic nucleus,
these 2 hormones are transported along the hypothalamo-hypophyseal tract to the posterior
pituitary, where they stored in secretory granule (Herring bodies) until mobilized for secretion
Vasopressin & oxytocin are released from posterior pituitary in response to stimuli that are
primarily detect at cell body in supraoptic nucleus & paraventricular nucleus of hypothalamus
With right stimulus, the neurons will depolarize & propagate an action potential down the
axon depolarize axon termini open Ca2+ channels intracellular Ca2+ exocytosis
of vasopressin- or oxytocin-containing secretory vesicle released into fenestrated capillary
Physiological effects of vasopressin
Vasopressin receptor is a member of the G protein-coupled receptors
Different receptors of vasopressin have been identified
V1aR is located in vascular smooth muscle cells
Activation (too high level) through Gq PLCB IP3 ( intracellular Ca2+) + DAG
(activates PKC) vascular smooth muscle contraction vasoconstriction
V2R is located in the renal collecting ducts
Activation (normal level) through Gs adenylyl cyclase cAMP PKA
trafficking of water channel (AQP-2)-containing vesicles to apical membrane of
collecting duct cells water reabsorption in renal collecting ducts (anti-diuretic effect)
 Physiological effects of oxytocin (ONLY 1 receptor)
Head of baby pushes against cervix nerve impulses from cervix transmitted to brain
brain stimulates pituitary gland to secrete oxytocin oxytocin carried in bloodstream to
uterus oxytocin stimulates contraction of myometrium by increasing intracellular Ca2+ and
pushes baby towards cervix labor (positive feedback)
In the mammary gland, oxytocin triggers contraction of the myoepithelial cells surround the
alveoli by increase intracellular Ca2+ SQUEEZING of milk into the nipple for the nursing
infants suckling stimulates nerves in breast nerve impulses sent to hypothalamus
hypothalamus sends impulse to posterior pituitary (positive feedback)

Posterior$ pituitary

Anterior$ pituitary

Contraction)of

Disorders related to vasopressin
Vasopressin deficiency (also known as diabetes insipidus) inability of kidney under
physiological conditions to concentrate urine adequately
Central diabetes insipidus (CDI) defect of vasopressin production or release
Nephrogenic diabetes insipidus (NDI) kidney is unable to respond to vasopressin by
producing a concentrated urine
Mode of transmission Gene Target site of action (mutations)
X-linked Xq28 Vasopressin 2 receptor (V2R)
Autosomal 12p13 AQP2 ( impaired trafficking to the plasma membrane)
Excess vasopressin (syndrome of inappropriate secretion of
ADH (SIADH)) when kidney conserving too much water
Commonly found in the hospital population
Types
Type A erratic ADH release (e.g. tumour)
Type B reset osmostat
Type C ADH leak (e.g. damage in posterior pituitary)
Causes
Central nervous system disorders Mediations and illegal drugs
v Head trauma v Antidepressants (selective serotonin reuptake inhibitors,
v Stroke venlafaxine, monoamine oxidase inhibitors, tricyclics & others)
v Tumour v Carbamazepine (Atretol and others)
v CNS infection v 3,4-methylenedioxymethamphetamine (Ecstasy)
v Hydrocephalus v Nonsteroidal anti-inflammatory drugs
v Subarachnoid haemorrhage v Haloperidol and other neuroleptics
Symptoms are associated with lowered levels of sodium (hypotonic hyponatremia)
Mild to moderate Headache, muscle cramps, tremor, nausea & vomiting
Advanced Cerebral oedema confusion & hallucination
Grave Seizures, coma, death
The Treatment of Pituitary Disorder

v General review of the hypothalamic-pituitary system

Pituitary gland is composed of 3 sections
Anterior pituitary
Secretes a number of hormones vital for normal physiological function, some of which are
involved in the regulation of other endocrine glands
Corticotrophin (ACTH)
Growth hormone (GH)
Gonadotrophins (FSH & LH)
Thyrotrophin (TSH)
Prolactin
Secretion from the anterior pituitary is largely regulated by the hormones derived from the
hypothalamus, which reach the pituitary through the bloodstream
Corticotrophin-releasing factor ACTH
Growth hormone-releasing hormone/Growth hormone-release inhibiting hormone
(somatostatin) GH
Gonadotrophin-releasing hormone FSH & LH
Thyrotrophin-releasing hormone TSH
Prolactin-releasing hormone/Prolactin-release inhibiting factor (dopamine) prolactin
tuberoinfundibular dopaminergic pathway
Intermediate lobe
Posterior pituitary
Consists largely of the axons of nerve cells (lie in the supraoptic and paraventricular nuclei of
the hypothalamus) form the hypothalamic-hypophyseal tract, and the nerve endings
terminate in close association with capillaries in the posterior pituitary gland
Peptides (anti-diuretic hormones and oxytocin) synthesized in the hypothalamic nuclei, pass
down the axons into the posterior pituitary where they are stored and eventually secreted
into the bloodstream.
There are negative feedback mechanisms regulating the hormones
Long negative feedback pathways
The mediators are the hormones which are secreted from the peripheral glands
Affect BOTH the hypothalamus and anterior pituitary
Short negative feedback pathway
The anterior pituitary hormones acting on the hypothalamus
v Disorder of anterior pituitary gland
Hyposecretion of anterior pituitary hormones (hypopituitarism)
Common causes
Ischaemia
Radiation
Inflammation
Non-functioning neoplasm of pituitary gland
Symptoms and signs are related to the specific pituitary hormones that are absent
Growth hormone (GH) (more common)
Responsible for many cases of pituitary dwarfism
gonadotrophins (luteinizing hormone & follicle-stimulating hormone) (more common)
Men Women
v Impotence
v Amenorrhea
v Testicular atrophy
v Regression of secondary sexual characteristics
v Regression of secondary sexual characteristics
v Infertility
v spermatogenesis with consequent infertility
 Corticotrophin (ACTH) (more common)
Hypoadrenalism
Attendant fatigue, tiredness, dizziness
Hypoglycemia
Hypotention
Weight loss
Intolerance to stress ( cortisol effects of adrenaline and noradrenaline)
Infection
Thyrotrophin (TSH) (very rare)
Hypothyroidism
Prolactin (very rare)
Women fail to lactate after delivery
Diagnosis
Hypothalamic hormones are usually used in diagnostic tests although it can be used to
stimulate pituitary secretion (if the hypopituitarism is due to hypothalamic defect)
Treatment is usually directed toward replacing the hormones for the hypofunctioning target glands
Treatment of pituitary dwarfism replacement therapy with somatropin (= native GH, but it is
synthetic recombinant GH)
Mechanisms of action
GH stimulates peripheral tissues directly & stimulates production of somatomedins (or
called insulin-like growth factor-1, IGF-1) mainly from liver. The effects of GH and
somatomedins include
Protein synthesis and uptake of amino acids into cells
Initially insulin-like effect glucose tissue uptake and lipolysis
After a few hours peripheral insulin antagonistic effect glucose uptake and
lipolysis
Somatomedins also uptake of SO4- into cartilage (chondroitin sulphate is a
structural component of cartilage) & bone growth by thymidine incorporation to
DNA and uridine incorporation to RNA
Adverse effects
Hypothyroidism
Growth hormone conversion of T4 to T3
Peripheral oedema
Growth hormone induces retention of sodium, due to the activation of sodium
channel in collecting ducts
Papilledema visual changes
Intracranial hypertension headache
Impaired glucose tolerance (secondary to anti-insulin actions of growth hormone)
Treatment of gonadotrophin deficiency replacement therapy with gonadotrophins
Examples
FSH
Follitropin (recombinant human FSH)
Human menopausal gonadotrophins (HMG)
Purified extract of human post-menopausal urine containing BOTH FSH and LH
LH
Lutropin (recombinant human LH)
Human chorionic gonadotrophin (HCG)
A preparation of a glycoprotein fraction secreted by the placenta and obtained
from the urine of pregnant women
Having the action of LH
Choriogonadotropin (recombinant HCG)
 Mechanisms of action
FSH (follitropin & , HMG) is used in the states of infertility to stimulate
Ovarian follicle development in women oestrogen
Proliferative phase of endometrium
Secondary sexual characteristics
Spermatogenesis in men
In both sexes, they must be used in conjunction with LH (lutropin , HCG or
choriogonadotropin ) to permit
Ovulation in women corpus luteum progesterone
Secretory phase of endometrium implantation
Testosterone production in men
Secondary sexual characteristics
Although HMG have both FSH & LH activity, FSH activity predominates & LH activity is
so low combined administration with HCG, choriogonadotropin or lutropin is still
necessary
Adverse effects
FSH
Ovarian hyperstimulation syndrome characterized by
Ovarian enlargement hemoperitoneum
Ascites
Hydrothorax difficult to breathe
Hypovolemia electrolyte imbalance & arterial thromboembolism
Hemoperitoneum
Fever
Arterial thromboembolism
Frequency of multiple births (~ 20%)
Gynaecomastia occasionally occurs in men*
LH
Headache
Depression
Oedema
Precocious puberty
Gynaecomastia occasionally occurs in men*
*FSH & LH encourages the action of the enzyme aromatase (in skin, fat and muscle) in the conversion of
the testosterone to oestrogens gynaecomastia occasionally occurs in men
Treatment of ACTH deficiency replacement therapy with corticosteroids
Examples
Hydrocortisone (cortisol, but it is synthetic)
Cortisone (cortisone is only active after conversion to hydrocortisone in the liver)
Which corticosteroid should be used and suitable?
In adrenocortical insufficiency (e.g. in Addisons disease or following adrenalectomy)
cortisol & aldosterone hydrocortisone alone does NOT usually provide
sufficient mineralocorticoid activity for complete replacement physiological
replacement is best achieved using corticosteroids with a COMBINATION of BOTH
glucocorticoid (hydrocortisone) & mineralocorticoid (fludrocortisone) activity
In hypopituitarism (ACTH deficiency) unlike that in adrenocortical insufficiency
cortisol but the production of aldosterone is still maintained by renin-angiotensin
system (ACTH has only minimal effect on mineralocorticoid production) using
corticosteroids with ONLY glucocorticoid (hydrocortisone) activity should be good
enough. No need to consider mineralocorticoid effect in the replacement therapy of
ACTH deficiency mineralocorticoid is NOT usually required
 Other corticosteroids, e.g. prednisone, prednisolone, methylprednisolone, triamcinolone,
betamethasone and beclomethasone are only the drugs of choice for anti-inflammatory
and immunosuppressive effects. Their relatively strong anti-inflammatory and
immunosuppressive actions are considered to be unwanted side effects during the
replacement therapy (e.g. increase risk of infection)
Glucocorticoid Mineralocorticoid Anti-inflammatory/immunosuppressive

effect effect effect
Hydrocortisone 1 1 1
Cortisone 0.01 0.8 0.8
Prednisolone 2.2 0.8 4
Methylprednisolone 11.9 Negligible 5
Triamcinolone 1.9 None 5
Dexamethasone 7.1 Negligible 30
Betamethasone 5.4 None 30
Fludrocortisone 3.5 150 15
Mechanisms of action
Steroid receptors are intracellular. Once the steroid transverses the cell membrane
and binds to the receptors, the steroid-receptor complexes in the cell nucleus then
bind to chromatin. The drug-receptor-chromatin complexes stimulate the formation
of mRNA and proteins which then produce the characteristic actions of the hormone
Effects of corticosteroids include
Effects of cortisol glucocorticoid activity
uptake & utilization of glucose + gluconeogenesis blood glucose
liver glycogen stores
Because of insulin effect triggered by blood glucose
catabolism of protein
lipolysis
Maintenance of cardiovascular function by potentiation of adrenaline and
noradrenaline effects
Effects of aldosterone mineralocorticoid activity
Act on the distal tubule of kidney to Na+ reabsorption & K+/H+ secretion
Adverse effects
Iatrogenic Cushings syndrome
Redistribution of fat and muscle wasting
Moon face
Buffalo hump
abdominal fat
Thin arms and legs
Thinning of skin
Hyperglycaemia
Hypertension
Growth suppression (by inhibiting the effects of growth hormone)
Osteoporosis
susceptibility to infection
Peptic ulcer
Psychological disturbances
Cataracts
Treatment of hypothyroidism
Mentioned in another lecture
Treatment of prolactin deficiency
No preparation is available
 Hypersecretion of anterior pituitary hormones (hyperpituitarism)
Common causes
Pituitary adenoma
Drugs (e.g. haloperidol)
Symptoms and signs are related to the specific pituitary hormones that are secreted in excess
Prolactin (hyperprolactinaemia) (more common)
Galactorrhoea
Prolactin stimulates mammary gland development & milk production lactation
Hypogonadism
Prolactin has inhibitory effects on hypothalamus ( GnRH secretion) production
of gonadotrophins (e.g. FSH & LH) infertility
E.g. breast-feeding prolactin level mediate an anti-gonadotrophic effect
lack of ovulation breast-feeding women cannot get pregnant
Amenorrhoea
Growth hormone (more common)
When growth hormone hypersecretion begins in childhood before closure of epiphyses,
exaggerated skeletal growth occurs pituitary gigantism
Very tall
Enlargement of facial structure, hands and feet
Excessive secretion of growth hormone in adults acromegaly
Enlargement of facial structures, hands and feet
Oesteoarthritic vertebral changes
Corticotrophin (ACTH) (more common)
Cushings syndrome
Thyrotropin (very rare)
Gonadotropins (very rare)
Treatment of hyperprolactinaemia dopamine receptor agonists (also used in Parkinsons
disease & acromegaly)
Examples
Bromocriptine
Cabergoline
Longer half-life
Higher selectivity for dopamine D2 receptors
Mechanisms of action
Stimulate dopamine D2 receptors on the anterior pituitary gland inhibition of prolactin
production and lactation
Cause significant reduction in the size of prolactin-secreting adenomas
Adverse effects
Postural hypotension
Nausea & vomiting
Dizziness
Constipation









 Treatment of acromegaly and gigantism
Somatostatin
Examples
Octreotide
Longer-acting analogue of somatostatin
Less hyperglycaemic effect
Lanreotide
Shorter-acting than octreotide
Mechanisms of action
Inhibit the release of growth hormone from anterior pituitary
Reduce the tumour size in a minority of patients
Adverse effects
Gastrointestinal disturbance
Nausea & vomiting
Abdominal cramps
Flatulence
Steatorrhoea
Because octreotide inhibits secretion of gastrointestinal peptides, e.g. gastrin,
vasoactive intestinal peptide (VIP), secretin, motilin & pancreatic polypeptide
Gallstones
Because of inhibition of gall bladder motility
Impaired glucose tolerance
Somatostatin inhibits the secretion of insulin from pancreas
Growth hormone receptor antagonists
Examples
Pegvisomant
Mechanism of action
Selectively blocks the growth hormone receptors interferes with growth hormone
signal transduction & hepatic production of somatomedins
Adverse effects
Elevates the levels of liver enzymes, e.g. alanine aminotransferase (ALT) & aspartate
aminotransferase (AST) in liver function test hepatotoxicity? hepatitis?
Nausea & diarrhoea
Dopamine receptor agonists
Examples
Bromocriptine
Cabergoline
Mechanism of action
In normal situation, D2 receptor agonist stimulates growth hormone secretion. In
some patients with acromegaly, by an unknown mechanism, it causes a paradoxical
decrease in growth hormone secretion. The best response have been seen in patients
whose tumours secreted BOTH growth hormone & prolactin
Treatment of Cushings Syndrome metyrapone and trilostane
Mechanism of actions
Metyrapone inhibits 11-hydroxylase in the biosynthetic pathways of corticosteroids
Trilostane inhibits 3-dehydrogenase in the biosynthetic pathways of corticosteroids
Adverse effects
Hypotension
Nausea & vomiting
Headache & dizziness
Rash
v Disorder of posterior pituitary gland
The 2 main hormones of the posterior pituitary are anti-diuretic hormone (ADH) and oxytocin
ADH is released in response to plasma tonicity, circulating blood volume & blood pressure
water reabsorption & vasoconstriction control water content of the body
Oxytocin elicits milk ejection in lactating women
In pharmacological dose, oxytocin used to induce uterine contractions & maintain labour
At physiological levels, its contribution to parturition is very small
Treatment of diabetes insipidus (MOST important disease associated with the disorder of posterior
pituitary gland ADH secretion is impaired continuous production of copious amounts of
hypotonic urine) replacement therapy with anti-diuretic hormone (ADH)
Examples
Vasopressin (= native ADH, but it is synthetic)
Desmopressin
Long-acting synthetic analogue of vasopressin
More selective to V2 receptors potent anti-diuretic effect & less vasopressor effect
Mechanism of action
Stimulate V2 receptors on the renal distal tubules & collecting ducts cAMP trafficking
of aquaporin type 2 to luminal membrane (aquaporin type 3 & 4 are constitutively expressed
on basolateral membrane) permeability of luminal membrane to water
Stimulates V1 receptors on vascular smooth muscle cells vasoconstriction BP
Adverse effects
Vasopressin and desmopressin
Fluid retention
Dilutional hyponatremia
Headache
Nausea
Allergy
Vasopressin (desmopressin is unlikely to cause those problems because desmopressin is less
selective to V1 receptors in smooth muscles)
Spasm of the coronary arteries angina
Abdominal and uterine cramps
v Summary
Treatment of hypopituitarism
Pituitary dwarfism
Somatropin
Gonadotrophin deficiency
Gonadotrophins (follitropin, lutropin a, HCG, choriogonadotropin a, HMG)
ACTH deficiency
Corticosteroids (hydrocortisone, cortisone)
Treatment of hyperpituitarism
Hyperprolactinemia
Dopamine receptor agonists (bromocriptine, carbergoline)
Acromegaly and gigantism
Octreotide & lantreotide
Pegvisomant
Dopamine receptor agonists
Cushings Syndrome
Trilostane & metyrapone
Treatment of posterior pituitary disorder
Diabetes insipidus
ADH (vassopressin, desmopressin)
Thyroid & Parathyroid Glands
Embryology, Anatomy of the Thyroid and Parathyroids

v Thyroid gland (ONLY gland that STORES hormone)

Development (NOT derived from pharyngeal pouches)
At midline caudal to the median tongue bud, an endodermal thickening at foramen caecum
It forms a bilobed structure & migrates ventral to the laryngotracheal tube to reach its definitive
position around the 7th week
During its migration, the thyroid remains connected to the tongue by the thyroglossal duct. This
duct later disappears around late 5th week
Thyroglossal duct cyst may lie at any point along the migratory
pathway of the thyroid gland but is always in the midline of the neck
Sometimes the cyst is connected to the outside thyroglossal fistula
Aberrant/ectopic thyroid tissue may be found anywhere along the
path of descent of the thyroid gland commonly found in base of
the tongue or with the lateral cervical lymph nodes
Ultimobranchial body give rise to C-cells in thyroid gland

Anatomy
Butterfly-shaped gland, which sits on the front of the neck (below thyroid cartilage)
Consists of 2 lobes lying on either side of the trachea and the larynx
The 2 lobes connected by the isthmus (a bridge) at the level of 2nd-4th tracheal cartilage
In 50% pyramidal lobe (an appendix extends from the isthmus towards the hyoid cartilage)
Encapsulated by a tough fibrous capsule
The pretracheal fascia binds the gland in front and at the back of the trachea
Between gland capsule & fibrous capsule posteriorly parathyroid glands
In front of the thyroid are sternothyroid & sternohyoid muscles and cervical fascia
Blood supply (HIGHLY VASCULAR)
Blood supply of the thyroid gland is from
Superior thyroid artery (a branch of the external carotid artery)
Inferior thyroid artery (a branch of the thyrocervical trunk from the subclavian artery)
They thyroid is drained by
Superior & middle thyroid veins draining into internal jugular veins
Inferior thyroid veins draining into the brachiocephalic veins
Nerves closely associated with the thyroid glands
External laryngeal nerve
A branch of the superior laryngeal nerve to supply cricothyroid muscle (tensor of vocal cord)
Recurrent laryngeal nerve
Lies in the tracheoesophageal groove posterior to the inferior thyroid artery
In ~50% cases, this nerve is embedded with the pretracheal fascia
Injury of this nerve results in partial (abductor) or total paralysis of the vocal cord
 Histology
Thyroid gland consist of vesicular follicles
Lined with simple cuboidal to squamous epithelium
Lumen (surrounded by follicular cells) filled with homogenous
colloid thyroglobulin/thyroid hormones
Parafollicular cells or C cells (light staining)
Lies between follicles or embedded within the follicle
Physiology
Follicular cells
Cellular processes of synthesis, iodination of thyroglobulin and its absorption and digestion
Polypeptide chains of thyroglobulin are synthesized (TSH ( cAMP) stimulate
thyroglobulin synthesis) post-translational modifications in the Golgi transport to
apical membrane in vesicles secrete into colloid of lumen of follicle by exocytosis
Iodide (I-) is taken up at the basolateral cell membrane by sodium/iodide symporter (NIS)
from capillaries (TSH stimulate NIS synthesis) transport to apical membrane release
into the thyroid peroxidase by iodide/chloride transporter (pendrin)
Thyroid peroxidase (integral membrane protein bound to apical follicular cell membrane)
catalyses 3 processes (TSH stimulate thyroid peroxidase synthesis)
Oxidation of I- to iodine atom (I2) release into the colloid
Organification
Iodination of tyrosine residue on thyroglobulin 3-monoiodotyrosine (MIT) &
3,5-diiodotyrosine (DIT) within thyroglobulin
Coupling
Condensation of 1 molecule of MIT & 1 molecule of DIT with the elimination of 1
alanine residue triiodothyronine (T3) (covalently bound to thyroglobulin)
Condensation of 2 molecules of DIT with the elimination of 1 alanine residue
tetraiodothyronine/thyroxine (T4) (covalently bound to thyroglobulin)
Thyroglobulin contains T4, T3, & leftover MIT & DIT (iodinated thyroglobulin) stored in
follicular lumen as colloid until thyroid gland is stimulated to secret its hormones (e.g. TSH)
Pseudopods (pinched off the apical cell membrane) engulf colloid (TSH rate of
endocytosis of colloid) by endocytosis into thyroid epithelial cells via 2 pathways
Lysosomal pathway (major pathway)
Lysosomal proteases cleave T4, T3, MIT & DIT from thyroglobulin
T4 & T3 diffuse into capillaries through basolateral membrane by exocytosis
Deiodination of MIT & DIT by thyroid deiodinase I- & tyrosine are salvaged
Megalin receptor-mediated transepithelial pathway
Thyroid hormones triiodothyronine (T3) & tetraiodothyronine/thyroxine (T4)
T4 (33-40% converted to T3 in cells T3 more potent)
Transported in blood bound to thyroxine-binding globulin from the liver
Bind with intracellular receptor molecules and initiate new protein synthesis
Principal actions
basal metabolic rate (BMR) protein synthesis, use of glucose for ATP
production & lipolysis body temperature
cholesterol excretion in bile
body growth (normal growth of many tissues are dependent on thyroid hormones)
Contribute to development of the nervous system
Parafollicular cells
Secrete calcitonin
Principal actions
blood levels of calcium (Ca2+) & phsophates (HPO42-) by inhibiting bone resorption
& accelerating uptake of calcium & phosphates into bone matrix
v Parathyroid gland
Development
During the 5th week, the dorsal recess of the 3rd pharyngeal pouch becomes solid by proliferation,
forming the inferior parathyroid glands
The dorsal recess of the 4th pharyngeal pouch forms the superior parathyroids
The migrate caudally with the thymus and become intimately associated with the dorsal aspect
of the thyroid gland
Ectopic parathyroid tissue may persist along the path of migration
Parathyroid glands are usually embedded between the posterior border & the capsule of thyroid
Most patients have 4 glands, the number vary from 2 to 6

Parathyroid scintigraphy dual phase planar imaging
Patients are injected with tracer (99mTc, Technetium-99m) and imaged at 5 minutes and images
repeated at 2 hours
99mTc is taken up by the thyroid gland, but cleared from the thyroid with a half-life of 30 minutes
It is usually retained by abnormal parathyroid tissue
Histology
2 kinds of epithelial cells
Principal cells (top and bottom)
The major source of parathyroid hormone (PTH) or parathormone
blood Ca2+, Mg2+
blood phosphate
Promotes formation of calcitriol
Oxyphil cells (centre)
Eosinophilic cells
Function unknown

 The Thyroid Gland
Physiology of the Thyroid The thyroid gland is located in the neck, in close approximation to the first part of the
trachea
v Anatomy of the thyroid gland Each lobe receives its blood supply from the superior and inferior thyroid arteries
Located in the neck, in close approximation to the 1st part of the trachea
The lobules of the gland are composed of follicles, the structural unit of the thyroid.
Each lobe receives it blood supply from the superior and inferior thyroid arteries
Each follicle is lined by a simple layer of epithelium surrounding a colloid-filled core.
The lobules of the gland are composed of follicles, the structural unit of the thyroid. Each follicle is
This colloid contains iodinated thyroglobulin, the precursor to thyroid hormones.
lined by a simple layer of epithelium surround a colloid-filled core. The colloid contains iodinated
Principal cells
thyroglobulin, the precursor to thyroid hormones capillary
v Hormones secreted from the thyroid gland capsule

Calcitonin (antagonize the action of PTH) Follicle

cavities
Overview containing
colloid
Produced by the parafollicular (C) cells
32-amino acid peptide hormone that
participates in Ca2+ metabolism regulation Parafollicular (C)
cell
Synthesis & secretion
Calcitonin is initially synthesized as a large precursor molecule that later processed to the
mature peptide hormone
Calcium sensing receptor (CaSR) (GPCR) is responsible for the molecular process of calcium
sensing on the parafollicular cells
concentrations of plasma calcium (> 11 mg/dL) triggers IP3/Ca2+ signalling pathway
calcitonin secretion by parafollicular cells (C cells) in the thyroid gland (thyroid gland response)
bone response, kidney response & intestinal response
Physiological effects NET effect of calcitonin is to reduce plasma calcium content
The activities of calcitonin are mediated by high affinity calcitonin receptor
Bone response
Calcitonin receptor is expressed in osteoclasts
Binding of calcitonin to its receptor inhibits osteoclast motility and induce retraction of
osteoclasts inhibiting bone resorption by osteoclast while osteoblasts continue to lock
and store Ca2+ in bone matrix for mineralization and formation of new bone
This effect is mainly mediated by cAMP/PKA pathway
Kidney response
Binding of calcitonin to its receptor enhances calcium excretion by inhibition of renal
tubular calcium reabsorption calcium loss in urine
calcitriol rate of intestinal absorption Ca2+ absorbed slowly (intestinal response)

 Triiodothyronine (T3) & Thyroxine (T4) known as thyroid hormones
Overview
Produced by the principal cells
Derived from the amino acid tyrosine and bound covalently to iodine (from nutrition)
Poorly soluble in water and are bound to carrier proteins in circulation
Contribute to growth, development, control of body temperature, and energy levels through
control to basal metabolic processes
Synthesis & secretion
Thyroid-stimulating hormone (TSH) from thyrotrophs in anterior pituitary act via TSH receptor
major stimulator for synthesis & secretion of thyroid hormones from follicular thyroid cells
TSH stimulates
The expression of Na/I symporter (NIS) on the basolateral membrane of the principal cells
The production of thyroglobulin and secretion of it into the colloid
Production of thyroid peroxidase initiating the 1st step in thyroid hormone production
Iodide is actively transported from blood into gland against chemical & electrical gradient (NIS)
Conversion of iodide to iodine
Iodine is transported to the follicle cavity and then incorporated into tyrosine molecules on
the protein thyroglobulin to form either mono-iodotyrosine (MIT) and di-iodotyrosine (DIT).
This step is catalysed by thyroid peroxidase
Coupling reaction T4 is formed from 2 DIT whereas T3 is formed from MIT + DIT. This
iodinated thyroglobulin is stored in follicle cavity as colloid
T3 and T4 need to be liberated from the scaffold before they can secrete free hormone into
blood. This requires endocytosis of the iodinated thyroglobulin and digestion by lysosomes
Secreted thyroid hormones circulate in the bloodstream by binding to carrier protein
(thyroxine-binding globulin (TBG), prealbumin & albumin). Only 0.05% is unbound
Active biological half-life of these hormones are 7 days for T4 & 1 day for T3
Physiological effects
T4 is the prohormone, whereas T3 is the active hormone. Therefore once inside the cells, T4
will be converted into T3 BEFORE interacting with thyroid hormone receptor (THR)
The binding of T3 to THRs can result in either OR transcription rates of target genes via
the thyroid hormone-response element (TRE)
2 THRs have been identified THR & THR (BOTH belong to the nuclear receptor superfamily)
THRs are expressed in ALL tissues thyroid hormone acts on essentially ALL cells and tissues!
THR is mainly expressed in brain, heart, skeletal muscle, kidney & liver
THR is highly expressed in brain, pituitary gland, retina, inner ear, lung etc.
v Promote foetal & post-natal central nervous system development by influencing
neuronal migration and myelination
Nervous system
v Enhance sympathetic nervous system activity wakefulness, alertness,
responsiveness to noxious stimuli
Cardiovascular v heart rate, stroke volume, the speed & force of myocardial contraction CO
system v systemic vascular resistance by vasodilation
Skeletal muscle v Development of muscle mass & differentiation of contractile characteristics
v Promote normal growth and skeletal development
Bone
v bone turnover and bone mineral density in adult
v Augment glucose absorption
Gut
v rate of secretion of the digestive enzymes and the motility of the GI tract
v Stimulate lipolysis in white adipose tissue plasma concentrations of fatty acids
Adipose tissues
v Promote thermogenesis and weight loss in brown adipose tissue
v Induce O2 utilization by metabolically active tissues energy expenditure & BMR
Others v cholesterol
v Regulate epidermal cell proliferation and homeostasis
 Disorders
Overview
Thyroid hormone acts on essentially ALL cells and tissues, and imbalances in thyroid
function constitute some of the most common endocrine diseases
Hyperthyroidism
Can occur
During pregnancy
Human chorionic gonadotropin (hCG) from embryos turn on the thyroid function
Graves disease
Autoimmune disease (thyroid-stimulating immunoglobulin, TSI) that continuous
stimulates thyroid hormones production
Signs & symptoms
v Intolerance to heat, facial flushing v Tremors
v Bulging eyeballs (Gravess ophthalmopathy) inflammation around eye area v Weight loss
v Goitre ( hyperplasia & hypertrophy of the gland) X breathe & swallow v Diarrhoea
v Cardiac hypertrophy, rapid and irregular heart beat v Weakness of bone
Hypothyroidism
Happens when there are too little thyroid hormone
Can occur from
Autoimmune inflammatory reaction that leads to atrophy of the gland in adults, e.g.
Hashimotos thyroiditis
Congenital diseases, e.g. cretinism
MOST SEVERE form of hypothyroidism poor development of thyroid gland
Associated with severe mental retardation and learning disability
Medical treatment
Iodine deficiency & overdose
Overdose inhibition of NIS
Signs & symptoms
v Extreme fatigue v Dry skin with brittle and thick nails
v Deep cocky voice
Deposition of mucopolysaccharides in vocal cords
v Weight gain
May also due to damage of external laryngeal nerve
& recurrent laryngeal nerve in thyroidectomy
v Slow heartbeat v Constipation
v Intolerance to cold, subnormal temperature v Muscle weakness
v Goitre v Myxoedema
thyroid hormone negative feedback Deposition of mucopolysaccharides
inhibition on hypothalamus & pituitary TSH (water-binding) in extremities
Resistance to thyroid hormone (RTH)
Happens when there is a mutation in THR reduction/lack of end-organ responsiveness
to thyroid hormone
v Delayed bone development
Mutations v Chronic constipation
in THR v Impaired neural development, abnormal cortical layering and cerebellum development
v SLOW heart rate
v Impaired negative feedback of the hypothalamic pituitary-thyroid axis
Mutations v Goitre impaired negative feedback TSH NOT even in the presence of T3 & T4
in THR v Impaired neural development, abnormal cerebellum and cortical layering
v FAST heart rate
Diagnosis is based on persistent elevations in plasma T3, T4 and often TSH
Affected individuals can have symptoms of BOTH thyroid hormone deficiency & excess
Pharmacological Agents in the Treatment of Thyroid Disorders

v Introduction of thyroid gland and thyroid hormones (triiodothyronine (T3) & thyroxine (T4))
Synthesis of thyroid hormones
Requires iodine, which is ingested as iodide in the diet
Iodide is concentrated in the follicular cells (iodide trapping) rapidly oxidized by peroxidase
iodine (more reactive)
Iodine reacts with tyrosine residues in thyroglobulin (organification) units of T3 & T4 are formed
Thyroglobulin containing these iodothyronines is secreted into the follicles and stored as colloid
Release of thyroid hormones
Controlled by a negative feedback system
Circulating levels of T3 & T4 thyroid stimulating hormone (thyrotrophin, TSH) is released
from the anterior pituitary gland stimulates the transport of colloid into the follicular cells
Colloid droplets fuse with lysosomes protease degrades the thyroglobulin by proteolysis
releasing T3 and T4 into blood circulation
Majority of released thyroid hormones is in the form of T4
Total serum T4 (90 nM) is 40-fold higher than serum T3 (2 nM)
Thyroid only contributes about 20% of the circulating T3, the reminder being produced by
peripheral conversion (mostly in liver)
T3 and T4 in circulation are largely bound to plasma proteins
Controlled by environmental factors, e.g. cold, trauma & stress
release of neurotransmitter by neurons that control peptidergic neurons which produce
thyrotropin releasing hormone (TRH) (hypothalamic releasing hormones) & somatostatin
(hypothalamic inhibiting hormones) change the secretion of TRH or somatostatin at the
median eminence of hypothalamus carried by the portal blood to anterior pituitary
or TSH release from the pituitary thyrotropes
Comparison of thyroid hormones
T3 T4
99.5% bound to plasma proteins 99.95% bound to plasma proteins
Small pool in the body Large pool in the body
Mainly intracellular Mainly in circulation
Fast onset of action Slow onset of action (T4 is converted to T3)
Fast turnover rate (t1/2 = 1 day) Slow turnover rate (t1/2 = 7 days)
Functions of thyroid hormones
Metabolism
in O2 consumption & heat production calorigenic action (IMPORTANT part of the
response to cold environment)
Modulation of the actions of other hormones such as insulin, glucagon, glucocorticoids &
catecholamines + control of enzymatic activities for carbohydrate metabolism directly
metabolism of carbohydrates, fats and proteins
Optimal growth, development, function and maintenance of body tissues
Stimulation of cell growth (direct action) + growth hormone production and its effects
(indirect action) + normal responses to parathormone and calcitonin normal growth of
body and maturation of central nervous system & skeletal development
Mechanism of action of thyroid hormones (similar to that of steroids)
After entering cells, T4 is converted to T3 (T3 is 3-5 times more active than T4)
In the absence of T3, thyroid hormone receptors associate with corepressors bind to promoter
regions of DNA inhibit gene expressions
In the presence of T3, corepressors dissociate from thyroid hormone receptors & coactivators
are recruited gene transcriptions occur generation of mRNA proteins response


v Hypothyroidism (myxoedema)
Causes
Hashimotos thyroiditis (cell-mediated immune response directed against the thyroid follicular
cells) primary hypothyroidism (MOST cases)
Hypopituitarism ( secretion of TSH) secondary hypothyroidism
Goitrogens (e.g. cabbage) [ inhibit iodide uptake]
Drugs (e.g. lithium) [treatment for bipolar syndrome]
Dietary deficiency of iodine
Symptoms
Tiredness and lethargy (MOST common symptoms)
Dry skin
Sebaceous gland secretion of oily sebum
Inhibit heat production sweating impaired
Depression of the basal metabolic rate, appetite and cardiac output
Thyroid hormone deprivation in early life irreversible mental retardation and dwarfism all
newborn infants are screened and replacement therapy should be given if necessary
Treatment
Liothyronine (i.e., Triiodothyronine, T3)
Used for severe and acute hypothyroid states, e.g. hypothyroid coma
Advantage of T3
More active than T4
Less protein bound acts more quickly than T4
Rate of clearance of T3 is 20 times faster than that of T4
Thyroxine (i.e. T4)
Used for routine replacement therapy in hypothyroidism of ANY cause
Advantage of T4
Half-life of T4 is longer
Adverse effects of liothyronine & thyroxine serum T4 & TSH should be monitored
Thyrotoxicosis (i.e. hyperthyroidism due to overdose of thyroid hormone)
Caution in patients with cardiovascular disorder
Thyrotoxicosis worsen ischemic symptom (e.g. angina pectoris, arrhythmias & cardiac failure)
Caution & contraindicated in patients with uncorrected adrenal insufficiency
Thyroid hormones metabolic clearance of adrenocortical hormones acute adrenal crisis
v Hyperthyroidism (thyrotoxicosis)
Causes
Graves disease (MAINLY)
Antibodies cause prolonged activation of TSH receptors excessive secretion of T3 & T4
Thyroid adenoma
Drugs (e.g. amiodarone) [anti-arrhythmic drug]
Amiodarone contains iodine thyroid hormone synthesis
Symptoms
basal metabolic rate heat intolerance & appetite
Warm and moist skin
Sympathetic overactivity
Tachycardia
Angina and high-output heart failure
Sweating
Tremor
nervousness and hyperkinesias
Upper eyelids are retracted a wide stare (exophthalmos)

 Short-term treatment of hyperthyroidism
Usage
For thyrotoxic crisis (thyroid storm) (due to undertreated or untreated hyperthyroidism,
infection associated with hyperthyroidism & sudden withdrawal of T3/T4)
Before surgery
Initial treatment of hyperthyroid patients while the thionamides and 131I are taking effect
Non-selective b-blockers (e.g. propanolol) to relieve acute thyrotoxic symptoms, e.g.
Anxiety/nervousness (b1 in brain?)
Tachycardia/palpitations (b1 in heart)
Tremor (b2 in skeletal muscle)
Non-selective b-blockers in conjunction with Lugols solution (5% iodine + 10% potassium iodide)
Logols solution
Mechanisms of action
Inhibits the iodination of tyrosine residues of thyroglobulin (organification),
PROBABLY by inhibiting H2O2 generation (for peroxidase to work)
Inhibits the release of T3 and T4 from the thyroid gland
size & vascularity of hyperplastic thyroid risk of bleeding during surgery
Usage
0.1-0.3 ml, 3 times daily well diluted with milk or water
The onset is rapid. It improves the thyrotoxic symptoms within 2-7 days
Used pre-operatively before thyroidectomy to reduce the vascularity of the thyroid
( VEGF?) reduce the risk of bleeding during surgery
Desensitization NOT for long-term treatment (usually given for 10-14 days)
Adverse effects
Hypersensitivity (e.g. rashes, fever, angioedema, conjunctivitis, bronchitis & pain in
salivary glands)
Secreted in breast bilk enlargement of thyroid gland in infants contraindicated
in breast-feeding mothers
Long-term treatment of hyperthyroidism
Thionamides (thioamides or thioureylenes) ONLY choice in pregnancy & breast-feeding!!!
Examples
Carbimazole (inactive) in vivo conversion to methimazole rapidly
Methimazole (active, has pharmacological activity)
Propylthiouracil
Mechanisms of action thiocarbamide group (essential for antithyroid activity)
Inhibit peroxidase inhibiting the iodination of tyrosine residues of thyroglobulin
(organification) synthesis of thyroid hormones
Propylthiouracil ALSO inhibits the peripheral conversion of T4 to T3
Usage
Slow onset of action. 3-4 weeks are required because the thyroid gland have large stores
of hormone need to be depleted before the drugs action can be manifest
Therapy is usually given for 18 months
Higher dose in the beginning. When patients become euthyroid, dose can be reduced
Propylthiouracil may be used in patients who suffer sensitivity reactions to carbimazole
(as sensitivity is not necessarily displayed to both drugs)
Adverse effects
Skin rashes, pruritus can be treated by antihistamines without discontinuing therapy
Bone marrow depression (e.g. thrombocytopenia & agranulocytosis, SERIOUS but RARE)
Cross placenta & secreted in breast milk CAN use in pregnancy & breast-feeding with
Use of lowest effective dose
Proper close monitoring
 Radioiodine

Examples
Na 131I
Mechanism of action
Taken up & processed by thyroid gland in the same way as normal iodide becoming
incorporated into thyroglobulin
Emits b radiation destruction of thyroid gland
Usage
For treatment of relapse of hyperthyroidism after thionamide therapy
In some thyroid tumors, to ablate residual tumor tissue after surgery
Single dose is used
Its cytotoxic effect on the gland is delayed for 1-2 months. Recurrence is rare provided
the dose is adequate
Adverse effects
Hypothyroidism will eventually occur after treatment with radioiodine
Managed and treated by replacement therapy with thyroxine
Potential damage to the thyroid gland of foetus and infants avoided in pregnant &
breast-feeding women
Risk of development of carcinoma and infertility (NEGLIGIBLE) theoretical
Surgery
For recurrent hyperthyroidism, large goiter or single adenoma
v Summary
Treatment of hypothyroidism
Liothyronine (T3) for acute hypothyroidism (hyperthyroid coma)
Thyroxine (T4) for routine replacement therapy
Side effects (e.g. thyrotoxicosis)
Treatment of hyperthyroidism
b-blockers and Lugols solution for short-term
Thionamides and radioiodine for long-term
Side effects (e.g. hypersensitivity for Lugols solution and thionamides, hypothyroidism for 131I)

Autoimmune Thyroid disorders and Thyroiditis

v Thyroiditis
Includes conditions that result in acute illness with severe pain and disorders in which there can be
relatively little inflammation and the illness is manifested primarily by thyroid dysfunction
Broadly classified into
Autoimmune types
Non-autoimmune types
v Autoimmune thyroiditis (uncommonly they occur in the same patient and appear to different stages of
one disease, e.g. transition from Graves disease to Hashimoto thyroiditis)
Graves' disease (diffuse toxic goiter, autoimmune hyperthyroidism) organ-specific
Pathogenesis
Production of autoantibodies bind to TSH receptors on the thyroid follicular epithelial cells
(thyrocytes) overstimulation & enlargement of thyroid gland overproduction of thyroid
hormone suppression of TSH production + clinical manifestation of hyperthyroidism
Clinically
The COMMONEST cause of hyperthyroidism
Typically occurs in women between 20 to 40 years old
Characterized by diffuse parenchymatous goitre, hyperthyroidism, ophthalmopathy
(exophthalmos) & sometimes dermatopathy (pretibial myxoedema)
Exophthalmos
Lid retraction & protrusion of eye balls
Pathogenesis
T cells and autoantibodies reactive to the extraocular eye muscles and retro-
orbital tissues inflammatory infiltrate, tissue deposits and weakness of the
extraocular eye muscles cause the eye signs
Possible complications
Keratoconjunctivitis blindness
Compression on optic nerve blindness
Dermatopathy
In < 5% of Graves disease patients
Localized non-pitting oedema of skin
Hyaluronic acid accumulates in dermis and subcutis
Associated with
HLA types (genetic factors 25% concordance in identical twins)
HLA-DR3 and HLA-B8 in Caucasians
HLA-DR9 in Chinese
Other autoimmune diseases
E.g. SLE, pernicious anemia, type I diabetes, Addison's disease, etc.
Laboratory testing
Autoantibodies to TSH receptors (long acting thyroid stimulator half-life of TSH is 1-2 hours)
Thyroid-stimulating immunoglobulin (TSI)
Thyrotropin receptor antibodies (TRA)
Thyroid growth-stimulating antibodies
Other antithyroid antibodies (anti-thyroglobulin & anti-thyroid peroxidase (microsomal)
antibodies) indicative of autoimmune thyroiditis may also
Histological appearance
Thyroid follicles are hyperplastic with papillary infolding
Scanty colloid content
Patchy lymphocytic infiltration
May be altered by drug therapy (e.g. towards normal by pre-operative iodide)

 Treatment
Antithyroid drugs (carbimazole, methmazole) for 6 months to 2 years
Positive thyrotropin receptor antibody at end of treatment predicts disease recurrence
-blockers
131I therapy
Subtotal thyroidectomy
Pre-operative treatment with iodide to decrease function and vascularity of gland
Related entity toxic nodular or multinodular goiter
The changes are similar to Graves disease EXCEPT
Limited to nodular foci rather than involving the entire thyroid gland in a diffuse process
Case studies
Clinical history
A 30 year old woman with palpitation, fatigue, nervousness, difficulty in sleeping, and
excessive sweating. Weight loss of 15 kg in the past year and hot weather intolerance
Physical findings
BP 160/70, pulse 118 per minute and irregular, respiration 30 per minute
Eye show lid-lag and lid retraction
Thyroid diffusely enlarged and has a systolic bruit
Hashimoto's thyroiditis
Pathogenesis
Cell mediated autoimmune reaction against the thyroid cells parenchymal destruction
Thyroid enlargement is a result of lymphoid infiltration AND TSH-stimulated proliferation
TSH is elevated due to ineffective production of thyroid hormones (Hrthle cell change) in
thyroiditis
Clinically
More common in middle-aged women
Usually associated with hypothyroidism, but patient may be euthyroid & later hypothyroid
May have an early phase of hyperthyroidism
Presence of diffusely enlarged thyroid gland (firm and lobular), progressive growth of goitre
or hypothyroidism indicates the need for replacement thyroid hormone
Associated with
HLA-DR haplotypes
HLA-DR3 and DR5
Other autoimmune diseases
E.g. SLE, rheumatoid arthritis, pernicious anaemia, etc.
Laboratory testing
Thyroid function tests
Antithyroid antibodies (anti-thyroglobulin & anti-thyroid peroxidase (microsomal) antibodies)
Often raised (moderately) in Graves disease and fibrous atrophy of thyroid
Usually measured clinically as a confirmatory test for autoimmune thyroiditis
High titres evidence of autoimmune thyroiditis
Histological appearance
Diffuse lymphocytic infiltration
Frequent lymphoid follicles with germinal centre formation
Variable fibrosis may be marked (fibrous variant), but the thyroid remains large
Loss of thyrocytes
Hrthle cell change
Oxyphilic or oncocytic metaplasia, when thyrocytes are enlarged with a distinctive
eosinophilic cytoplasm increased number of mitochondria
Ineffective hormone production
 Complication
Tracheal compression, especially when the thyroid is retrosternal
Malignant lymphoma (uncommon but well recognized)
Usually diffuse large B cell lymphoma
Treatment
Observe and wait (early period)
Replacement thyroid hormone
Surgery
Relieve pressure effects (especially for retrosternal goitre)
Cosmetic reasons
Variants and related entities
Fibrous variant
Hashitoxicosis
Clinically
Evidence of Graves disease
Histological features
Hashimotos thyroiditis (including lymphocytic infiltration, follicular atrophy &
oxyphilic metaplasia)
Lymphocytic thyroiditis
Clinically
NO clinical or gross disease attributable to thyroiditis
May be non-specific or represent a mild form of Hashimotos thyroiditis
Histological features
Scattered lymphoid aggregates are present in the thyroid gland
Laboratory testing
May indicate a mild degree of subclinical hypothyroidism
Laboratory evidence of autoimmune thyroiditis is usually absent
Juvenile form of lymphocytic thyroiditis
Histological features
Chronic lymphocytic infiltrate
Follicular atrophy and oxyphilic metaplasia are focal or absent
Hyperplastic epithelial changes may be seen
Laboratory testing
Mildly to markedly elevated anti-thyroglobulin antibodies may be present
Silent thyroiditis/Painless thyroiditis with hyperthyroidism, e.g. postpartum thyroiditis
Clinically
Affects young and early middle age men and women
Symptoms are similar to Graves' disease but milder
Thyroid gland is slightly enlarged episodic hyperthyroidism
Exophthalmos (opthalmopathy of Graves' disease) does NOT occur
Needs no long term treatment, 80% of patients show complete recovery and return
of the thyroid gland to normal after 3 months
Histological features
Lymphocytic infiltration
Oxyphilic metaplasia
Follicular hyperplasia
Laboratory testing
Elevated anti-thyroglobulin antibody levels
Hashimotos thyroiditis & Graves disease sometimes share common features. They are both autoimmune
diseases. One disease can develop into another. Despite their shared features, there are sufficient
differences to consider them as distinct disorders & not the opposite end of the spectrum of a single entity
 Fibrous atrophy of the thyroid (idiopathic myxoedema)
Pathogenesis
Antibodies directed against thyroglobulin and microsomal antibodies, detectable years
before the onset of hormonal failure, and cell-mediated immune mechanisms contribute to
the pathogenesis
When 90% of the gland is destroyed, the secretion of thyroid hormones (T3/T4) falls below
normal needs
Pituitary thyrotrophs react by producing > 100 times the normal amount of TSH which should
normally lead to regrowth of the gland as happens in goitrous Hashimoto thyroiditis
The inability of the thyroid in primary myxoedema to respond to TSH suggests that blocking
antibodies exist in this disease which compete with TSH for its receptors
Myxoedema
Skin puffiness due to infiltration with hyaluronic acid and chondroitin sulphate
These skin changes are due to hypothyroidism
Facial puffiness and periorbital swelling
Periorbital haemorrhage is due to increased fragility of swollen dermal tissues
Clinically
Progressive shrinking of the thyroid gland
Presents with hypothyroidism
May represent the end stage of the fibrous variant of Hashimotos thyroiditis
Histological features similar to those of the fibrous variant of Hashimotos thyroiditis, including
Loss of epithelium
Oxyphilic and squamous metaplasia of follicular cells
Dense infiltration by sensitized lymphocytes and plasma cells (chronic inflammatory cells)
Final replacement of the gland by prominent keloid tissue-like fibrosis tissue
Marked atrophy and loss of follicles
v Non-autoimmune thyroiditis
Acute Infectious thyroiditis (RARE)
Histologically
Presence of an inflammatory cell infiltrate is dominated by polymorphs
Abscess and microorganisms (bacteria, fungi) could be found
Granulomatous thyroiditis
Infectious
TB & fungal infection
Subacute granulomatous thyroiditis (De Quervain's thyroiditis)
Clinically
Usually follows a URTI, probably due to viral infection self-limiting
Pain and tenderness, enlarged thyroid gland
Histological features
Follicular necrosis
Infiltration by a mixture of polymorphs, macrophages, multinucleated giant cells, plasma
cells and lymphocytes
Painless (Silent) subacute thyroiditis
Clinically
Enlargement of thyroid gland with NO tenderness or pain
Clinical course similar to subacute granulomatous thyroiditis
Histological features
Similar to subacute granulomatous thyroiditis
Palpation thyroiditis
Vigorous clinical palpation of the thyroid traumatically induced lesions
Involvement in sarcoidosis
 Invasive fibrous thyroiditis (Riedels thyroiditis) (RARE) UNKNOWN aetiology
Clinically
Prone to be mistaken for malignancy
The very hard gland densely adheres to the surrounding soft tissue
Fibrosis may compress the trachea or oesophagus
Patient is usually euthyroid (remain stable over many years), or may progress slowly
hypothyroidism may supervene (approximately 30%)
May also be a form of the IgG4-related sclerosing disease (multifocal fibrosis)
Presence of circulating anti-thyroid antibodies in a large proportion of patients favours an
autoimmune pathogenesis may overlap with autoimmune thyroiditis
Associated with other diseases
E.g. idiopathic, multifocal fibrosis (e.g. mediastinal, retroperitoneal)
Histological features
Replacement of the thyroid parenchyma by fibrous tissue
Chronic inflammatory cell infiltration
Radiation thyroiditis
Causes
External radiotherapy
Radioiodine treatment
Histological features
Architectural and nuclear atypia
Parenchymal fibrosis
Chronic (lymphocytic) inflammation
Vascular sclerosis
Intimal thickening
Benign and malignant tumours may develop secondary to external radiation
Drug-induced thyroiditis
Clinically
Similar to silent thyroiditis
Relatively acute onset
Thyroid function ranging from hyper to hypothyroidism
Histological features
Similar to silent thyroiditis
Focal lymphocytic infiltration
Follicular disruption
Agents, e.g.
Iodide
Lithium
Anticonvulsant drugs
Amiodarone
Peri-tumor thyroiditis
A lymphoid infiltrate probably results from a reaction to the altered antigens on the tumour cells
v Summary
Graves disease Hashimotos thyroiditis
v Hypothyroidism
v Hyperthyroidism
v Diffuse goitre
Characteristics v Diffuse goitre
v Thyroid lymphoid infiltrations
v Exophthalmos
v Autoantibodies to thyroglobulin & peroxidase
Cell mediated autoimmune reaction against the
Pathogenesis Autoantibodies to TSH receptors
thyroid cells

Introduction to Radiology of Thyroid Disorders & The Use of Radioactive Iodine Therapy

v Introduction to radiology of thyroid disorders

Thyroid gland
Anatomy
Bilobed across trachea
Joined by isthmus
Bound by pretracheal fascia
Pyramidal lobe = accessory lobe of the thyroid gland
Up to 50%
From isthmus
Hypothalamus-pituitary-thyroid axis
Neurons in the hypothalamus secrete thyroid releasing hormone (TRH) stimulates cells in
the anterior pituitary to secrete thyroid-stimulating hormone (TSH) binds to TSH receptors
on epithelial cells in thyroid gland stimulates synthesis & secretion of T3 & T4
Malignancy
Carcinoma
Papillary 75%
Follicular 10%
Medullary 5%
Anaplastic < 5%
Lymphoma < 5%
Metastases (lung, breast, renal)
Sarcoma (rare)
Imaging
Required to
Confirm enlargement of thyroid gland (US, CT)
Characterize nodules or masses (US, radionuclide scan)
Investigation of thyroid function (radionuclide scan)
Evaluate local disease in known cases of thyroid carcinoma (US, CT, MRI)
Detect recurrent after thyroidectomy or treatment in known cases of thyroid carcinoma (US,
CT, MRI, radionuclide scan)
Techniques
Plain radiographs (limited value)
E.g. retrosternal goitre extending into superior mediastinum with tracheal displacement
Limitations
Does NOT give extent of compression or displacement of trachea
CANNOT evaluate other mediastinal structures
Ultrasound
Normal thyroid gland
Transverse section showing
2 lateral lobes on either side of trachea
Narrow isthmus anterior to the trachea
Longitudinal scan
Homogenous echogenicity with smooth outlines
Advantages
No radiation
Excellent for evaluating superficial structures such as the thyroid gland
High frequent (7.5-10 MHz) probe
Excellent spatial resolution
Sensitive in detecting tiny nodule
 Functions
Characterize nodule (solid VS cystic), e.g.
Colloid cyst (2 features)
Acoustic enhancement
echoes deep to structures that transmit sound exceptionally well
Characteristic of fluid filled structures, e.g. cysts
Ring-down artifact inspissated colloid calcification in benign thyroid nodule
Hyperplastic nodules/adenomas
Solid nodule +/- cystic centre

Vascularity (colour Doppler), e.g.
Graves disease
Diffuse enlargement of thyroid
Increased vascularity shown on colour Doppler

Papillary carcinoma
Colour Doppler shows rich intranodular vascularisation

Guides needle aspiration/biopsy
***Major limitation
CANNOT distinguishable between follicular adenoma and follicular carcinoma
requires histology rely on capsular or venous invasion
Assess neck for lymph node metastasis in thyroid cancer

 Sonographic signs
Calcifications in BOTH benign and malignant conditions (non-specific)
Microcalcifications (psammoma bodies, 10-100m) specificity 85.8-95%
Malignant
Common in papillary carcinoma
Follicular carcinoma (nodule & shadowing)
Anaplastic carcinoma
Benign
Follicular adenoma (nodule & shadowing)
Hashimoto thyroiditis
Coarse calcifications
Common in medullary carcinoma
Dystrophic calcifications (large, irregular)
Related to tissue necrosis
Common in multinodular goitre
If solitary 75% malignancy

Margin/Contour
Ill-defined/Irregular margin 53-89% malignant
AP/transverse dimension ratio (taller than its width) 93% malignant
E.g. infiltrative margin with local invasion in anaplastic carcinoma

Vascularity
Complete avascular is unlikely to be malignant
Intrinsic vascularity 69-74% malignant
Perinodular vascularity 22% malignant
Hypoechoic darker the appearance risk of malignancy
Size (non-specific) > 4 cm slight favour of malignancy but not absolute
Number (non-specific)
Comparable risk of malignancy between multinodular goitre and solitary nodule
Follicular carcinoma is FREQUENTLY found in multinodular goitre
Sonographic features of malignancy
Invasion into surrounding tissues
Microcalcification
Lymph node > 8 mm in short axis diameter
Key messages!!!
UNABLE to differentiate ACCURATELY between benign and malignancy
Purely cystic very rarely malignant Purely solid 23% malignant Mixed solid & cystic 14% malignant
 Computed tomography (CT) & magnetic resonance imaging (MRI) cross-sectional anatomy
Functions
Intrathoracic extension of goitre
Evaluate local and distal extent of disease
Post-surgical or radioactive treatment surveillance for recurrence
CT scans examples

Enlarged thyroid with cystic areas Large mass in the left side of neck
Enhancing normal thyroid tissue
extending below level of clavicles with malignant node in anaplastic
at base of neck
into the retrosternal area carcinoma of thyroid
MRI scans examples

Axial Coronal
10 years post thyroidectomy for papillary carcinoma, found enlarging neck mass. Excision biopsy showed
metastatic node
Radionuclide scans
99mTc pertechnetate VS Iodide scan provide functional information
99mTc pertechnetate
Trapped by thyroid tissue
NOT incorporated into thyroglobulin (X organification)
Imaging at 20 mins after injection
Anterior, left & right oblique views
Normally uniform uptake in thyroid
Iodide scan
Trapped and organified (iodine incorporated into thyroglobulin to form T3 & T4)
2 isotopes for use 123I vs 131I

 Thyroid imaging radiopharmaceuticals
KeV Options Functional information
99m
140 Tc pertechnetate Iodine Trap
123
159 I Iodine Trap + Organification
131
365 I Iodine Trap + Organification
201
69-80 Tl Perfusion
99m
140 Tc MIBI Perfusion & Mitochondrial Density
Relationship between clinical, in vivo & in vitro results
Clinical Uptake T4 TSH
Normal Normal Normal Normal
Hyperthyroid High High Low
Iodine deficiency High Normal Normal
Thyroiditis (acute/subacute) Low High Low
Hypothyroid Low Low High
Functions
Assesses metabolic function
Hot (increased uptake)
Virtually exclude cancer (<1% are hot)
33%-50% are autonomous
Lost their normal ability to be regulated by TSH produce excess amount
of thyroid hormone (functioning hot adenoma) hyperthyroidism
Accounts for 30% of solitary nodules
Cold (no uptake)
Almost ALL cancers are cold
CA thyroid, e.g. papillary carcinoma
Lymphoma
Metastasis
Most cold nodules are benign lesions
Colloid nodule & hyperplastic nodule
Adenomas (clinically silent)
Thyroiditis normal uptake in salivary glands, enlarged gland with non-
uniform patchy decreased uptake of tracer (cold)
10-25% of solitary cold nodule is malignant
Key messages!!!
Majority is still benign
Likelihood of malignancy increases if solitary lesion
ALWAYS require needle biopsy/aspiration for the benefit of doubt
Examples of hot & cold nodules
Adenoma
Multinodular goitre

 Shows position of ectopic thyroid gland, e.g.
Uptake at tongue due to failure of descent of thyroid gland along the thyroglossal
duct tract from foramen caecum absence of normal thyroid in neck

Follow-up after treatment
Whole body 131I scan (left)
Thyroid hormones to be discontinued before
4 weeks for T4
2 weeks for T3
Low iodine diet for 7 days before
Increased detection rate if scan after 7 days
Elevated thyroglobulin but negative 131I scan
201TI 49%
99mTc-MIBI 88%
18F-FDG PET/CT 94% (right)

Summary
US & radionuclide scans are usual imaging modalities
US is sensitive but not specific useful for guiding FNA of nodules
CT and MR are reserved for evaluation of
Intrathoracic extension
Post-resection/therapy evaluation
v The use of radioactive iodine therapy
Radioactive iodine
Radioactive iodine can be used for diagnosis and treatment of malignant diseases
Medically used iodine include 123I, 124I, 125I & 131I
131I is the MOST commonly used iodine isotope as therapy for thyroid-related diseases
125I as nuclear imaging tracer and radioactive treatment for prostate cancer
123I & 124I used as nuclear imaging tracers for thyroid diseases
Hyperthyroidism
Causes
Graves disease
Toxic adenoma
Toxic multinodular goiter
Thyroiditis
Iodine-induced hyperthyroidism (e.g. amiodarone)
Excessive pituitary TSH or trophoblastic disease
Excessive ingestion of thyroid hormone (thyrotoxicosis factitia)
Ectopic thyroid production or functional metastatic CA thyroid
Treatment
Surgery thyroidectomy
Usually total thyroidectomy with T4 replacement afterwards. Cure rate > 90%
Uncommonly practiced nowadays
Usually reserved for multinodular/large goiter
With compressive symptoms (3Ds dysphagia, dysphonia, dyspnoea)
Pregnant patients intolerant to antithyroid drugs
Suspected coexistent thyroid cancer
Cautions
Need to restore rapid euthyroidism before surgery
Safe in 2nd trimester of pregnancy
Potential complications
Hypoparathyroidism (<5%)
Vocal cord paralysis (1-2%)
Complications of surgery and general anesthesia
Anti-thyroid medication propylthiouracil, methimazole & carbimazole
Restore euthyroidism within 3-4 weeks in 90% of patients
Duration of treatment
12-18 months
Long term remission
40-60% in Graves disease
Limitations
Retreatment for relapse needed and seldom curative
NOT definitive treatment for toxic nodular goiter
Uses
For pregnant patients
For control of disease before definitive treatment
For toxic crisis
Side effects
Thioamides (propylthiouracil, methimazole & carbimazole)
5% allergy
0.5% agranulocytosis
PTU (propylthiouracil)
Raised liver transaminases
 131
I radioactive iodine treatment
Overview
- & -emitting radionuclide
Principle -ray 364 KeV (10%)
Principle -ray particles
Maximum energy of 0.61 MeV, average of 0.192 MeV
Range in tissues 0.8 mm
Physical half-life 8.02 days
Administration sodium iodide (oral)
Targeted because of preferential thyroid uptake via sodium-iodide symporter or co-
transporter (NIS)
Actual delivered dose to thyroid depends on
Amount of 131I given
Uptake by thyroid cells
Size of thyroid gland
Estimate of thyroidal turnover rate (effective half life)
Difficult to titrate dose to achieve euthyroidism may require repeated treatment
Fixed dose (74-111MBq (Becquerel ) or 2-3mCi (Curie ))
Ablative dose (370-740MBq or 10-20mCi)
1mCi = 37MBq
Clinical use
Treatment of benign thyroid disease (hyperthyroidism)
Treatment of well-differentiated thyroid cancer including papillary thyroid cancer
and follicular thyroid cancer
Treatment for Graves disease, toxic nodular goiter
Can also be used as a radioactive label for certain radiopharmaceuticals (e.g. 131I-
metaiodobenzylguanidine i.e. 131I-MIBG for pheochromocytoma and neuroblastoma)
Effects
80-90% euthyroid within 8 weeks after a single dose
Reduce goiter size by 40% in toxic multinodular goiter
Caution
Graves ophthalmopathy may develop or worsen after treatment with 131I
Contraindication
Absolute
Pregnancy
Lactation
Relative
Children
Adolescents
Adverse effects
Acute side effects mild and well-tolerated (e.g. mild neck swelling, pain on swallowing)
Long-term safety
NO effect on fertility
NO increased incidence of congenital malformations
NO increased risk of developing cancer in patients or their offspring
Risk of post-RT hypothyroidism
Monitoring for hypothyroidism with regular serum thyroid function test
Requiring life-long thyroxine (T4) replacement if hypothyroid



 Preparation
Observe national and local legislation and regulations on the safe use of radioisotope
therapy
Facilities must have trained personnel, equipment for storage and radiation
protection, procedures for waste handling and disposal, monitoring, controlling, and
handling contaminants
Discussion of treatment options, patients consent, instruct patients on post-therapy
precautions and follow-up
Avoid iodine-containing food, medicine (e.g. some cough suppressant) or radiographic
contrast at least 4 weeks before 131I therapy
Avoid anti-thyroid medication 4 weeks before 131I therapy
Precaution
Pregnancy test for patients with child-bearing potential
Control of symptoms of hyperthyroidism before and after 131I (e.g. propranolol for
palpitation)
Home immediately after 131I therapy
No close contact with spouse/partner and children (keep away for 3 meters) for 1-2
weeks
Safe contraception for at least 6 months
Avoid pregnancy and breast feeding for at least 6 months after 131I therapy
IMPORTANT!!!
131
Surgery Anti-thyroid drugs I therapy
Relapse Low High Low to intermediate
Risk of long-term hypothyroidism Intermediate to high Low Intermediate to high
Low but significant
Other long-term complications Rare Rare
morbidity
Ease of treatment and cost Intermediate Least favourable Simple and easy
Onset of therapeutic effects Immediate Days to weeks Slow (3-4 months)
Well-differentiated thyroid cancer
Overview
Papillary (~80%), follicular (~20%), Hurthle cell CA
Can still concentrate iodine but defects in metabolism
Uptake via NIS is reduced and even undetectable in 1/3 cases
Iodine organification is markedly reduced
Compared with normal thyroid tissue
Shorter effective half-life of 131I (more rapid clearance of 131I)
Less responsive to TSH stimulation but can be stimulated to uptake iodine and
thyroglobulin production
Large 131I dose required to eradicate residual normal thyroid tissues and tumour cells (0.9-
3.7GBq or 30-100mCi) or even larger dose for recurrence/distant metastasis (3.7-5.5GBq
or 100-150mCi)
131I therapy (after total thyroidectomy)
Recommended for most EXCEPT the very low-risk patients (e.g. solitary tumour < 1 cm in size)
Eradicates ANY residual microscopic tumour cells & remaining normal thyroid tissue
Makes serum thyroglobulin (Tg) a more specific tumor marker
Facilitates future surveillance for relapse with 131I-Whole Body Scan (WBS)
Advantages
Reduces loco-regional recurrences
Eradicates distant metastases
Reduces relapse and improves overall survival
Can be safely adopted after surgery and before external radiotherapy
 Preparation before 131I therapy
Similar as that for benign hyperthyroidism
Withdrawal from T4 for at least 4 weeks or T3 for at least 2 weeks TSH production
from pituitary iodine uptake by residual thyroid tissue/tumour cells
Low iodine diet for at least 1-2 weeks
Can consider recombinant human TSH (rh-TSH) injection to increase iodine uptake ability
for those who cannot tolerate prolonged hypothyroidism
rh-TSH is made from recombinant human DNA technology to provide an exogenous
source of TSH
Procedures after 131I therapy
Post-131I therapy 131I- whole body scan
~ 7 days after 131I therapy screen for residual thyroid uptake or distant metastasis
6-12 months after 131I therapy detect any relapse/metastasis
Start supra-physiological dose of thyroxine (TSH suppression therapy) to keep TSH below
the lower limit of normal range
Regular monitoring with serum thyroglobulin
Avoid pregnancy for 1 year and until disease stable
Monitor thyroid function during pregnancy
Side effects
Usually minimal and transient
E.g. sialadenitis, nausea/vomiting, epigastric discomfort, cystitis
People with residual thyroid tissue after surgery neck pain/swelling may need
steroid cover
Large dose of 131I
Bone marrow suppression (very rare)
Aplastic anaemia (very rare)
Leukaemia (very rare)
Pulmonary fibrosis (increased in those with lung metastasis)
131I therapy for bone metastases
Risk of neurological complication if vertebral metastases
Steroid cover should be given
Small dose to gonads
Effect on fertility usually transient
NO hormonal failure
NO evidence of increased genetic defects/malignancy in offspring
Summary
Radioactive iodine especially 131I is commonly used for benign hyperthyroidism and well-
differentiated thyroid cancer
Aware of the comparison with surgery and anti-thyroid medication for benign hyperthyroidism
Preparation and precaution before 131I therapy
Acute and long-term complications of 131I therapy










Physiology of Calcium and Phosphate Metabolism

How calcitriol acts on GI epithelium to increase calcium absorption?

It binds to cytoplasmic receptor to promote the expression of calcium binding protein
Extracellular calcium concentration is regulated b calcitonin, parathyroid hormone and vitamin D
1. Name the cell type in the parathyroid land which is responsible for PTH synthesis.
PTH is synthesized in the chief cells
2. List TWO effects of PTH on the bone cells and TWO effects on the kidney.
On the bone, PTH stimulates the formation of new osteoclasts & activates the existing osteoclasts
On the kidney, PTH enhances calcium ion reabsorption in the distal tubule & promotes the
conversion of vitamin D to its biologically most active form, 1,25-dihydroxyvitamin D
3. Describe the regulation of calcitonin secretion AND the principal effect of calcitonin.
Increase plasma calcium ion promotes calcitonin secretion which reduce plasma calcium ion level
4. How does Vitamin D affect the actions of PTH on bone?
Vitamin D augments PTH activity by increasing the number of osteoclasts and by increasing the
osteoclastic activity
v Calcium
Physiological roles
Calcium salts in bone provide structural integrity of the skeleton
Calcium ions in extracellular and intracellular fluids are essential to many cellular processes e.g.
neuromuscular excitability, blood coagulation, hormonal secretion and enzymatic reactions, etc.
Human body contains ~ 1 kg calcium
99% of calcium is found in the bone. Most of it in the form of hydroxyapatite crystal,
Ca10(PO4)6(OH)2
0.3% of calcium is located in muscle
0.1% of calcium is found in extracellular fluid (~ 1,000 mg)
Plasma calcium concentration is maintained within a very narrow range (8.5 ~ 10 mg/dL) exists
in 3 forms
Ionized calcium (Ca2+) 50%
Protein-bound (albumin & globulins) 40% non-diffusible
Complexed with anions, e.g. citrate or phosphate 10%
Turnover two types of calcium in bone
Readily exchangeable reservoir that is in equilibrium
with ECF
Large stable calcium pool that is slowly exchangeable
by bone remodelling
v Phosphate
Physiological roles
Phosphate serves as an important component of intracellular pH buffering and various metabolic
intermediates
Exists in DNA, RNA and phosphoproteins
A major component of bones
Body contains about 600 g phosphorous 50% to 150% variation
86% in the bone
14% in cells
0.08% in extracellular fluid
Plasma phosphate concentration is maintained within a very narrow range (2.5 to 4.5 mg/dL)
exists in 2 forms
Diffusible phosphate (87%) MOST
Primarily as inorganic orthophosphate (PO43-), e.g. HPO42- (80%) and H2PO4- (20%)
Non-diffusible phosphate (13%)
Bound with protein
v 2 mechanisms are involved in the regulation of plasma Ca2+ & PO43-
Non-hormonal regulations (rapid but limited capacity) 1st line defence
Protein-bound calcium
Association of calcium with protein is a simple, reversible chemical equilibrium process
Ca2+ + protein Ca:protein
Serve as a buffer
Effect is rapid, NO complex signalling pathway is required
Limited capacity (~500 to 600 mg)
Serve a short-term role
Exchangeable pool in bones
Approximately 4 to 5 g exchangeable bone calcium is in equilibrium with plasma calcium
Located on the surface of newly formed bones (amorphous calcium phosphate, CaHPO4)
Ca2+ + HPO42- CaHPO4.2H2O Ca10(PO4)6(OH)2 (hydroxyapatite)
Hormonal regulation (slower but greater capacity)
3 principal hormones regulate Ca2+ resorption, reabsorption, excretion and absorption & 3 organs
(bone, kidney & intestine) are involved in Ca2+ homeostasis
Parathyroid hormone (PTH)
Origin
The parathyroid glands are four pill-sized structures, embedded in the upper and
lower thyroid poles
The parathyroid glands receive blood supply from
Inferior thyroid arteries ONLY
Drain into superior, middle and inferior thyroid veins
Superior & middle thyroid veins internal jugular vein
Inferior thyroid veins brachiocephalic vein
The glands contain numerous small rounded cells called chief cells, which synthesize
& secrete parathyroid hormone (PTH) in response to plasma Ca2+ concentration
Ca2+ PTH Ca2+
Synthesis
PTH is translated as a pre-prohormone (115 amino acids)
Cleavage of leader and pro-sequences yields a biologically active prohormone (84
amino acids)
Further cleavage occurs in liver and kidney
The N-terminal fragment (34 amino acids) is bioactive while C-terminal fragment
(PTH-C) is an inactive peptide
Regulation of secretion
The dominant regulator of PTH secretion is plasma Ca2+
Secretion of PTH is inversely related to [Ca2+]
Maximum secretion occurs at plasma [Ca2+] below 3.5 mg/dL
At [Ca2+] above 5.5 mg/dl, PTH secretion is maximally inhibited
Mechanism of secretion
PTH secretion responds to small alternation in plasma Ca2+ within seconds
A unique calcium receptor (CaSR) on the plasma membrane of parathyroid cells senses
changes in extracellular [Ca2+]
Coupled to BOTH
Phospholipase C (activate)
Adenylate cyclase (inhibit)
plasma Ca2+ binding of Ca2+ to the receptor intracellular [Ca2+] &
cAMP prevents exocytosis of PTH from secretory granules PTH
Active vitamin D inhibits PTH gene expression, providing another level of feedback
control of PTH
 Action
Main action plasma Ca2+ and plasma phosphate
Bone
Ca2+ resorption release of calcium into plasma
Physiological effect on osteoclasts (indirect, occurs over several days)
Activates the osteoclastic activity
Promotes formation & proliferation of osteoclasts
Physiological effect of PTH on osteoblasts and osteocytes (fast phase)
Promotes osteocytic osteolysis
Form an interconnected membrane network known as the osteocytic
membrane that overlying the bone matrix with a thin layer of bone fluid
PTH promotes Ca2+ pump activity in the osteocytic membrane system
Osteocytes take up Ca2+ from the bone fluid and transport it to ECF through
the osteoblasts
Kidney
Ca2+ reabsorption in distal tubule Ca2+ urinary excretion
formation of 1,25-(OH)2 vitamin D GI Ca2+ absorption (intestinal)
phosphate reabsorption in proximal tubules phosphate urinary excretion
1,25-dihydroxyvitamin D (calcitriol) steroid hormone (binds to cytoplasmic receptor)
Origin (2 sources)
Produced in skin by UV radiation
Ingested from the diet
Synthesis
UV stimulates vitamin D formation in keratinocytes of the skin
7-dehydrocholesterol is photoconverted to previtamin D converts to vitamin D3
spontaneously
Diet/ supplements
Egg yolk, fish oil etc. vitamin D3
Ergosterol (plant form of vitamin D) vitamin D2
Vitamin D3 & D2 are inactive requires sequential modifications (hydroxylations) to
form the active metabolite 1,25-(OH)2 vitamin D
1st hydroxylation (liver)
Vitamin D 25-hydroxylase yielding 25-(OH) vitamin D (calcidiol) from vitamin
D3 & vitamin D2 loosely regulated
nd
2 hydroxylation (kidney)
VD3 1-hydroxylase yielding active 1,25-(OH)2 vitamin D (calcitriol) from 25-
(OH) vitamin D stimulated by PTH & low [Ca2+]
Action
Main action absorption of Ca2+ in intestine epithelium
Intestine
Induces the production of calcium binding proteins (CaBP or calbindins) which
sequester Ca2+, buffer high [Ca2+] that arise during initial absorption and allow Ca2+
to be absorbed against a high Ca2+ gradient
production/activity of Ca2+ channel & transporter (TRPV6, NCX & PMCA) in
intestinal epithelium
absorption of phosphate
Bone
activity of osteoclasts potentiate PTH effect on Ca2+ resorption from bone
Kidney (MINOR effect)
Ca2+ & PO43- reabsorption in kidney tubules Ca2+ & PO43- urinary excretion

 Calcitonin
Origin
It is secreted by the thyroid (parafollicular cells or C cells)
Secretion is stimulated by high plasma Ca2+
Ca2+ CT Ca2+
Action
Main action plasma Ca2+
While PTH & vitamin D plasma Ca2+ ONLY calcitonin plasma Ca2+
Bone
inhibiting osteoclastic activity and proliferation bone resorption
Kidney
renal Ca2+ reabsorption
renal phosphate excretion
In addition to PTH, vitamin D and calcitonin, many other hormones affect the bone formation and
resorption (bone remodelling) affect the calcium metabolism
Bone remodelling
Ca2+ is continually being deposited and resorbed bone remodelling
3 principal cell types are involved
Osteoclasts (hemopoietic origin)
Are responsible for bone resorption
Large multinucleated cells located on bone surface
Secrete acid and proteolytic enzymes into bone surface
No PTH receptor
Osteoblasts (derived from osteoprogenitors)
Are responsible for osteoid synthesis (organic matrix that allow mineral deposition)
Located on bone surface
Osteoblasts become trapped and buried and differentiated into osteocytes
Interconnected with cytoplasmic extension (bone membrane called osteocytic
membrane system)
Osteocytes
Functions
Maintains bone strength
Repairs microfractures
Preserves Ca2+ homeostasis
Hormonal regulation (in addition to PTH, vitamin D and calcitonin)
GH
Ca2+ absorption from gut bone formation
Cortisol
bone formation and bone resorption bone resorption osteoporosis
Thyroid hormones
Activation of osteoblast osteoclastic formation bone resorption
osteoporosis

Oestrogens
Inhibition of the stimulatory effects of certain cytokines (IL-6) on osteoclast
bone resorption prevent osteoporosis
v Endocrine disorders
PTH disorders
Hyperparathyroidism
Overview
Calcium homeostasis loss due to excessive PTH secretion
Hypercalcemia results from combined effect of PTH-induced bone resorption, intestinal
calcium absorption & renal reabsorption
Causes
Primary disorder
Parathyroid tumour (adenoma, 85%)
Parathyroid hyperplasia (15%)
Secondary disorder (chronic Ca2+ stimulates PTH secretion)
Chronic renal disease
Vitamin D deficiency
Clinical features
Excessive bone resorption
Hypercalcemia*
Depression of CNS/PNS
Muscular weakness
Hypertension
Constipation
Peptic ulcer
Polyuria
Kidney stones
Diagnosis
X-ray
Osteitis fibrosa cystica presenting as painful knee cystic change and resorption in
tibia and fibula
Fasting then blood test for plasma Ca2+ & PTH level (serology)
Primary type
High PTH
High serum Ca2+
Secondary type
High PTH
Low to normal serum Ca2+
Treatments
Surgical removal of tumour (primary type)
Correct the underlying causes (secondary type)
Severe hypercalcemia can be corrected by rehydration saline together with loop diuretic
Injection of calcitonin or infusion of disodium pamidronate to inhibit bone resorption











 *Hypercalcemia
Causes ( bone resorption, GI Ca2+ absorption or renal Ca2+ excretion)
Primary hyperparathyroidism (MOST common)
Malignancy (second most common)
Diagnosis
Normal serum Ca2+ level is about 8 to 10 mg/dL
Hypercalcemia is defined as total serum Ca2+ > 10.5 mg/dL or ionized Ca2+ > 5.6 mg/dL
Hypercalcemia crisis
Severe neurological symptoms or cardiac arrhythmias are present in patient with serum
Ca2+ > 14 mg/dL
Hypercalcemia has a negative bathmotropic effect which inhibits Na+ channels more
difficult to reach threshold to trigger action potential
Clinical manifestation
Renal
E.g. dehydration, nephrogenic diabetes insipidus, nephrolithiasis
Skeleton
E.g. arthritis, osteoporosis, bone pain
Gastrointestinal
E.g. nausea, vomiting, anorexia, weight loss, constipation
Neuromuscular
E.g. impaired concentration & memory, confusion, stupor, coma, muscle weakness
Cardiovascular
E.g. hypertension, cardiac arrhythmias, vascular calcification
Other
E.g. itching, keratitis, conjunctivitis
Hypoparathyroidism
Overview
Calcium homeostasis loss due to insufficient PTH secretion
Hypocalcemia results from bone resorption and vitamin D activity
Causes
Damage to blood supply during thyroidectomy
Autoimmune disease
Clinical features
Hypocalcemia
neuromuscular excitability (tetany)
Treatments
Intravenous calcium infusion (for severe hypocalcemia)
Oral calcium (1 to 2 g) + vitamin D
PTH replacement (synthetic PTH)
Vitamin D deficiency
Causes
Malabsorption of vitamin D
Lacking of sunlight
Kidney disease
Low mineral/matrix ratio due to defective calcification of bone matrix
Rickets (children), osteomalacia (adult)
Symptoms
Weak bones
Bone pain
Bending of bones
Treatment vitamin D supplements
 Osteoporosis
Overview
Characterized by the decreased in bone density may lead to higher risk of fracture
Total bone mass reduced with an EQUAL loss of mineral & matrix
Causes
bone formation
bone resorption
PTH secretion
Cushing syndrome (inhibits osteoblasts)
Thyrotoxicosis
Postmenopausal oestrogen deficiency ( osteoclast formation and their apoptosis)
Risk factors
Unchangeable risks
Sex
Women are much more likely to develop osteoporosis than men
Age
Elderly has greater chance to develop osteoporosis
Race
White or Asian descent are at high risk
Family history
Higher risk if parent or sibling with osteoporosis
Frame size
People who have small body frames tend to have greater risk because of less bone
mass to draw from as they age
Hormonal factors
Sex hormones
Reduction of oestrogen at menopause is one of the strongest risk factors
Men with lower testosterone also easier to develop osteoporosis
Thyroid problems
Hyperthyroid can cause bone loss
Other endocrine disorders
Osteoporosis has been associated with overactive parathyroid & adrenal glands
Long-term use of steroid medications
E.g. prednisone or cortisone
Dietary factors
Low calcium intake
Eating disorders
People who have anorexia are at higher risk of osteoporosis
GI surgery
A reduction in size of stomach or a bypass or removal of part of intestine limits the
surface area for nutrients absorption, including calcium
Lifestyle
Lack of exercise
Weight-bearing exercise is beneficial for bones
Excessive alcohol consumption
Alcohol can interfere calcium absorption
Excessive caffeine intake
Tobacco use



Pathology of Parathyroid Glands

v Parathyroid glands
Average total weight is about 200 mg
3 types of parathyroid cells
Chief cells
Produce, store and secrete parathyroid hormone (PTH)
Clear cells
Glycogen rich chief cells
Oxyphil cells
Function unknown

Main functions of PTH
Mobilizes calcium from bone by stimulating
Howships
osteoclastic resorption lacuna

Osteoclasts occupy small depressions on the Lamellar

bone
bone's surface (Howship lacunae)
Stimulates 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)
(active form of vitamin D) synthesis from 25-OH-D3 by
the kidneys promotes calcium absorption from guts
Vitamin D3 is absorbed from the gut 25- 1

hydroxyvitamin D3 (25-OH-D3) by liver microsomes 1

Promotes renal excretion of phosphate by decreasing tubular reabsorption of phosphate

The half life of PTH in circulation is about 4 minutes
Parathyroid hormone-related protein
PTHrP is an essential tissue factor
It can bind to PTH receptors and acts like PTH
Occasionally produced in excess by malignant tumours hypercalcemia
The best known examples are squamous cell carcinoma of lung and breast cancers
v Parathyroid disorders
Hyperparathyroidism
Overview
PTH is ALWAYS ELEVATED in hyperparathyroidism may be due to
Autonomous increase in PTH secretion primary hyperparathyroidism
Secondary to low Ca2+ secondary hyperparathyroidism
Primary hyperparathyroidism
Causes
Adenoma (80%)
Hyperplasia (15%)
Carcinoma (5%)
Hyperplasia/adenoma is a manifestation of MEN I, with a high penetrance. However, ONLY 2% of primary
hyperparathyroidism is associated with MEN I
Effects
Hypercalciuria
Urinary stones and associated infection
Hypercalcaemia
Metastatic calcification in multiple sites, e.g.
nephrocalcinosis, stomach, lungs, myocardium,
cardiac valves, blood vessels, skin etc.
Bone diseases
Osteopenia
Prominent osteoclasts erode bone matrix & mobilize Ca2+ salts, particularly in the
metaphyses or long tubular bone severe bone absorption thin cortical bone
Bone resorption is accompanied by increased osteoblastic activity and the
formation of new bone matrix

Osteitis fibrosa cystica
In more severe cases, the cortex is grossly thinned. The
marrow contains increased amounts of fibrous tissue,
accompanied by foci of haemorrhage & cyst formation
Fractures
Brown tumour
Aggregates of osteoclasts, reactive giant cells & hemorrhagic debris occasionally
form masses that may be mistaken for neoplasm
Must NOT be misdiagnosed as osteoclastoma of bone remember to have
blood calcium level checked before a diagnosis of osteoclastoma is made

Gastrointestinal disturbances pancreatitis & gallstones
 Secondary hyperparathyroidism
Pathogenesis
Persistent low blood calcium (hypocalcaemia) parathyroid hyperplasia (chief cell
hyperplasia) persistent high blood PTH
Parathyroid hyperplasia normal secretory cells diffuse early nodularity
nodular (monoclonal) single nodule (monoclonal)

Cause of hypocalcaemia
Chronic renal failure (MOST COMMON)
phosphate excretion hyperphosphatemia serum phosphate levels &
ionized Ca2+ level (MAIN mechanism) stimulate parathyroid gland activity
Contributing/co-existing factors
Dietary vitamin D and calcium deficiency
synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (active form of
vitamin D) synthesis by kidneys
Inadequate dietary intake of calcium
Vitamin D deficiency
Malabsorption
Effects
Bone diseases excessive bone resorption
Osteopenia
Osteitis fibrosa cystica
Fractures
Brown tumour
Normal

Normal

Tertiary hyperparathyroidism
In some patients with secondary hyperparathyroidism, the glands become autonomous
(with high output of PTH) and would not respond to a high or normal level of calcium in blood
Features
Normal or high calcium levels
High PTH
Parathyroid hyperplasia/adenoma
Past history of secondary hyperparathyroidism
Treatment
Surgery (radio-guided) to remove an adenoma/carcinoma or the hyperplastic glands
Indicated in primary, secondary and tertiary hyperparathyroidism
Part of excised benign parathyroid tissue may be transplanted back to the patient
 Hypoparathyroidism (less common than hyperparathyroidism)
Effect
Hypocalcaemia related neuromuscular symptoms
Causes
Surgical removal
Congenital absence, as in DiGeorge syndrome
Autoimmune parathyroiditis primary (idiopathic) atrophy
Pseudohypoparathyroidism
A rare heterogeneous group of disorders having a common feature of resistance to parathyroid
hormone (PTH insensitivity in the target organs)
Low calcium
PTH high, parathyroid hyperplasia
Type Ia, associated developmental bone defect (Albright hereditary osteodystrophy)
Genetic defects affecting GNAS1 on chromosome 20
v Lesions of parathyroid
Developmental anomalies
Ectopia
Supernumeration
Absence
Hyperplasia
Hyperplasia involves ALL parathyroid glands
The weights of the glands are increased
The hyperplastic gland shows stromal fat
Tumours
Adenoma
Occurs in women and men in the fourth decade
Male to female ratio is about 1:3
Usually functional
Accounts for about 80% of primary hyperparathyroidism
Genetic changes
Somatic mutation of MEN1 (~20% of all sporadic parathyroid adenomas)
Relocation of cyclin D1 to near the PTH gene transcriptional activation (~20% of all
sporadic parathyroid adenomas)
Carcinoma
Uncommon
Usually functional
Large, adheres to the adjacent tissue
Increased mitotic activity, invasion of blood vessels and capsule and metastases
Secondary tumours
Rare
Others
Infarction
Atrophy
Cyst
Amyloidosis
Parathyroiditis





 v Adenoma VS carcinoma the diagnosis of malignancy is
Mainly by the behaviour of the tumour
Large tumour size
Infiltration of adjacent tissues
Invasion of blood vessels
Metastases
Cytological details of the parathyroid tumour cells are NOT helpful
Technetium 99m Sestamibi scan
15 minutes uptake by thyroid
2 hours 99mTc retained in parathyroid adenoma

Role of pathological examination of parathyroid gland
Intra-operative (frozen section) diagnosis may be of 2 fold (EXPIRED!!!)
Determine if the tissue is of parathyroid origin
Determine the nature of the lesion. To distinguish between adenoma, hyperplasia and
normal gland, the following points should be considered
Normal weight is 20 to 35 mg per gland. The combined weight of the glands in men is
120 3.5g and in women 142 5.3mg
Normal size is 3 to 6 mm in length, 2 to 4 mm in width, and 0.5 to 2 mm in thickness
Fat content is usually decreased in hyperplasia and virtually absent in adenoma
The presence of capsule or compressed glands strongly favours adenoma
Capsule + fat cells normal parathyroid gland
Definite diagnosis usually requires the examination of at least 2 parathyroid glands,
preferably all 4 glands
Radio-guided parathyroidectomy
The probe will detect minute levels of radioactivity surgeon uses it during the operation
to find the hyperactive parathyroid/tumour which is made radioactive for a few hours


















Pancreas
Physiology of Insulin & Glucagon

v Insulin
Site of production
Pancreatic Islets of Langerhans secrete various peptide hormones
Different cell types according to histological staining
Insulin is produced by (beta) cells which are centrally located within the islet and constituted
65-80% of the islet mass
Glucagon is produced by (alpha) cells which are located at the periphery of the islet and
constitute 15-20% of the islet mass
Synthesis & structure
Insulin is synthesized as preproinsulin
Preproinsulin (109 amino acids)
Proinsulin + hydrophobic 23 amino acids extension at NH2 end
Proinsulin (86 amino acids)
Insulin + C-peptide & 4 basic amino acids
C peptide (31 amino acids) NO known biological action
Insulin (51 amino acids, molecular weight 5808)
Chain A & chain B are connected by 2 disulphide bridges
Intrachain disulphide bridge on chain A
Biologically active
Plasma half-life of insulin about 6 minutes
Insulin receptor
Composed of 2 -subunits and 2 -subunits (transmembrane domain)
Disulphide bridge connected between 2 -subunits
-subunits & -subunits are connected by disulphide bridge
Insulin binds to -subunits of insulin receptor dimerization -subunits transmits a signal
from bound insulin to the cytoplasm activates the receptors tyrosine kinase domain in the
1/2/2016
cytoplasm phosphorylates insulin-response substrates (IRS) or enzymes triggers chemical
responses inside the cell, e.g. glucose transport, protein synthesis, fat synthesis, glucose synthesis,
growth and gene expression etc.

Insulin receptor

Guyton & Hall Fig 78-3

7
 Actions
Secreted by cells when blood glucose rises
Effect blood glucose
glucose uptake (facilitates glucose transporter GLUT4) & utilization in most cells
EXCEPT brain cells require glucose for energy, are permeable to glucose & do NOT
require insulin for uptake
Carbohydrate metabolism
gluconeogenesis
glycogenesis
glycogenolysis
Protein metabolism
amino acid uptake & protein synthesis in muscle cells
proteolysis & gluconeogenesis
Lipid metabolism
FFA entry into adipocytes, lipogenesis & fat storage
lipolysis
serum K+ by K+ entry into cells
plasma insulin plasma insulin
v glucose uptake & utilisation
v glucose uptake & utilisation
v Net glycogen catabolism
v Net glycogen synthesis
Muscle v Net protein catabolism
v Net amino acid uptake
v Net amino acid release
v Net protein synthesis
v Fatty acid uptake & utilization
v glucose uptake & utilization
v glucose uptake & utilization
Adipocytes v Net triglyceride catabolism release
v Net triglyceride synthesis
of glycerol and fatty acids
v glucose uptake
v glucose uptake due to net glycogen
v Net glycogen synthesis
Liver catabolism & gluconeogenesis
v Net triglyceride synthesis
v ketone synthesis & release
v NO ketone synthesis
Control of secretion
Chemicals in blood
Blood glucose induces insulin release
Glucose enters cells through glucose uniporter GLUT2 and is used to produce ATP
(oxidative phosphorylation)
ATP closes ATP-gated K+ channels membrane depolarization
Depolarization opens voltage gated Ca2+ channel
Ca2+ influx causes insulin exocytosis
Amino acids potentiate the effect of blood glucose
Hormonal
GH, cortisol, adrenaline, glucagon insulin release whereas somatostatin insulin release
GI hormones (anticipatory effect)
Neural
Parasympathetic insulin release
Sympathetic insulin release






v Glucagon
Structure
29 amino acids, molecular weight 3485
Actions
Secreted by cells when blood glucose falls
blood glucose level
Effects MAINLY on the liver
glycogenolysis
gluconeogenesis
glycogenesis
lipolysis in adipose tissue
Regulation of secretion
Negative feedback by blood glucose
Release is inhibited by blood glucose
Other factors
Sympathetic stimulates release
Insulin inhibits release
blood amino acids release (prevent insulin-induced hypoglycaemia by gluconeogenesis)
v Regulation of blood glucose
Factors controlling blood glucose
Insulin blood glucose
Glucagon blood glucose
Insulin/glucagon ratio high after feeding, low during fasting
Insulin & glucagon have antagonistic effects on blood glucose, it is the ratio & NOT the
absolute values that is important
Feeding insulin/glucagon ratio high
Fasting insulin/glucagon ratio low
Autonomic stimulation
Sympathetic blood glucose
Parasympathetic blood glucose
Other hormones
Cortisol, growth hormone, catecholamines & thyroid hormones blood glucose
Insulin/glucagon/catecholamines
Fast action minute to minute regulation
GH/cortisol
Slow acting but longer lasting NOT for minute to minute regulation
Importance
Glucose is the ONLY nutrient normally can be used by the brain, retina & germinal epithelium for
energy supply
High blood glucose causes harmful effects
ECF osmotic pressure & cellular dehydration
Osmotic diuresis & volume depletion
Vascular injury & related health problems








v Hyperglycaemia
Normal
Fasting plasma glucose (FPG) < 110 mg/dL (6.1 mmol/L)
2-hour postprandial plasma glucose (PPG) <140 mg/dL (7.75 mmol/L)
Diabetes mellitus
Overview
Diabetes means syphon or running through, denotes urinary volume
Mellitus means sweet
Diabetes mellitus means sweet urine
Compared to insipid meaning non-sweet denotes non-sweet urine in diabetes insipidus
(due to insufficient ADH production)
Types
Type 1 insulin dependent diabetes mellitus (IDDM)
Deficiency of insulin
Immune mediated or idiopathic
Genetic/environmental/autoimmune factors destruction of cells
Less common (3%). Peak age of diagnosis 12 years juvenile diabetes mellitus
Treatment
Treated by insulin replacement
Dosage matched to blood glucose level
Type 2 non-insulin dependent diabetes mellitus (NIDDM)
More common (97%)
Decreased response to insulin (insulin resistance)
Stronger genetic relationship than IDDM
Related to obesity or other causes of insulin resistance (e.g. stress)
Adult onset diabetes mellitus
Treatment
Usually may not require insulin replacement
Weight reduction
Diet control
Oral hypoglycaemia drugs
E.g. glibenclamide, sulphonylurea (close ATP sensitive K channels) to stimulate
insulin secretion
Other types
Pancreatic diseases
E.g. pancreatitis, neoplasm etc.
Endocrine disorders
Acromegaly
Cushings syndrome
Thyrotoxicosis
Pheochromocytoma
Glucagonoma
Drug-induced
Gestational DM (GDM)
Due to increased hormone secretion during pregnancy
Seen if patient has predisposition, if previous or potential glucose intolerance has been
noted
Importance
mortality risk for mother & child
May progress to diabetes mellitus in later life

 Positive findings from any 2 of the following tests on different days
Symptoms of diabetes mellitus (polyuria, polydipsia or unexplained weight loss) + causal
plasma glucose concentration 200 mg/dL (11.1 mmol/L)
FPG 126 mg/dL (7.0 mmol/L)
2-hour PPG 200 mg/dL (11.1 mmol/L) after a 75-g glucose load
Clinical features and manifestations related to insulin lack or insulin resistance
Insulin lack or insulin resistance, glucose is not taken up out of the blood at the target cells
hyperglycaemia
Hyperglycaemia glucose filtered at renal glomerulus, exceed renal glucose transport
maximum glucose in urine (glycosuria)
Glucose in urine osmotic diuresis polyuria (classical symptoms) thirst and polydipsia
(classical symptoms)
Weight loss
Patient eats, but nutrients are not taken up by the cells and/or are not metabolized
properly cellular utilization of glucose polyphagia (classical symptoms)
Osmotic diuresis fluid loss
utilization & metabolism of protein & fat loss of body tissue
utilization & metabolism of protein & fat ketone bodies (acidic) as by products
ketoacidosis & ketouria compensations for metabolic acidosis hyperpnoea (air hunger),
acetone given off in breath
Complications
Chronic complications
Macrovascular
atherosclerosis, coronary artery disease, stroke, peripheral vascular disease (PVD)
Microvascular
Nephropathy
Neuropathy
Retinopathy
resistance to infection
Acute complications
Diabetic coma (diabetic ketoacidosis) insulin deficiency
glucose uptake by cells + glycogenolysis + gluconeogenesis plasma
glucose renal filtration of glucose
lipolysis plasma free fatty acids ketone synthesis plasma ketones
renal filtration of ketones + plasma [H+] (acidosis)
renal filtration of glucose & ketones osmotic diuresis Na+ & water
excretion plasma volume arterial blood pressure brain blood flow
brain blood flow + plasma [H+] (acidosis) impaired brain function, coma &
death
Hypoglycaemia or insulin shock
Impaired glucose homeostasis
Impaired fasting glucose
FPG from 110 to <126 (6.1 to <7.0 mmol/L)
Impaired glucose tolerance (IGT)
2-hour PPG from 140 to <200 (7.75 to <11.1 mmol/L)






v Hypoglycaemia
Insulin excess disease
Causes
Accidental or deliberate injection of excessive insulin
Insulinoma
Pancreatic islet cell tumour
v Can be functioning or non-functioning
v Most functioning tumours produce one type of hormone, e.g. insulinoma, glucagonoma, gastrinoma
Insulinoma Glucagonoma
v Very rare tumour & usually cancerous, tends to
v 90% benign
spread and get worse
v Excessive secretion of insulin symptoms v Excessive secretion of glucagon symptoms
related to low blood glucose (e.g. tiredness, related to high blood glucose (e.g. excessive
weakness, tremulous, frequent hunger) thirst, polyuria, increased appetite, weight loss,
hypoglycaemic shock diabetes mellitus, necrolytic migratory erythema)
v Diagnosis by low blood glucose and high
v Diagnosis by high serum glucagon
insulin, localization by imaging
v Treatment by surgical removal v Treatment surgical excision after localization
v Can be benign or malignant
v Can be part of multiple endocrine syndrome (MEN)
Symptoms
Due to effects of hypoglycaemia on CNS
Autonomic discharge
Palpitation
Sweating
Nervousness


























Biochemical Basis of Diabetes Mellitus I

v Insulin molecule
Overview
A peptide hormone that regulates the nutrient/fuel status of the human body
Interacts with specific receptor located at the cell surface (plasma membrane)
Disruption of insulin biosynthesis results in a wide spectrum of metabolic impairments with
detrimental health problems
Physiological actions/metabolic functions take good care of the fuel resources of the human body
Liver Striated muscle Adipose tissue
v gluconeogenesis v glucose uptake v glucose uptake
v glycogen synthesis v glycogen synthesis v lipogenesis
v lipogenesis v protein synthesis v lipolysis
The opposing actions of Insulin and glucagon on the metabolism of glucose
Glycolysis Glycogen synthesis Gluconeogenesis Glycogenolysis
Insulin
Glucagon
Amino acids as raw material for the synthesis of glucose (gluconeogenesis)
Tissue proteins amino acids inhibit by insulin but promote by glucagon
Amino acids glucose (gluconeogenesis) inhibit by insulin but promote by glucagon
Regulation of glucose metabolism by insulin
Diet + de novo synthesis glucose in circulation glucose in cells (insulin-dependent or
independent transport) glycolysis, glycogen synthesis etc. stimulated by insulin
Lack of insulin/insulin resistance inhibit insulin-dependent transport
Regulation of fatty acid metabolism
Triacylglycerol in adipocytes fatty acids in circulation (hormone sensitive lipase activity
by epinephrine & glucagon but activity by insulin) fatty acids in cells fatty acids in
mitochondria (inhibited by malonyl CoA insulin promotes the conversion of acetyl CoA to
malonyl CoA) -oxidation
Biosynthesis takes place in specialised cells of the pancreas
Insulin gene messenger RNA (transcription)
mRNA nascent polypeptide (preproinsulin) (translation)
Synthesis of the N-terminal signal peptide, followed by the B, C, & A chains on ribosomes
Preproinsulin post-translational modification
Microsomal enzymes cleave the N-terminal signal peptide to produce proinsulin as the
peptide enters the endoplasmic reticulum (proteolytic cleavage)
Proinsulin is folded into a conformation that permits disulphide linkages to form between the
A & B chains (disulphide bond formation)
Post-translational modification (proinsulin) packaging into secretory vesicles
Proinsulin is packaged in the Golgi apparatus into membrane-bound secretory granules
Proinsulin contains the amino acid sequence of insulin, 31-amino acid C (connecting) peptide
& 4 linking amino acids
Proprotein convertases 1/3 & 2 are packaged with proinsulin within the secretory granule to
cleave off the C peptide complete insulin synthesis (mature) (further proteolytic cleavage)
The mature insulin consists of two chains, an chain and a chain, connected by two disulfide
bridges. A third disulphide bridge is contained within the chain
Insulin is stored in secretory granules in zinc-bound crystals (electrondense core of the
granule) whereas the C peptide molecules are in the peripheral halo areas of the granule
Packaging into secretory vesicles secretion
On stimulation (e.g. intracellular Ca2+), the contents of the granule (i.e. insulin & C peptide)
are released to the outside of the cell by exocytosis

v Diabetes mellitus control of insulin secretion
Diabetes mellitus type 1 (DMT-1)
Histology
Loss of -cell mass what may cause the self-destruction of -cells?
Presence of insulitis (infiltration of lymphocytic cells)
Due to loss of insulin function due to inability to synthesize insulin (loss of -cell)
Normal -cell dead -cells (environmental/genetic factors + immune-mediated, e.g.
macrophages, T-cells & cytokines) impaired biosynthesis of insulin metabolic disorders
IDDM (Type 1 DM)
-cell death is T-cell mediated presence of autoreactive T-cells. How do they come about?
Genetic predisposition
MHC
Susceptibility and protective MHC haplotypes found in Caucasians with Type 1 diabetes
Haplotype Ratio T1Ds:Normal
Susceptibility
v B62, SC31, DR4 17.0
The occurrence of these gene alleles in T1D patients was
v B18, F1C30, DR3 14.6
significantly HIGHER compared to normal population,
v B62, SB42, DR4 5.8
hence they are termed susceptibility alleles
v B62, SC33, DR4 4.4
v B8, SC01, DR3 2.1
Neutral
v B60, SC02, DR6 1.0 The occurrence of these gene alleles in T1D patients was
v B35, FC(3, 2)0, DR1 1.0 NOT significantly different from the normal population,
v B44, SC30, DR4 0.77 hence they are termed neutral alleles
v B35, SC31, DR5 0.45
Protective
The occurrence of these gene alleles in T1D patients was
v B7, SC31, DR2 0.22
significantly LOWER compared to normal population,
v B44, FC31, DR7 0.21
hence they are termed protective alleles
v B57, SC61, DR7 0.14
MHC/HLA locus in human chromosome 6
The MHC genes are highly polymorphic
Usually it is the peptide binding region of the MHC molecule that is affected by the
polymorphism of the gene, e.g. gene allele 1, 2 & 3
Certain alleles of MHC genes occur more frequently than others in Type 1 diabetic
individuals. But how does it matter?
Antigen presentation by the MHC I and MHC II molecules
MHC class I processing cytosolic pathway
Endogenous antigen intracellular bacteria, virus, self-proteins, protein in cytosol
Protein are digested by proteasomes peptides
Transport of peptides (via TAP, Transporter associated with Antigen Processing)
into endoplasmic reticulum (ER) and loading onto MHC class I molecules
MHC-I/peptide complexes translocate by Golgi body to cell surface for
presentation to CD8+ T cells
MHC class II processing endocytic pathway
Exogenous antigens extracellular microbes and protein
Antigen taken up by endocytosis/phagocytosis enclosed in endocytic vesicles
fuse with lysosomes containing proteolytic enzymes protein degradation
Biosynthesis and folding of MHC class II molecules in ER, transport via Golgi body
to MHC class II vesicles
Fusion of Class II vesicles with endolysosomes loading of digested peptides onto
MHC class II molecule translocate to cell surface for presentation to CD4+ T cells
 Significance of forming a peptide:MHC complex
Shaping the T-cell repertoire (NOT ALL the T-cell receptor isoforms are functional or
beneficial to individual) positive/negative selection of T-lymphocytes maturation
Immature T-cells MHC-restricted T-cells
Positive selection (happening in the thymus cortex)
Low-affinity/avidity recognition of peptide-MHC complex on thymic
epithelial cell rescue CD4+CD8+ thymocyte from programmed cell death
conversion to single positive
Lack of positive selection
Failure to recognise peptide-MHC complex on thymic epithelial cell
apoptotic cell death
MHC-restricted T-cells non-self T-cells (with some being autoreactive in disguise)
Negative selection (happening in the thymus medulla)
High-avidity recognition of peptide-MHC complexes on thymic antigen-
presenting cell (some antigens induced by AIRE in thymic medullary
epithelial cells) apoptotic cell death
Non-self T-cells (with some being autoreactive in disguise) migrate to periphery
Directing subsequent peripheral T-cell responses
Activation of CD4+ mediated or CD8+ mediated responses
How may MHC molecules lead to selection of potentially autoreactive T-cells in T1D
susceptible individuals?
T-cell receptor on the surface of a T-lymphocyte recognizing 2 polymorphic residues
of a MHC molecule & 1 residue of its bound peptide epitope. MHC polymorphism that
affects the binding affinity will determine the appearance of 2 outcomes either
Below an affinity threshold TCR released to periphery
TCR with close threshold affinity for p:MHC liable to act as autoreactive T-cells
TCR with affinity for p:MHC well below threshold will be the non-self
Above affinity threshold TCR deletion
For a resistant individual
Pp:MHC1 & Pp:MHC2 (MHC1 & MHC2 are T1D predisposing) weak interaction
with TCR TCR survives
Pp:MHC3 (MHC3 is T1D protective) strong interaction with TCR autoreactive
TCR deleted
For a susceptible individual
Pp:MHC1 & Pp:MHC2 weak interaction with TCR TCR survives
Pp:MHC3 weak interaction (or strong interaction but without activation of cell
death) maybe genuinely a non-self TCR but could be autoreactive. TCR survives
The same pancreatic antigen peptide (Pp) will be likely to produce several peptide
fragments in addition to Pp the same TCR may undergo several rounds of such
screening procedure involving different peptide fragments & may be screened with
peptide fragments derived from other self-proteins. If survives all these screening
processes leave thymus as a non-self TCR (still can be potentially autoreactive)
The autoreactive effects of autoreactive T-cells maybe be inhibited by Treg cells
Immature T-cells selection & maturation in thymus CD4+, CD8+ & Treg cells
Peripheral antigen/autoantigen
Autoreactive CD4+ T-cells T-helper cells
Treg cell INHIBIT T-helper cells
Possible roles of MHC molecules polymorphism in predisposing to DMT1
Immature T-cells thymus autoreactive T-cells (maturation & faulty selection)
inactive autoreactive T-cells (peripheral tolerance/anergy)
MHC II molecules cause faulty selection & inhibit peripheral tolerance/anergy
 Proinsulin gene
Promoter region has variable number of tandem repeats (VNTR) & transcription starts
from coding region to produce insulin mRNA
Proinsulin is expressed in the thymus to serve as one self-antigen for positive & negative
selection of T-cells
Speculated role of proinsulin gene as a genetic determinant for DMT1
T cell maturation in thymus (medullary epithelial cells)
Class III (140-200 repeats) expression of insulin normal selection of Treg cells
and T-cells (protective)
Class I (26-63 repeats) under-expression of insulin faulty selection of Treg cells
and T-cells (predisposing)
PTPN22 (protein phosphotyrosine-specific phosphatase)
AIRE (autoimmune regulator)
A transcription factor regulating the expression of peripheral self-antigens in thymic
epithelial cells
Environmental trigger
Virus-mediated (molecular mimicry model)
Pathogen (virus) infected pancreatic cell (the pathogen expresses a protein that may
give rise to a peptide that is very similar to the self-reactive peptide (autoantigen)
MHC class II display of viral peptide on APC activation of autoreactive CD4+ T cells
(Th2-subtype) (cytokine mediated?) activation of cell that make Islet cell
antibodies cell elimination
MHC class I display of viral peptide on infected cell surface activation of
autoreactive CD8+ T cells (?) cell elimination
Other environmental stimuli (diet, trauma)
Metabolic consequences of insulin deficienc
cell damaged cells cell proteins (autoantigens) acquired and processed by APC
presentation of cell autoantigens in MHC II on surface of APC activation of CD4+
T-cells (Th1 subtype)
Secretion of IL-1, TNF, INF killing of cell
Activation of CD8+ T-cells killing of cell
Diabetic ketoacidosis
Insulin deficiency
hepatic glucose output + non-oxidative
glucose metabolism in skeletal muscle
hyperglycemia polyuria dehydration
lipolysis fatty acid oxidation ketone diabetes
body production ketoacidosis
Permanent Neonatal Diabetes Mellitus (PNDM)
Permanent activation of KATP channel
Maternally Inherited Diabetes with Deafness (MIDD)
Mutation of mitochondrial genome
Maturity Onset Diabetes of the Young (MODY)
MODY2 inactivating glucokinase gene mutations
Mutations of transcription factors, e.g. MODY3 HNF-1, MODY1 HNF-4 & MODY5 HNF-1
expression of genes encoding protein components of TCA-cycle, glucose transport & insulin
expression
v Summary
Regulation of biosynthesis and secretion of insulin (basis for insulin-deficient monogenic diabetes)
The molecular basis for the loss of -cell mass (giving rise to DMT1)
The metabolic functions of insulin
The metabolic basis for diabetic ketoacidosis

Biochemical Basis of Diabetes Mellitus II

v Diabetes Mellitus Type 2 (DMT2)

Overview
Environmental factors over-nutrition obesity
Obesity insulin resistance (genetic factors?)
Insulin resistance hyperglycemia (impaired glucose tolerance), hyperlipidemia & high fatty acid
level metabolic stress in -cell -cell dysfunction -cell death (apoptosis)
hyperglycaemia diabetes
-cell dysfunction insulin resistance (genetic factors?)
The role of obesity
Special relationship between abdominal fat and insulin sensitivity
Usually has high lipolytic rate (perhaps due to higher abundance of adrenergic receptors)
Resistant to antilipolytic effect of insulin
Produce cortisol locally due to expression of 11-hydroxysteroid dehydrogenase type 1
Regulation of fatty acid release in normal adipocytes
Perilipin forms a protein coat on the surface of lipid droplet regulating lipolysis
HSL, Desnutrin are hormone-sensitive TG lipases
Lipolysis
TAG DAG + FA (desnutrin/ATGL)
DAG MAG + FA (HSL)
MAG glycerol +FA (MGL)
Pro-lipolytic
Glucocorticoids stimulate lipolysis by inducing desnutrin
Catecholamines 1, 2 & 3 adrenergic receptors activation of adenylyl cyclase (Gs)
cAMP activation of protein kinase A activation of hormone sensitive lipase
(HSL) catalyses the conversion of DAG to MAG & FA
Anti-lipolytic
Insulin binds to insulin receptor to inhibit lipolysis by (response to insulin blunted in
abdominal adipose tissue)
IRS PI3K/PKB PDE3B cAMP
IRS PP1 inhibit HSL
Desnutrin inhibition
Catecholamines adrenergic receptors inhibition of adenylyl cyclase (Gi)

Altered adipocyte lipid metabolism in obesity release of fatty acids
basal rate of lipolysis
leptin-stimulated lipolysis
expression of IRS-1 sensitivity to insulin
release of fatty acids secondary inhibitory effects on insulin action via IRS loss of
antilipolytic effect of insulin release of fatty acid magnified (vicious cycle)
 The consequence of fatty acid over-abundance in liver and skeletal muscle
Obesity, over-nutrition & lack of exercise fatty acid supply >> fatty acid utilization
accumulation of lipid metabolites/TAG dysregulated lipolysis in adipose tissue release
of fatty acids fatty acid-coenzyme A (fatty acid acyl CoA) (transport into cell)
DAG triacylglycerol
VLDL-TAG (liver)
intramyocellular TAG (skeletal muscle)
Transport into mitochondria acetyl CoA (-oxidation) energy (ATP) (TCA-cycle)
Ineffective due to lack of physical exercise
Metabolism of glucose in liver and skeletal muscle
Normal pathway
Insulin insulin receptor tyrosine phosphorylation of IRS recruitment of PI3K
synthesis of phosphatidylinositol 3,4,5-trisphosphate recruitment of PDK to plasma
membrane
Skeletal muscle
Activation of GLUT4 translocation glucose transport
Activation of AKT kinase glycongenolysis & glycogen synthesis
Liver
Activation of AKT kinase glycongenolysis, glycogen synthesis &
gluconeogenesis
Effect of lipid metabolites on regulation of glucose metabolism
Lipid metabolites (diacylglycerol) activation of novel protein kinase C serine/threonine
phosphorylation of IRS impairment of insulin signaling downstream of IRS selective
inhibition of insulin effects. BUT accumulation of DAG in skeletal muscle is NOT always
correlated with insulin resistance, suggesting presence of other mechanism to induce IR
Fatty acids PPAR/ (peroxisome proliferator activated receptor) expression of
enzymes of -oxidation pathway -oxidation of fatty acids production of NADH,
FADH and acetyl CoA saturation of respiratory electron transport chain in mitochondria
production of reactive oxygen species activation of protein kinase insulin receptor
substrate (IRS) phosphorylation insulin resistance
Metabolism of TAG in liver
Normal pathway
Insulin insulin receptor SREBP-1c (sterol regulatory element binding protein 1c)
expression of genes for de novo lipid biosynthesis (essentially does NOT display insulin
resistance) fatty acids (also from lipolysis in adipose tissue) triacylglycerol (TAG)
VLDL-TAG (VLDL1). VLDL packaging inhibited by insulin very little VLDL is exported out of
liver in the postprandial period
Effect of fatty acids on the metabolism of TAG in liver
Fatty acids insulin resistance VLDL packaging VLDL secretion
Consequence of insulin resistance in liver
Hyperglycaemia
Persistent gluconeogenesis
Persistent glycogenolysis
Impaired glycogen synthesis
Hyperlipidaemia
Enhanced de novo lipid synthesis
Enhanced VLDL1 secretion
Transfer of TAG from VLDL to HDL
causing HDL to degrade rapidly
TAG rich LDL is converted to the small
dense LDL that is highly atherogenic
 Strategies for treating DMT2
Non-pharmacological treatment, e.g. physical exercise
Insulin/glucagon regulates nutrients/fuel status of tissues

AMP-activated protein kinases regulate energy status of tissues
AMPK dependent mechanisms
Physical exercise utilization of fatty acids
Physical exercise ATP ADP AMP activate AMP-activated kinase
Fatty acid acyl CoA (cellular) transport into mitochondria acetyl CoA (-oxidation)
energy (TCA cycle) consumed in physical exercise
(If lack of physical exercise, acetyl CoA will accumulate)
Acetyl CoA malonyl CoA (active acetyl CoA carboxylase, NOT phosphorylated)
inhibit the transport of fatty acid acyl CoA to mitochondria for -oxidation & fatty acid
utilisation (negative feedback)
Active acetyl CoA carboxylase (NOT phosphorylated) is inactivated to inactive acetyl
CoA carboxylase (phosphorylated) by AMP-activated kinase (active) promote -
oxidation & fatty acid utilisation antagonized by insulin
inhibitory phosphorylation of insulin receptor restoration insulin sensitivity
improved glucose metabolism in skeletal muscle
AMPK independent mechanisms
Physical exercise translocation of GLUT4 to plasma membrane glucose transport
into skeletal muscle improved glucose metabolism in skeletal muscle
Molecular targets for treatment
Sulphonylurea drugs
Insulin gene messenger RNA nascent polypeptide post-translational modification
packaging into secretory vesicles secretion (sulphonylurea drugs)
Glucose (stimulus) glucose-6-phosphate (transport into cells) further
metabolism ATP:ADP close of KATP channel ( by sulphonylurea drugs bind
to the regulatory subunit of KATP channel closure) inhibit the outflow of K+
from inside to outside cell membrane depolarisation activation of voltage-gated
Ca2+ channel changes in intracellular Ca2+ level insulin release into extracellular
space from secretory vesicles (membrane fusion) insulin secretion from cells
Thiazolidinediones (e.g. rosiglitazone & pioglitazone)
fatty acid uptake by adipocytes
Preferential differentiation of pre-adipocytes
to subcutaneous rather than visceral adipocytes
Adipocytes formed are more insulin-sensitive
Suppress inflammatory activities
Metformin (a biguanide drug) insulin sensitisers
AMP-protein kinase (inactive) AMP-protein
kinase (active) (?) active FFA oxidation,
glycolysis, glycogen synthesis etc.
DPP-IV inhibitors
DPP-IV catalyzes breakdown of incretins
-glucose inhibitors, e.g. acarbose and miglitol
Inhibits breakdown of complex carbohydrates to monosaccharides
v Summary
Lipolysis and its regulation
The causal relationship between fatty acid metabolism and the development of insulin resistance
-cell loss in DMT2
Molecular targets for treatment of DMT2
Pathophysiology of Diabetes

v Metabolic functions of insulin

Regulation of glucose metabolism by insulin & glucagon
Diet + de novo synthesis glucose in circulation glucose in cells (insulin-dependent or
independent transport) glycolysis, glycogen synthesis etc. stimulated by insulin
Lack of insulin/insulin resistance inhibit insulin-dependent transport glucose in
circulation redistribution of glucose to cells using insulin-independent mechanism
Glycolysis Glycogen synthesis Gluconeogenesis Glycogenolysis
Insulin
Glucagon
Amino acids as raw material for the synthesis of glucose (gluconeogenesis)
Tissue proteins amino acids inhibit by insulin but promote by glucagon
Amino acids glucose (gluconeogenesis) inhibit by insulin but promote by glucagon
Lack of insulin/insulin resistance leads to overall increase in glucose production (in the liver)
Regulation of fatty acid metabolism by insulin and glucagon
Storage of lipid (LPL) Fatty acid synthesis Lipolysis (HSL) Fatty acid oxidation
Insulin
Glucagon
Triacylglycerol in adipocytes fatty acids in circulation (HSL activity by epinephrine &
glucagon but activity by insulin) fatty acids in cells fatty acids in mitochondria (inhibited
by malonyl CoA insulin promotes the conversion of acetyl CoA to malonyl CoA) -oxidation
v Consequences of hyperglycaemia (diabetic complications)
Microvascular diseases & macrovascular diseases
Type 1/Type 2 DM hyperglycaemia/fatty acids extracellular & intracellular effects
glycolytic flux, TCA cycle activity & NADH & FADH mitochondrial respiration/electron
transport superoxide production nuclear DNA damage polyadenine ribose
polymerase inactivation of glyceraldehyde 3-phosphate dehydrogenase by polyribosylation
NAD (ADP-ribose + nicotinic acid) ADP-ribose (PARP)
GAPDH + ADP-ribose GAPDH with Poly (ADP-ribose) (inactive) (PARP)
Inactivation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by polyribosylation
AGE formation (1)
Synthesis of diacylglycerol polyol pathway (2)
Disrupted metabolism of reactive oxidative species polyol pathway (3)
Hexosamine pathway (4)
1 + 2 + 3 + 4
Microvascular disease, e.g. retinopathy & nephropathy
Increased cellular proliferation
Impaired breakdown of extracellular matrix vessel wall thickening
Disruption of basement membrane structure permeability changes
Impaired lipid transport atherogenesis
Protein deposition vessel blockade
Blood flow abnormalities (due to NO)
Macrovascular disease (?), e.g. atherosclerosis
Diabetic ketoacidosis
Type 1/Type 2 DM insulin deficiency
hepatic glucose output + non-oxidative glucose metabolism in skeletal muscle
hyperglycemia polyuria dehydration
lipolysis fatty acid oxidation ketone body production ketoacidosis



v Non-enzymatic glycation
Overview
Reaction between glucose (& its metabolites) with macromolecules (proteins, lipids, nucleic acids)
Elevated by hyperglycaemia
Takes place both within and outside cells
Involves multiple reactions, producing multiple products
Advanced glycation end-products (AGE)
Formation
Extracellular glucose
Extracellular glucose + NH2 groups in proteins Schiff base adducts (reversible) (hours)
Schiff base adducts Amadori products (irreversible) (days)
Amadori products re-arrangements, elimination, condensation & oxidation reactive
carbonyl compounds (extremely reactive intermediates) (irreversible) (days)
Reactive carbonyl compounds (e.g. glyoxal, methylglyoxal & 3-deoxyglucosone)
crosslinking with proteins structural and functional modifications of proteins AGE
Glucose within cells (glucose uptake is not dependent on insulin, e.g. endothelial cells)
(MAJOR pathway of glycation of proteins further react with proteins intra- & extracellularly)
Auto-oxidation glyoxal
Glycolysis (breakdown of glyceraldehyde-3-phosphate) methylglyoxal
Reaction with proteins (Amadori pathway) 3-deoxyglucosone
Metabolism of AGE
Intermediates rendered inactive by reductases
Methylglyoxal and glyoxal catabolized by glyoxalase system
AGE degraded by cells
Products excreted in the kidney
Production of AGE exceeded rate of degradation under hyperglycaemic condition
Stimulation of cellular activities by AGE
AGE binds to cells with receptor for AGE intracellular signals change in cell activities
Macrophages/monocytes
Secrete cytokines, e.g. IL-1, IGF-1, TNF- proliferation of these cells
Endothelial cells
production of thrombomodulin & production of Tissue Factor overall in
procoagulant activity
Effects of glycation
Modification of protein function, e.g. lipoproteins (LD)
BOTH the lipids and protein components are modified
Impairs binding & degradation of LDL by fibroblast
Abolishes recognition by receptors
Generation of anti-glycated LDL-antibody
Foam cell formation
Compromised reverse-transport of cholesterol (glycation of HDL)
Modification of extracellular matrix
Inhibits lateral association of Type IV collagen molecules
Disrupt binding of heparin sulphate & other proteoglycan molecule to basement membrane
Alters packing of Type 1 collagen and laminin
Abolish cell-matrix interaction
Dampens the action of nitric oxide




v Polyol pathway
Overview
Glucose
Glucose 6-phosphate (hexokinase production inhibition of hexokinase at high G6P)
Glycolysis (NAD NADH)
Pentose phosphate pathway (NADP NADPH)
Sorbitol (NADPH NADP) fructose (NAD NADH) polyol pathway
Effect on glycolysis
Glucose glucose 6-phosphate glyceraldehyde 3-phosphate (accumulates)
Methylglyoxal (AGE)
Dihydroxyacetone phosphate (ENHANCED) glycerol 3-phosphate (accumulates) (NADH
NAD) (ENHANCED NAD is depleted by sorbitol pathway) diacylglycerol synthesis (+ fatty
acids from lipolysis) PKC activation
Vascular occlusion (due to procoagulant activity)
Capillary occlusion (due to extracellular matrix synthesis)
Vascular permeability
Blood flow abnormality
Inhibits NO formation by expression of eNOS
Pyruvate (NAD NADH) (IMPAIRED NAD is depleted by sorbitol pathway)
Consequence
Competes with the glycolytic pathway for NAD accumulation of glycerol 3-phosphate
Consumes NADPH & slows down re-generation of gluthathione (GSH, intracellular antioxidant)
cells are more prone to oxidative damage
Glucose glucose 6-phosphate ribulose 5-phosphate (NADP NADPH)
Oxidized glutathione reduced glutathione (NADPH NADP) (IMPAIRED NADPH depleted)
Intracellular reactive oxidative compounds inactivated oxidative compounds (reduced
glutathione oxidized glutathione) (IMPAIRED)
In lens cells, accumulation of sorbitol changes intracellular osmotic pressure alteration of
crystalline structure of lens proteins (also altered due to AGE formation)
v The hexosamine pathway
Glucose glucose (intracellular) (transport) fructose 6-phosphate glucosamine 6-phosphate
(glutamine:fructose-6-phosphate amidotransferase (GFAT) & glutamine glutamate) UDP-N-
acetylglucosamine (UDP-GlcNAc)
The functional pathway of insulin and the sites
Nuclear transcription factors GlcNAc-linked nuclear transcription factors (O-linked glycosylation
of disease development
& UDP-GlcNAc) activation of gene transcription, e.g. PAI & TGF-
v The functional pathway of insulin and the sites of disease development
Pancreatic beta cells

Insulin gene Environmental

factors
Insulin mRNA Dead beta-cell
Genetic
Insulin protein factors

Target tissues Loss of insulin

function

Glucose homeostasis Insulin receptor

v Summary
The AGE mechanism
The polyol pathway
Activation of PKC
Hexosamine pathway
A unifying hypothesis based on mitochondrial production of superoxide
Loss of regulation of glucose and lipid metabolism
Insulin and Oral Hypoglycaemia Agents

v Rationale and strategies for maintaining glucose homeostasis (Why? How?)

Blood glucose levels are controlled within a narrow range in health individuals (4-7 Mm)
Input
Food intake (postprandial)
Glycogen breakdown & gluconeogenesis (fasting)
Output
Energy
Glycogen storage
Lipid synthesis
What happens when glucose homeostasis is broken?
Fasting blood glucose < 4 mmol/L hypoglycaemia
Fatigue, nausea, dizziness, coma & confusion
Fasting blood glucose > 7 mmol/L or 2 hours oral glucose level > 11.1 hyperglycaemia (diabetes)
Stroke, gangrene, heart attack, nephropathy, neuropathy & retinopathy
Classification of diabetes mellitus
Type 1
Autoimmune disease that causes pancreatic islet cell destruction
Insulin-dependent
Lack of insulin production
Onset usually before age 20 (10-20% DM)
Absolute requirement for exogenous insulin
Type 1B
Idiopathic diabetes
Type 2
Major form (> 90%)
Caused by a combined defect of insulin secretion & insulin resistance

Often associated with obesity
Non-insulin-dependent at EARLY stage
Gestation diabetes (GDM)
Associated with pregnancy
LADA (1.5 type)
Latent autoimmune diabetes
Maturity Onset Diabetes of Yong (MODY)
Strategies for management of diabetes
Diet Exercise Insulin Anti-diabetic drugs
Type 1
Type 2
GDM
v Different forms of insulin for treating diabetes
Insulin as a medication
Used to treat ALL patients with Type 1 DM, 1/3 of patients with Type 2 DM & women with
gestational DM
Biology of insulin secretion from pancreatic cells and actions
Preproinsulin (N-terminal signal sequence, chain B, chain C & chain A) proinsulin (proteolytic
cleavage of signal sequence) insulin (proteolytic cleavage of chain C)
Interchain disulphide bond chain A & chain B
Intrachain disulphide bond chain A
Insulin is RAPIDLY released from the granule of cells upon stimulation with nutrients (glucose
and fatty acids etc.) short half-life in the circulation (~5 minutes)
Uptake of glucose into cells (GLUT2) glycolysis mitochondria production of ATP
ATP/ADP closure of ATP sensitive KATP channel depolarization of cells activation
of voltage-gated calcium channel Ca2+ cAMP insulin exocytosis (< 5 minutes)
24-hour profile physiological insulin secretion is ALMOST IDENTICAL to 240 hour glucose profile
administration of exogenous insulin should mimic the pattern of endogenous insulin secretion
Basal-bolus insulin concept criteria for basal and bolus insulin preparation
Basal insulin Bolus insulin
Mimic normal pancreatic basal insulin secretion Rapid onset of action can be given just before meal
Long-lasting effect of 24 hours or longer Short duration of action to avoid hypoglycaemia
Reproducible and predictable effects Reproducible and predictable effects
Smooth, peakless profile

4 principal types of insulin preparations ALL are produced by recombinant DNA technology using
special strains of E. coli or yeast
Short acting
Regular human insulin (Humulin, Novolin)
A crystalline zinc insulin in soluble form
Self-aggregate in antiparallel fashion to form dimers that stabilize around zinc ions to
crease hexamer
The hexameric nature causes delayed onset and prolongs time to peak actions
Its effect appears within 30 minute, peaks between 1 & 2 hours and last 5-8 hours
Useful for the management of
Diabetic ketoacidosis
When insulin requirement is changing rapidly (post-surgery and acute infection)
Limitations of using regular insulin for bolus injection
Slow onset of action, due to self aggregation (hexameric form of insulin cannot bind
to insulin receptor)
Requires inconvenient administration (20-40 minutes prior to meal)
Risk of hypoglycaemia if meal is further delayed
Mismatch with postprandial hyperglycemia peak
Long duration of activity
Up to 12 hours
Potential for late postprandial hypoglycaemia
 Rapid onset and ultrashort-acting
Lispro insulin (Humalog, Eli Lily)
Produced by reversing the 2 amino acids near the carboxyl terminal of B-chain (proline
28 & lysine 29) prevents the hexameric formation of insulin, but does NOT affect its
receptor binding activity
Rapid acting 10-15 minutes onset, peak effect 30-60 minutes
2-4 hour duration of action
CAN BE taken JUST before meal
Closely mimics endogenous postprandial insulin secretion provides improved
postprandial glucose control without risk of hypoglycaemia between meals
Aspart insulin (NovoLog, Novo Nordisk)
Produced by substitution of the B-chain proline 28 with a negatively charged aspartic acid
Rapidly breaks into monomer after subcutaneous injection
Rapid onset 10 minutes, peak effect 1 hour
Duration 2-4 hours
Intermediate acting
NPH insulin and Lente insulin
Protamine (NPH) insulin
Mixture of insulin and protamine
Lente insulin
A mixture of 30% semilente with 70% ultralente insulin (a poorly soluble crystal of
zinc insulin with a delayed onset and prolonged duration of action)
Insulin bound to zinc or protamine slowly dissolve in body fluids
Facilitates control of glycaemia over an extended period peak effect 4-10 hours
Effective duration 10-18 hours
Long acting
Glargine insulin (Lantus, Sanofi-Aventis)
Produced by the attachment of 2 arginines to the B chain carboxyl terminal & substitution
of a glycine for asparagine at the A21 shift isoelectric point to pH 7.0 precipitates
in the subcutaneous milieu after injection, stabilizing insulin hexamers, delaying their
dissociation & allowing for slow, consistent absorption into the systemic circulation
Ultra-long-acting, the maximum activity is maintained for 24 hours or longer
Peakless activity, clear solution (no zinc in formula)
Once daily at bedtime
Detemir insulin (Levemir)
Developed by Novo Nordisk
A fatty-acid moiety myristic acid is added to the lysine amino acid at position B29
Threonine in position B30 of the B chain has been omitted
When it enters the circulation, as the fatty acid causes it to bind to albumin slow
release and extended circulating life
Acting half-life 23 hours

 Mode of insulin administration
Subcutaneous or intramuscular injection
Insulin pump continuous subcutaneous insulin infusion device (CSII). Major components are
The pump itself (including controls, processing module and batteries)
A disposable reservoir for insulin (inside the pump)
A disposable infusion set, including a cannula for subcutaneous insertion (under the skin)
and a tubing system to interface the insulin reservoir to the cannula
Still at the trial stage
Transdermal
Inhalation approved by FDA at 2004, but discontinued
Oral insulin
Pancreatic transplantation and stem cell therapy
Key points for using insulin preparations to treat diabetes
Keeping the blood glucose relatively normal yet avoiding hypoglycaemia and ketoacidosis
Balancing the dose and timing of insulin injections with the content of meals and the amount of
physical activity
Requiring the patient be educated about their disease & monitor blood glucose level at home
Complications of insulin therapy
Hypoglycaemia!!! glucose administration as treatment
Manifestations confusion, weakness, bizarre behaviour, coma etc.
Insulin allergy and immune resistance
Seldom happens in nowadays due to the improvements in insulin preparation
Lipodystrophy at injection sites can be corrected by multi-site injection
Abuse
Long-term risks may include development of type 2 diabetes, and potentially a lifetime
dependency on exogenous insulin
150 years of insulin (1869-1969 discovery | 1977-2014 advancement)
1869 Discovered Islets of Langerhans in the pancreas
1901 Destruction of Islets of Langerhans leads to diabetes in dogs
1921 Injection of pancreas extracts (insulin) lowers blood and urine glucose in animals
1922 1st patient, 14 year old Leonard Thompson with T1DM, was treated with insulin with great success
v Insulin purified in large scale from cattle (Eli Lilly)
1923
v Nobel prize given for the discovery of insulin
1936 Protamine reported to extend insulin action
1950 Intermediate-acting insulin (with protamine, NPH) introduced (Nordisk)
1955 Insulin sequenced by Frederick Sanger, who was awarded Nobel Prize
1963 Insulin became the 1st human protein to be chemically synthesized
1969 3D structure of insulin determined by Dorothy Hodgkin, who was awarded Nobel Prize
1977 DNA sequencing developed by Frederick Sanger, who was awarded Nobel Prize
1978 1st recombinant human insulin cloned, expressed and purified from bacteria (Genentech)
1982 1st recombinant human insulin (Humulin-R) entered market (Eli Lilly)
1st human insulin analogue (Humalog) introduced. Formation of dimer and hexamer blocked and
1996
therefore is fasting-acting for post-prandial injections (Eli Lilly)
Long-acting analogue (Detemir) introduced. Fatty acid moiety allows slow dissociation from
2000
circulation albumin (Novo Nordisk)
2006 1st inhalable insulin analogue (Eubera) introduced, but withdrawn in 2007 due to poor sales (Pfizer)
Ultra-long-acting analogue (Degludec) introduced. Hexadecanedoic acid moiety allows formation
2013
of multi-hexamers and hence slow release (Novo Nordisk)
v Long-acting analogue (Glargine) introduced. Low solubility at physiological pH allows extended
2014 action (Sanofi)
v Another inhalable insulin (Afrezza) approved by FDA (Mannkind)
v Major types of anti-diabetic drugs
Insulin secretagogues enhances insulin secretion
Sulfonylureas (glipizide, glimepiride)
Bind to a 140 kDa high-affinity receptor that is associated with a cells inward rectifier ATP-
sensitive potassium channel membrane depolarization activation of voltage-gated
calcium channel Ca2+ entry stimulates exocytosis increase insulin secretion from
pancreatic cells decrease blood glucose
1st generation sulfonylureas (e.g. chlorpropamide, tolbutamide)
NOT commonly sued because of long duration of action & adverse reactions
2nd generation sulfonylureas (e.g. glipizide, glimepiride)
More commonly used because of fewer adverse effects & drug interactions
Used in Type 2 patients with residual cells function
Adjunctive to nutritional and exercise therapy
20-25% of newly diagnosed diabetics will fail to respond to initial therapy (primary failure).
Of the 75% who achieve good control, 3-5% loss responsiveness each year (secondary failure)
Adverse effects
Stimulates appetite and often causes weight gain
Often cause hypoglycaemia (especially in hepatic & renal insufficiency)
Can cause GI upsets ( given with food) and rashes
Can traverse placenta and deplete insulin from foetal pancreas
Meglitinide analogues (repaglinide and nateglinide)
Similar to sulfonylureas, their actions are dependent on functioning cells
Meglitinides bind to a distinct site on the sulfonylurea receptor of ATP-sensitive K+ channels
stimulating a very rapid and transient insulin release
In contrast to sulfonylurea, meglitinides have rapid onset & short duration of action (~2 hours)
Good to control postprandial glucose, but minimal effect on overnight & fasting glucose level
The incidence of hypoglycaemia is much LOWER than sulfonylureas
Insulin sensitizers increases insulin actions
Biguanides (metformin HCl (Glucophage)) originates from French lilac
Form folk medicine to a miracle anti-diabetic drug 1910s (folk medicine) 1950s
(phenformin) 1970s (metformin in EU) 1990s (metformin in USA)
Major mechanism
Inhibits hepatic glucose production POSSIBLY through activation of AMP-activated
protein kinase (AMPK)
gluconeogenic genes (PEPCK, G6Pc) glucose production hyperglycaemia
fatty acid synthesis & fatty acid oxidation hyperlipidaemia
Recommended for obese patients or patients with insulin resistance
Used alone does NOT cause hypoglycaemia
Reduce risk of cardiovascular complications
Decreases the incidence of diabetes-related cancers
Adverse effects
MOST frequent GI upsets including abdominal discomfort and diarrhoea
Metformin-associated lactic acidosis (MALA) a rare but potentially fatal complication
Inhibition of pyruvate dehydrogenase activity & mitochondrial transport of reducing
agents anaerobic metabolism pyruvate to lactate conversion
Long term use causes vitamin B12 deficiency
Contraindications in patients with
Renal disease
Alcoholism
Hepatic disease
Severe infection
 Thiazolidinediones (rosiglitazone (Avandia), pioglitazone (Actos))
Major action site
Adipose tissue (fat)
Major molecular target
Peroxisome proliferator-activated receptor (PPAR) (a nuclear hormone receptor)
insulin sensitivity in fat (partly by induction of adiponectin)
Possess anti-inflammatory properties and improve lipid profiles
Perhaps the MOST POTENT insulin-sensitizing drugs
Major adverse effects
Weight gain
Fluid retention
Increased risk of heart attack (for rosiglitazone)
Restricted in USA and EU
Should NOT be used in patients with heart disease
Possible bladder cancer link (for pioglitazone)
Suspended in EU and many other countries
Can be potentially used for prevention of type 2 diabetes
-glucosidase inhibitors (acarbose (precose) & miglitol (Glyset)) inhibits glucose uptake
Inhibit -glucosidase through competition with the substrate of this enzyme block
postprandial digestion and absorption of starch and disaccharides from small intestine lower
blood glucose and insulin levels after meals
NO effect on body weight
Use alone does NOT cause hypoglycaemia
Not absorbed into the blood stream
Major side effects
Flatulence
Diarrhoea
Abdominal pain
Relatively weak anti-diabetic effect, usually used in combination with other drugs
Incretin pathway as a therapeutic target for a new class of anti-diabetic drugs
v Incretins (GLP-1 & GIP)
Incretins are gut-derived hormones that can enhance glucose-dependent insulin synthesis &
secretion from pancreatic cells and inhibit glucagon release from pancreatic cells after food
ingestion glucose level
The endogenous incretins include
Glucagon-like peptide-1 (GLP-1)
Gastric inhibitory peptide (also called glucose-dependent insulinotropic peptide or GIP)
GLP-1 and GIP have a very short half-life due to the rapid degradation by dipeptidyl peptidase 4
(DPP-IV) DPP-IV inhibitors incretin
Incretin analogues (mimetics) (GLP analogues & agonists exenatide & liraglutide) enhances
insulin secretion
Exenatide (a 39-amino acid peptide)
Synthetic version of exendin-4, a hormone found in the saliva of the Gila monster
1st GLP-1 agonist approved for the treatment of type 2 diabetes
ONLY 53% homology with GLP resistance to degradation by DPP-4 & extends half-life
Weight loss through slowing down gastric emptying time
Decrease fatty liver
Liraglutide
Long-acting glucagon-like peptide-1 (GLP-1) analogue has been developed by Novo Nordisk
Recently approved by BOTH EMEA and FDA, but has cancer concerns

 Incretin enhancers dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin phosphate (Januvia) and
vidagliptin) enhances insulin secretion
Mixed meal intestinal GLP-1 release active GLP-1 (7-36) rapidly degraded by DD4 to
inactive GLP-1 (9-36) DPP4 inhibitor inhibition of DPP-4 increase active GLP-1
As a monotherapy or as combination therapy with other anti-diabetic agents
Provide a long-term blood glucose control
Side effects
Upper respiratory tract infection
Sore throat
Diarrhoea
SGLT2 (sodium glucose transporter protein-2) inhibitors (new anti-diabetic agent)
Glucose filtration at glomerulus reabsorption from proximal tubule by SGLT1 & SGLT2
SGLT2 inhibitor glucose reabsorption from proximal tubule glucose excretion
dose-effect relationship ( dose of SGLT2 inhibitor mean cumulative urinary glucose)
Generic name Trade name Manufacturer
Dapagliflozin Forxiga Bristol-Myers Squibb in partnership with AstraZeneca
Canagliflozin Invokana Mitsubishi Tanabe Pharma, marketed by Johnson and Johnson
Empagliflozin Jardiance Boehringer Ingelheim and Eli Lilly
Summary
Drug class Action sites Mechanisms Adverse effects
Bind to a receptor (K-ATP
Sulfonylureas Weight gain, hypoglycaemia
channel) in pancreatic cells
Pancreatic cells
Meglitinide membrane depolarization Weight gain, hypoglycaemia
analogues insulin secretion (rarely compared to SU)
Inhibit hepatic glucose
GI disturbance, lactic acidosis
Biguaides Liver production possibly by
& vitamin B12 deficiency
activation of AMPK
Bind to PPAR insulin
Adipose tissue, sensitivity in fat ( insulin Weight gain, fluid retention
Thiazolidinediones
muscle & liver resistance), party by induction of and heart risk (?)
adiponectin
-glucosidase Inhibit -glucosidase in GI tract Flatulence, diarrhoea and
Gut
inhibitors block absorption of glucose abdominal cramping
Mimic the effect of incretins to
Pancreatic & GI disorders, dizziness,
GLP agonists stimulate insulin secretion and
cells headache
inhibit glucagon secretion
Inhibit DPP-4 activity
Upper respiratory tract
degradation of incretins
DPP-4 inhibitors Gut infection, sore throat and
GLP-1 glucose-mediated
diarrhoea
stimulation of insulin secretion
Promotes glucose excretion by
SGLT2 inhibitors Kidney Genital infection
inhibiting reabsorption in kidney
v Stepwise management of type 2 diabetes
Diet & exercise monotherapy combination insulin anti-diabetic agents
v Challenges for diabetes management
How to control hyperglycaemia without causing hypoglycaemia?
How to achieve a tight glycaemic control?
How to convince your patients to receive treatments in the absence of obvious symptoms?
How to ensure your patients to maintain a lifelong treatment compliance?
How to recommend a first-line anti-diabetic therapy for your patients? (Personalized therapy?)
How to address the concerns of potential risks of anti-diabetic drugs?
v Possible future anti-diabetic therapies
Pancreas
GLP1-gastrin dual agonists
Islet transplantation & immunotherapy
Compounds stimulating cells differentiation
Chemokine receptor antagonists
Gastrointestinal
Modulation of microbiota
Liver, muscle & gastrointestinal
Bariatric surgery
Adipocyte
Adiponectin agonists
Kidney
Canagliflozin
SGLT1+2 inhibitors





































Adrenal Glands
Adrenal Steroidogenesis

v Why is the study of adrenal steroidogenesis of major biological interest?

Steroid hormone concentrations are regulated at the level of synthesis rather than secretion.
Steroidogenic cells do not store preformed hormones and steroids, once formed, can freely diffuse
across cell membrane because of their lipophilic nature
Enzymatic defects in adrenal steroidogenesis lead to Congenital Adrenal Hyperplasia (CAH), which
are common endocrine disorders
Characteristic properties of principal types of mammalian hormones
Properties Steroids T4 Peptides & proteins Catecholamines
Feedback
regulation of Yes Yes Yes Yes
synthesis
Storage of
Several days in adrenal
performed Very little Several weeks 1 day
medulla
hormone
Mechanism Diffusion through Proteolysis of Exocytosis of storage Exocytosis of storage
of secretion plasma membrane thyroglobulin vesicles vesicles
Binding to Yes (serum albumin
plasma & other specific Yes Rarely No
proteins carriers)
Lifetime in
Hours Days Minutes Seconds
blood plasma
Time course
Hours to days Days Minutes to hours Seconds or less
of action
Receptor Cytosolic or nuclear Nuclear Plasma membrane Plasma membrane
Hormone binding Hormone binding causes
triggers synthesis of change in membrane
Mechanism Receptor-hormone complex controls
cytosolic second potential or triggers
of actions transcription and stability of mRNAs
messengers or protein synthesis of cytosolic
kinase activity second messengers
v Adrenocortical steroid biosynthesis (steroidogenesis)

 Involves progressive loss of carbons and hydroxylation
ALL derived from cholesterol (C27) cyclopentanophenanthrene (basic backbone)
Estrane (C18) estradial (estrogens)
Androstane (C19) testosterone (androgens)
Pregnane (C21) progesterone (progestogens), cortisol (glucocorticoids) & aldosterone
(mineralocorticoids)
All but one (3-HSD) are cytochrome P450 (CYP) enzymes (family of hydroxylases)
Properties
Cyto present in mitochrondria and microsomes (endoplasmic reticulum)
Chrome P450 heme-containing (electron-rich planar ring with iron (Fe2+ Fe3+) accept or
donate electrons to facilitate electron transfer), absorbs at 450 nm when complexed with CO
RH + O2 + NADPH + H+ ROH + H2O + NADP+
Mixed-function oxygenases as both RH and NADPH + H+ are oxidized
Monooxygenases/hydroxylases as only one atom of O2 is incorporated into the RH substrate
Substrates can be drugs and carcinogens or endogenous compounds like steroid hormones,
bile acids, prostaglandins etc.
About 100 different isoenzymes with different, but overlapping, specificity found in the
human (57 genes identified in Human Genome Project)
Multiprotein complexes consisted of two functional components
Cytochrome P450 that binds the substrates and carries out the reaction
Electron-donating system
Within adrenocortical cells, the mitochondrial & microsomal enzymes have distinct electron-
donating systems
Mitochondria (make use of iron-sulphur protein)
Electron-donating component
NADPH + H+ + oxidized flavoprotein (adrenodoxin reductase) NADP+ + reduced
flavoprotein
Reduced flavoprotein + iron-sulphur protein (Fe3+) (adrenodoxin) oxidized
flavoprotein + iron-sulphur protein (Fe2+)
Cytochrome P450 component
Iron-sulphur protein (Fe2+) + SCC or C11 (Fe3+) (P450) iron-sulphur protein (Fe3+)
SCC or C11 (Fe2+)
RH + O2 + SCC or C11 (Fe2+) ROH + H2O + SCC or C11 (Fe3+)
Microsomes
Electron-donating component
NADPH + H+ + oxidized flavoprotein NADP+ + reduced flavoprotein
Cytochrome P450 component
Reduced flavoprotein + C17 or C21 (Fe3+) (P450) oxidized flavoprotein + C17 or
C21 (Fe2+) (P450)
RH + O2 + C17 or C21 (Fe2+) ROH + H2O + C17 or C21 (Fe3+)

= cytochrome P450 component = electron-donating component

 Steps catalyzed by enzymes with different subcellular localization and tissue distribution
CYP11A
Rate limiting step cholesterol pregnenolone
20-hydroxylation
22-hydroxylation
Cleavage of cholesterol side chain at C20-22
Mitochondrial
Expressed in ALL primary steroidogenic tissues, including cortex, ovary, testicular Leygid cells
& placenta
Stimulated by adrenocorticotropic hormone (ACTH)
Regulated by steroid hormones by negative feedback
3-hydroxysteroid dehydrogenase (3-HSD)
ONLY non-cytochrome P450 steroidogenic enzymes
Oxidation of 3-hydroxyl group to 3-ketone and isomerization of C5,6 double bond to C4,5
position
Pregnenolone progesterone
17-hydroxypregnenolone 17-hydroxyprogesterone
Dehydroepiandrosterone (DHEA) androstenedione [ estrone (aromatase)]
Besides the primary steroidogenic tissues, also found in breast, prostate, liver and skin
Microsomal
CYP17
1 enzyme catalysing BOTH hydroxylation at 17 position & 17,20-lyase reaction
Pregnenolone 17-hydroxypregnenolone DHEA [ DHEA-S]
Progesterone 17-hydroxyprogesterone androstenedione [ estrone (aromatase)]
Required for formation of glucocorticold and androgen (but NOT aldosterone) (expressed in
many steroidogenic tissues!) expressed in the inner zones (fasciculata-reticularis) but NOT
the outer zonal glomerulosa of adnreal cortex
Microsomal
Adrenal androgens
v DHEA, DHEA-S (highest) and androstenedione are the major androgens synthesized in the inner zone
v Biological effects unclear
v Metabolized to more potent sex steroids in extra-adrenal tissues like liver, gonads, skin and adipose
tissue
17-ketoreductase
Androstenedione testosterone
Estrone estradiol
5-reductase
Testosterone dihydrotestosterone
Aromatase
Testosterone estradiol
CYP21
Mediates
Progesterone 11-deoxycorticosterone (DOC) [ aldosterone]
17-hydroxyprogesterone 11-deoxycortisol [ cortisol]
Microsomal
Expressed ONLY IN ADRENAL CORTEX
CYP21 deficiency
Most common inherited disorder of steroid hormone biosynthesis



 CYP11B (CYP11B2 and CYP11B1)
CYP11B has 2 closely related isoenzymes (CYP11B2 and CYP11B1)
In the outer zone (glomerulosa)
CYP11B2 2 distinct enzymatic activities (CMO I & CMO II) synthesis of aldosterone
11-DOC corticosterone (CYP11B2)
11-hydroxylation
Corticosterone 18-hydroxycorticosterone (aldosterone synthetase [encoded by
CYP11B2] corticosterone methyloxidase I [CMO I])
18-hydroxylation
18-hydroxycorticosterone aldosterone (aldosterone synthetase CMO II)
18-oxidation
In the inner zones (fasciculata-reticularis)
CYP11B1
11-deoxycortisol cortisol
Mitochondria
Differential expression of CYPs in the appropriate cortical zones can account for differences
in steroid hormone biosynthesis
Outer zone
CYP11B2 but not CYP17 expressed aldosterone but not cortisol synthesized
Regulation of adrenocortical steroidogenesis by ACTH and angiotensin II
ACTH
Secreted from the corticotrophs in response to corticotropin-releasing hormone (CRH)
(released at median eminence) from the parvocellular neurons of the hypothalamic
paraventricular nucleus
Diurnal & stress CRH secretion but glucocorticoids CRH secretion (negative feedback)
Act MAINLY on the zona fasciculate/reticularis stimulates CYP11A activity (seconds to
minutes) and its transcriptions (hours to days) to production of cortisol & corticosterone
chronic increased in ACTH will result in hyperplasia of adrenocortical tissue
Progesterone DOC
18-OH DOC
Corticosterone 18-OH corticosterone
Progesterone 17-OH progesterone 11-deoxycortisol cortisol
Transiently secretion of aldosterone by the glomerulosa
Angiotensin II & serum K+ concentration (less important role)
Renin produced by the kidney hydrolyses angiotensinogen secreted by liver to angiotensin
Under the effects of angiotensin converting enzyme in the lung, angiotensin I is transformed
into angiotensin II
Vasoconstrictive properties
Bind to a membrane receptor of the cells of the zona glomerulosa of the adrenal cortex
activate the secretion of aldosterone
Main inducers of mineralocorticoid secretion (e.g. aldosterone)
Progesterone DOC corticosterone 18-OH corticosterone aldosterone









v Congenital adrenal hyperplasia
Due to 21-hydroxylase (CYP21) deficiency
Pathogenesis
Glucocorticoid ACTH secretion adrenal gland enlargement with pregnenolone
synthesis level of progesterone & 17-hydroxyprogesterone marked in androgen
metabolism to active androgens in extra-adrenal tissues virilisation
Females
Masculinization of external genitalia
Males
Sexual precocity
Accelerated growth
Early bone maturation ( short stature)
Aldosterone persistent loss of Na+ in urine dehydration & hypotension shock &
sudden death
Early diagnosis essential for effective steroid treatment
Accounts for >90% CAH cases
1/10,000 to1/25,000 (births) in Europe, USA and Japan
1/50 to 1/80 mutant gene carrier frequency
Classified into three forms reflecting severity of deficiency
Salt-losing (~67% of classic) (SL)
Acute adrenal crisis early in life
Severe decreased or total lack of glucocorticoid and aldosterone production
Simple virilizing (~33% of classic) (SV)
Musculinization of external genitalia in females
Virilism in young males
Late-onset (non-classic)
Manifested ONLY in females
Genetic mutations (higher mutation rate due to gene duplication)
CYP21P (pseudogene) (CYP21A)
Most CAH mutations are found in the CYP21P pseudogene SL & SV type of CAH
98% homologous to CYP21 (CYP21B) on 6p21
Deleterious mutations (e.g. 8-base pairs deletion in exon 3) generate premature
termination codons no functional CYP21 production
Close proximity mutation of CYP21 by multiple mechanism, e.g.
Unequal crossing over
Tandomly arranged CYP21P & CYP21 meiotic mispairing & unequal crossing
over gene deletion (loss of functional CYP21) & mostly non-functional CYP21P
Gene conversion













Physiology of the Adrenal Cortex and Medulla

v Anatomy
Suprarenal glands
2 portions
Cortex
Mesodermal origin
Produces steroids
3 zones
Zona glomerulosa mineralocorticoids (aldosterone)
Zona fasciculate glucocorticoids (cortisol)
Zona reticularis androgens (DHEAS)
Go Find Rex, Make Good Sex
Medulla
Neuroectodermal origin (chromaffin cells)
Functionally related to the sympathetic nervous system
Innervated by cholinergic preganglionic sympathetic neurons. Acetylcholine released binds
to nicotinic receptors on chromaffin cells
Secretes catecholamines (epinephrine (EP) & norepinephrine (NE)) in response to
sympathetic stimulation

v Adrenal medulla
Secrete catecholamines
80% of adrenalmedullary cells secrete EP (adrenaline), 20% secrete NE (noradrenaline)
70% of circulating NE comes from postganglionic sympathetic nerve terminals, only 30% comes
from adrenal gland
Functionally integrated with sympathetic activation (3F response)
Synthetic steps Location Enzyme Modulators
Tyrosine dihydroxyphenylalanine Cytoplasm Tyrosine hydroxylase Sympathetic stimulation
XDOPA dopamine Cytoplasm Amino acid decarboxylase
Dopamine NE Granule Dopamine -hydroxylase Sympathetic stimulation
Phenylethanolamine-N-
NE EP (uptake into granule) Cytoplasm Cortisol stimulation
methyltransferase
Regulation of secretion
Stimulate by sympathetic signal in response to stress, primary autonomic centre in hypothalamus.
ACh from preganglionic sympathetic neurons binds to nicotinic receptors on chromaffin cells
Stress releases cortisol which induces expression of PNMT which converts NE to EP
Secretion of adrenal catecholamines stimulated by sympathetic signals in response to stress,
effect coordinated with sympathetic nervous system
3F (Fight, Flight or Fright) response
Physiological effects
Metabolic
serum glucose by
gluconeogenesis
glycogenolysis
FFA by lipolysis
Cardiovascular effects
cardiac output
Selective effects on blood flow to different organ
Vasoconstriction ( receptors)
Vasodilation (2 receptors)
Degradative metabolism (MAO stimulates deamination, COMT simulates methylation)
Epinephrine metanephrine (COMT) vanillylmandelic acid (MAO + AO) 3-methoxy-4-
hydroxyphenylglycol
Norepinephrine normetanephrine (COMT) vanillylmandelic acid (MAO + AO) 3-methoxy-
4-hydroxyphenylglycol
Epinephrine/Norepinephrine dihydroxymandelic acid (MAO + AO) vanillylmandelic acid
(COMT) 3-methoxy-4-hydroxyphenylglycol
Clinical application urinary VMA & metanephrines used clinically to assess the level of
catecholamine production (majority comes from neuronal rather than adrenal catecholamines)
Phaeochromocytoma
Tumour of chromaffin cells producing excessive catecholamines
90% are adrenal medullary tumours
Clinical features paroxysmal hypertension, headaches, sweating, anxiety, palpitations, chest
pain, orthostatic hypotension
Diagnosis
circulatory catecholamines
urinary metabolites (VMA & metanephrine)
Adrenal venous sampling
Location of tumour shown by imaging & adrenal venography
Treatment by excision of tumour

v Zona glomerulosa
Produces mineralocorticoids, major one secreted is aldosterone
Synthetic steps Location Enzyme
Cholesterol pregnenolone Mitochondria CYP11A1 removal of side-chain
Pregnenolone progesterone sER 3-HSD conversion of 5 to 4 steroid
Progesterone 11-deoxycorticosterone sER CYP21A2 21-hydroxylase
11-deoxycorticosterone corticosterone Mitochondria CYP11B2 11-hydroxylase
Corticosterone 18(OH) corticosterone Mitochondria CYP11B2 18-hydroxylase
18(OH) corticosterone aldosterone Mitochondria CYP11B2 18-oxidase
Actions of aldosterone
urinary excretion of NaCl by stimulating Na+ reabsorption by distal tubule & collecting duct (to
a lesser extent, at thick ascending limb of loop of Henl)
urinary reabsorption of water, with consequent extravascular fluid
urinary excretion of K+ & H+
cellular uptake of K+
Excess hypertension, K+, mild alkalosis, muscle weakness (NO Na+)
Deficiency hypotension, circulatory shock, K+, cardiac toxicity, acidosis
Aldosterone escape (NO Na+)
Excess aldosterone ONLY cause transient sodium retention
Because aldosterone mediated extracellular fluid BP renal excretion of BOTH salt
(pressure natriuresis) and water (pressure diuresis), returning renal output of salt and water
normal despite high aldosterone
Regulation of aldosterone secretion
ACTH has little effect on aldosterone secretion
Regulated of aldosterone secretion by
Renin-angiotensin-aldosterone system
Juxtaglomerular (JG) cell secretion of renin is stimulated by
perfusion pressure (dehydration & haemorrhage blood volume)
sympathetic stimulation
NaCl delivery to macula densa cells
Renin converts angiotensinogen (synthesized by liver) to angiotensin I which is converted
in the lungs to angiotensin II (by angiotensin converting enzyme, ACE)
renin angiotensin II aldosterone
Angiotensin II
growth & vascularity of zona glomerulosa aldosterone synthesis
Vasoconstriction of arterioles
Plasma [K+]
plasma [K+] aldosterone
Atrial natriuretic peptide (ANP)
ANP released by atria in response to high BP inhibits aldosterone secretion & renal Na+
reabsorption diuresis & BP

v Zona fasciculata
Produces glucocorticoid, principal one is cortisol (hydrocortisone) important stress hormone
95% of glucocorticoid activity of the adrenocortical secretions come from cortisol
Synthetic steps Location Enzyme
Cholesterol pregnenolone Mitochondria CYP11A1 removal of side-chain
Pregnenolone progesterone sER 3-HSD conversion of 5 to 4 steroid
Progesterone 17(OH) progesterone sER CYP17 17-hydroxylase
17(OH) progesterone 11-deoxycortisol sER CYP21A2 21-hydroxylase
11-deoxycortisol cortisol Mitochondria CYP11B1 11-hydroxylase
Metabolic actions of cortisol
Carbohydrate metabolism
blood glucose
gluconeogenesis (formation of glucose form amino acids) by
breakdown of peripheral protein
transport of amino acids into liver
hepatic gluconeogenic enzymes
glycogenolytic effects of glucagon & adrenaline (permissive action)
glucose uptake
glucose utilization (FFA-glucose cycle)
Excess hyperglycaemia (adrenal diabetes)
Deficiency hypoglycaemia
Protein metabolism
Cortisol mobilizes amino acid from non-hepatic tissues & amino acids utilization in liver
protein breakdown & protein synthesis in extrahepatic tissues
amino acid uptake, gluconeogenesis & plasma & other protein synthesis in liver
Excess muscle wasting, weakening of blood vessel walls (striae, easy bruising, purpura)
Fat metabolism
lipolysis plasma FFA
lipogenesis
Excess truncal obesity (due to ? excessive stimulation of food intake resulting in fat being
generated in some tissues more rapidly that it is mobilized & utilized)
Anti-inflammatory actions
Along with catecholamines, production of pro-inflammatory cytokines & production of anti-
inflammatory cytokines
Stabilizes lysosomal membranes
Decreases permeability of capillaries
Lowers fever because it reduced WBC interleukin-1 release
Clinical application use of steroid in the treatment of inflammatory disease such as
rheumatoid arthritis & SLE
Immunosuppression actions
circulating T-lymphocytes & their migration to site of antigenic stimulation & phagocytosis
of the damaged cells
Promote atrophy of thymus & other lymphoid tissues
Clinical application use for immunosuppression (e.g. in organ transplant)
Effects on bones
PTH secretion bone resorption mobilizes Ca2+
serum [Ca2+] by
intestinal Ca2+ absorption
renal Ca2+ reabsorption
Inhibits osteoblasts & protein synthesis
Excess osteoporosis
 Effects on connective tissue
Inhibit fibroblast proliferation & collagen formation
Excess easy bruising, striae
Effects on muscles
Muscle weakness (related to K+ via mineralocorticoid effects & excessive proteolysis)
Effects on kidney
Inhibits secretion & action of ADH
Slight mineralocorticoid action
Effects on blood
erythropoietin & RBC production
Excess polycythaemia
Gastrointestinal effects
Stimulates acid & pepsin production
Excess peptic ulcer formation
Cardiovascular effects
Permissive actions on catecholamines
BP CO
Excess hypertension
Psychological effects
Excessive initially produces feeling of well-being, continued excessive exposure lead to emotional
lability & depression or frank psychosis
Excess psychosis
Deficiency depressed, apathetic & irritable
Regulation of cortisol secretion
Hypothalamic-pituitary-adrenal axis
Hypothalamic neurons with cell bodies in paraventricular nucleus (PVN) releases CRH from
median eminence into hypophyseal portal veins supplying anterior pituitary
The hypothalamic PVN receive input of
Emotion via limbic system
Trauma via nociceptive pathways
Drive for circadian rhythm (SCN)
CRF releases ACTH from anterior pituitary
ACTH releases cortisol from adrenal cortex
Diurnal rhythm
Diurnal rhythm of CRF, ACTH & cortisol
Cortisol high in the morning, low in late afternoon & at night
CRH under strong diurnal rhythmic regulation emerging from hypothalamic SCN
Under control of suprachiasmatic nucleus (SCN)
Negative feedback
Long loop
Negative feedback of plasma cortisol on hypothalamic CRF & pituitary ACTH production
Short loop
Plasma ACTH on CRF secretion
Stress
CRH, ACTH & cortisol






v Zona reticularis
Zona reticularis secretes weak androgens (androgen precursors DHEA, DHEAS & androstenedione)
that can be converted into active androgen peripherally
Synthetic steps Location Enzyme
Cholesterol pregnenolone Mitochondria CYP11A1 removal of side-chain
Pregnenolone 17(OH) pregnenolone sER CYP17 17-hydroxylase
17(OH) pregnenolone DHEA sER CYP17 17,20-lyase
DHEA DHEAS sER SULT2A1 sulfotransferase
DHEA androstenedione (minor product) sER 3-HSD conversion of 5 to 4 steroid
Adrenal androgens begins to appear after birth at about 5 years of age. DHEAS become detectable
in the circulation at about 6 years of age (adrenarche), contributes to the appearance of axillary &
pubic hair at about 8 years old
Level continue to increase, peak during mid-twenties, and the progressively decline with age
In men, contribution of adrenal androgen to active androgens is negligible
In female, adrenal contributes 50% of circulating active androgens, required for growth of axillary
& public hair and for libido
Excessive androgens in women can lead to virilisation
(Enlargement of clitoris, hirsutism or excessive facial & body hair)
Acne in adult women
Ovarian dysfunction
Secretion regulated by ACTH, other factors NOT well understood

v Adrenal disorders
Hyposecretion (adrenal insufficiency)
Causes
Primary adrenocortical insufficiency
Due to
Autoimmune atrophy of the adrenal cortices (Addisons Disease) MOST cases
TB destruction of adrenals
Tumour invasion
ACTH , BOTH cortisol & aldosterone are deficient
Secondary adrenocortical insufficiency
Due to
Hypothalamic problems (tertiary)
Pituitary problems (secondary), e.g. tumour damaging pituitary gland
ACTH , ONLY cortisol is deficient
Clinical manifestation
Primary adrenal insufficiency = deficiency of
Glucocorticoids hypoglycaemia, fatigue, anorexia & weight loss
Mineralocorticoids K+, ( Na+), hypotension & dizziness
Androgens pubic and axillary hair in women
Clinical features (pigmentation)
Hyperpigmentation in primary hypoadrenalism
Concomitant hypersecretion of ACTH has MSH (melanocyte-stimulating hormone) effect
Note the generalised skin pigmentation (in a Caucasian patient) but especially the
deposition in the palmer skin creases, nails & gums
NO hyperpigmentation in secondary hypoadrenalism
Treatment
Replacement of mineralocorticoid & glucocorticoid
Steroid cover during surgery or stress to prevent Addisonian Crisis

Hypersecretion (3 distinctive clinical syndromes)
Hyperaldosteronism
Hypersecretion of aldosterone due to overactivity of zona glomerulosa
Causes
Primary hyperaldosteronism plasma renin
Adrenal hyperplasia or adrenal adenoma (Conns syndrome)
Clinical features
Muscle weakness often episodic attributed by potassium deficiency
Hypertension ( sodium retention)
K+, Na+, alkalosis, plasma renin, plasma & urinary aldosterone
Pre-operative tumour localization with adrenal venography, venous sampling &
CT scan, radioisotope scan
Treatment
Surgical excision
If surgery not possible spironolactone
Secondary hyperaldosteronism plasma renin
 Cushings Syndrome
Hypercortisolaemia
Causes
Adrenal adenoma or carcinoma (low plasma ACTH)
Increased pituitary ACTH secretion, e.g. adenoma of anterior pituitary (Cushings disease)
Abnormal function of the hypothalamus with increased in CRF
Ectopic ACTH syndrome
Exogenous glucocorticoids (exogenous or iatrogenic Cushing Syndrome) MOST cases
in clinical practice
Clinical features
Endocrine and metabolic systems
Diabetes mellitus with glucose tolerance, fasting hyperglycaemia & glycosuria
Musculoskeletal system
Muscle weakness due to hypokalaemia or to loss of muscle mass from catabolism
Pathological fractures due to bone mineral
Skeletal growth retardation in children
Skin
Purplish rash
Fat pads above the clavicles, over the upper back (buffalo hump), on the face (moon
face) and throughout the trunk, with slender arms and legs
Little or no scar formation
Poor wound healing
Acne and hirsutism in females
GI system
gastric secretions and pepsin production + gastric mucus peptic ulcer
Central nervous system (CNS)
Irritability & emotional lability, ranging from euphoric behaviour to depression or
psychosis
Insomnia
Cardiovascular system
Hypertension due to sodium & water retention
Left ventricular hypertrophy
Capillary weakness due to protein loss bleeding, petechiae & ecchymosis
Immune system
susceptibility to infection due to lymphocyte production & Ab formation
resistance to stress (suppressed inflammatory response may mask even a severe
infection)
Renal and urological systems
Sodium & secondary fluid retention
potassium excretion
Inhibited antidiuretic hormone secretion
Ureteric calculi from bone demineralization with hypercalciuria
Reproductive system
androgen production with clitoral hypertrophy, mild virilism and amenorrhea or
oligomenorrhea in females
Sexual dysfunction
Treatment
Depending on cause
Removal of adrenals if this is the cause
secretion of ACTH by removing the pituitary tumour (surgery or irradiation)

 Adrenogenital/Virilizing Syndrome
Under normal conditions, adrenal secretes small amount of androgens which does NOT have
significant effects on sex organs or sexual function
Aetiology
Congenital Adrenal Hyperplasia (CAH)
Caused by congenital enzyme deficiency (mostly 21-hydroxylase deficiency) that
blocks production of cortisol
Enzyme blockage results in ACTH secretion stimulates excessive in size of
adrenal cortex & androgen production
Tumour of zona reticularis
Secrete abnormal quantities of adrenal androgen
Characterised by development of secondary sexual characteristics of the opposite sex
In female
Ambiguous genitalia in infants
Adrenal virilism in adolescent ( excess androgen)
Hirsutism
Deeper voice
Male pattern baldness
Masculine distribution of hair on body & pubis
Growth of clitoris to resemble a penis
Masculine muscular pattern
In male
Precocious puberty
Feminization ( oestrogen secreting tumour)
Gynaecomastia
Atrophy of testes
Loss of libido
























Growth Control
Molecular Mechanism of Growth Control

v Growth
What is growth?
Life, death and the in-betweens
When does life begin?
Life has never really stopped since it is created
Are we really creating life by reproduction? OR are we just describing different forms of life and
assigning legal/biological significances to some of them?
The fertilization process normally helps to restore the ability for the organism to live in another
life form
However, with the proven success in cloning mammals through somatic cell nuclear transfer
(SCNT) technique, the dependency on such process should be viewed as preferred rather than
absolute
Are there advantages of this preferred mode of reproducing life?
General concepts
Growth is not simply a culmination of mass
It is a carefully orchestrated accumulation of mass, occurring only at specific times and places
In the case of Hartwells unicellular yeast, growth occurs only at a discrete site on the cell surface
(Hence the name budding yeast)
In metazoans, the problem of growth is compounded by the need to adhere to an overall body
plan during development, e.g. the different organs of the body need to grow to a specific size to
maintain a desired body proportion
To achieve an appropriate cell, organ, or organism size, cell growth must be coordinated with cell
proliferation and, in the case of metazoans, cell death
How is cell growth controlled, and how does this control integrate with those of cell proliferation
and death?
Body growth
Morphogenesis, organ maturation and maintenance
Measurement of the balance account of the body/organ
/ in cell number, cell size, cell content and extracellular matrices/other components
Not to be confused with functional performance
Programmed versus reactionary to environmental needs
Cellular growth
Cell cycles Go-G1-S-G2-M
Regulated by various peptide growth factors, cyclin dependent kinases
Cell cycle counting/auditing
Intrinsic clock, telomere/telomerase activity
Trophic support
Linking nutrient to growth/cell division
ATP is the immediate source of energy for many cellular processes
Secondary signals
High energy Low energy High glucose Low glucose
v ATP
v cAMP
v Citrate
v AMP v Fructose 2,6-P2
v Fatty acids v cAMP
v ADP v Glucose 6-P
v NADH
v Pi
v Acetyl-CoA
Stem cell, progenitor cell, immature cell, differentiated cell
Programmed versus restorative and regenerative
 Central controllers of cell proliferation and growth
Cell growth (increase in cell mass) and cell proliferation (increase in cell number) are distinct yet
coupled processes
Delicate balance of these two processes give rise to an organ, organism, or tumour
Cyclin-dependent kinase(s) central regulator of cell proliferation
Signal receptor GTP-G complex activation of adenylyl cyclase conversion of ATP
to cAMP
Amplification of the original extracellular signal by increasing levels of cAMP activates
cAMP-dependent protein kinase (PKA) conversion of ATP to ADP phosphate is used to
phosphorylate specific proteins (activation)
Mammalian target of rapamycin (mTOR), a conserved kinase central regulator for cell growth
Functions
Transcription, RNA processing, translation, autophagy & protein stability
Pathway
Insulin/IGF insulin receptor tyrosine phosphorylation of IRS1 activation of PI3K
synthesis of phosphatidylinositol 3,4,5-trisphosphate recruitment of PDK1 to plasma
membrane activation of AKT kinase inhibition of the TSC1/2 disinhibition of Rheb
activation of mTOR
AMP-activated protein kinase (AMPK) being an important partner in the regulatory system
Low energy (AMP) or LKB1 activation of AMPK activation of TSC1/2 inhibition of
Rheb inhibition of mTOR
Increases AMPK via ATP depletion (metabolic benefits obtained through exercise)
GLUT4 translocation + insulin sensitivity glucose uptake hyperglycaemia
Cell death
Overview
An active determinant and integral component in growth control
Dynamic balance between proliferation, survival and death is important in morphogenesis
Also participates in establishing a functional system
Simple scheme for cellular development
Stem cells (regenerate) transit amplifying terminal differentiation death
History
Nobel Prize in Physiology or Medicine 2002 for the discoveries concerning genetic regulation
of organ development and programmed cell death
Caenorhabditis Elegans (a Nematode) cell lineage (1090 cells) C Elegans (959 cells) +
programmed cell death (31 cells) [105 out of the 131 are in the nervous system]
Programmed cell death (apoptosis)
Overview
The human body consists of hundreds of cell types, all originating from the fertilized egg
During the embryonic and foetal periods, cells increase dramatically in number, mature
and become specialized to form tissues and organs
Lots of cells are formed also in the adult body > thousand billion cells each day
To counter cell production and maintain an appropriate number of cells in the tissues,
extensive cell death occurs both in the foetus and in the adult
This delicate, controlled elimination of cells is called programmed cell death
Examples
Programmed cell death eliminates unwanted structures during the development of the
male and female inner reproductive organs
In the human foetus, the interdigital mesoderm, initially formed between fingers and toes,
is removed by programmed cell death.
The intestinal lumen and other tissues are sculpted by programmed cell death

 Regulation
Protein synthesis regulated by the genes affected by the activated transcription factors
Alteration of the relative abundance of pro-apoptotic (Bax, Bclxs, Bad, p53) and anti-
apoptotic proteins (Bcl2, Bclxl, Rb, NAIP)
Changes and reactions
Changes in mitochondrial activity release of cytochrome-c, procaspase-9, apoptosis
inducing factor and other related molecules
Activation of the caspase cascade breakdown of DNA
Clinical implications of dysregulated control of apoptosis
Defective death cancer, SLE, rheumatoid arthritis & polycythaemia vera
Excessive death Huntingtons disease, ALD, Shigellosis, AIDS, stroke & MI
v Growth control (OUR CURRENT UNDERSTANDING IS STILL LIMITED)
How do our bodies know when to initiate or stop growing? And why?
Contact inhibition
Supply and demand energy as focus
Cell division counting telomere
Cell mass sensor chalone hypothesis
Sensing body mass leptin
Negative cellular growth regulator Tuberin (TSC2)
Examples
Mesenchymal stem cell potential source of multiple tissue
Pre-implantation-stage blastocyst (6-7 days after conception)
CNS
Development of the permanent kidney the ureteric bud and the metanephric blastema interact
and induce each other by reciprocal induction to form the permanent kidneys
Conceptual aspects
Autocrine, paracrine, endocrine
Bi- (or even multi-) VS unidirectional communications sensor (internal vs external), effector
Individual cell VS the welfare of the whole functional organism
Redundancy one of natures defense mechanism?
Molecular mechanisms
Genetic programme
Commitment of cells to be specialized cells
Once exiting the stem cell mode, the life span will be finite with some built in sensor system
(e.g. counting the cell clock by telomere length)
Paracrine
Activity dependent proliferation and differentiation (e.g. neuronal axon and oligodendrocyte)
Cell mass regulates the mitogenesis rate (Chalone hypothesis)
End-organ directed growth and survival (e.g. neurotrophic factor from muscle and skin
regulating the number of innervating neurons)
Bone matrix cells supporting haematopoiesis
Endocrine
Key molecules involved in fetal growth morphogenic events, organ maturation and birth size
The primary stimuli to mitogenesis is provided by a phylogenetically ancient and ubiquitous
intercellular communication system generally termed peptide growth factors
Insulin, Insulin-like growth factor I and II
Fibroblast growth factor (FGF)
Platelet derived growth factor (PDGF)
Epidermal growth factor (EGF)
Transforming growth factor (TGF)
Human placental prolactin
 Key molecules involved in postnatal growth
Insulin-like growth factor I
Thyroid hormone
Growth hormone
Sex steroid
Insulin
Primary target of regulators of linear growth bone (growth plate)
Factors involved in the regulation of growth plate development
Stem cell giving rise to the mesenchymal cell condensation
Chondrocyte proliferation
Formation of pre-hypertrophic chondrocytes
Cessation of hypertrophic chondrocyte growth
Local regulators of growth plate
Indian hedgehog (Ihh)
Secreted molecule
Ihh deficient mice display greatly reduced proliferation of chondrocytes in the growth
plate, reflecting the importance of Ihh in longitudinal bone growth
These mice lack functional osteoblasts in all skeletal elements
Ihh is specifically needed for osteoblast differentiation in the endochondral bones
Parathyroid hormone-related peptide (PTHrP) Ihh/PTHrP feedback loop
PTHrP is secreted from perichondrial cells and chondrocytes at the ends of long bones
PTHrP acts on receptors on proliferating chondrocytes to keep the chondrocytes
proliferating and, thereby, to delay the production of Ihh
When the source of PTHrP production is sufficiently distant, then Ihh is produced
Ihh acts on its receptor on chondrocytes to increase the rate of proliferation &, through
a poorly understood mechanism, stimulates the production of PTHrP at the ends of bones
Ihh also acts on perichondrial cells to convert these cells into osteoblasts of bone collar
Fibroblast growth factors (FGF)
FGFR 3 is expressed in proliferating chondrocytes
FGFR 1 is expressed in prehypertrophic & hypertrophic chondrocytes and perichondrium
FGFR 2 is expressed in the perichondrium, periosteum and the primary spongiosa
FGF 18 is expressed in the perichondrium phenotype of its knockout suggests it acts on
FGFR 3 to decrease chondrocyte proliferation
FGFR 1 to delay terminal differentiation of hypertrophic chondrocytes
FGFR 1 and 2 to delay osteoblast development
FGF 7, 8 and 17 also expressed in the perichondrium (function in growth plate is unknown)
Bone morphogenetic proteins (BMP)/transforming growth factor (TGF)
FGFs act to (BMPs act at each of these steps in a manner opposite to that of FGFs)
Decrease chondrocyte proliferation
Increase the production of Ihh the production of Ptc-1 & PTHrP
Accelerate the differentiation of hypertrophic chondrocytes into terminally
differentiated chondrocytes (express osteopontin & other characteristic markers)
Vascular endothelial growth factor (VEGF)
Cbfa1/Runx2
Phases of growth ICP model of JPE Karlberg
Infancy
Thyroid hormone, insulin-like growth factor, insulin
Childhood
Growth hormone + others
Pubertal
Sex steroid + others
 FGFR 3***
v Chondrocyte FGFR3 regulates bone mass by inhibiting osteogenesis
Fibroblast growth factor receptor a family of 4 membrane bound receptor tyrosine kinases (FGFR
1-4)
Linked to downstream pathways including MAPK, PKC-, PI3K/AKT, and STAT signalling pathways
FGFR 3 negative regulator of bone growth endochondral bone development
FGFR 3 inhibits both proliferation and hypertrophic differentiation of chondrocytes
Chondrocyte FGFR 3 is involved in the regulation of bone formation and bone remodelling by a
paracrine mechanism
v Mutations
Gain-of function mutations
Mice showed remarkably smaller body and skeleton size
Thanatophoric dysplasia a lethal condition
Short, curved femora and humeri
Prominent platyspondyly of the vertebrae
Hypochondroplasia
Achondroplasia
Down-regulated FGFR 3 activity CATSHL syndrome
Camptodactyly
Tall stature
Scoliosis
Hearing loss
Knock-out
Mice showed overgrowth of skeleton
Endocrine regulators of growth plate
GH
Proliferation of resting zone chondrocytes
Stimulates local IGF-1 expression
IGF-1
Increases proliferation of resting and proliferative chondrocytes
Increases hypertrophic chondrocyte cell size
Glucocorticoid
Inhibits chondrocyte proliferation
Delays growth plate senescence
Induces chondrocyte apoptosis
Thyroid hormone
Permissive for proliferation in the proliferative zone
Oestrogen
Inhibits proliferation in the proliferative zone
Accelerates growth plate senescence lack of the enzymes or receptors continue to
grow (same in both female and male no by androgen in males) (may be used to
stimulate growth in short people in the future)
Androgen
Stimulates proliferation, matrix production
Increases IGF-1 expression
Vitamin D
Permissive for normal differentiation and apoptosis of hypertrophic chondrocytes
Leptin
Stimulates proliferation and differentiation


 GH-IGF axis
v Overview
Hypothalamic & pituitary regulation of GH secretion as the higher level of control somatostatin
vs growth hormone releasing hormone (GHRH) determine episodic/continuous GH secretion
24-hours GH secretary patterns from the anterior pituitary bind to GH-binding protein & GH
receptor on the target tissue (defect) signal transduction (defect) IGF-binding protein & IGF
synthesis (defect) IGF release (defect) endocrine/autocrine/paracrine action bind to IGF-
binding protein & type I IGF receptor on bone signal transduction growth
v Different levels of control in the GH-IGF-I axis
Alteration of the secretion of GH
Alteration of IGF-I secretion
Modulation of the bioavailability of IGF-I by IGFBPs
Modulation of IGF-I binding to IGF-I receptor
Regulation of the IGF-I receptor level
v Insulin-like growth factor (IGF) systems
Components
IGF, IGFBP-3 (high-affinity), acid labile subunit, other IGFBPs, circulating IGF-I & bound VS free
IGF-I
IGF-I is important for both fetal & postnatal growth, more important than GH for postnatal growth
The type I IGF receptor mediates anabolic actions of both IGF-I and IGF-II
IGF-II is a major foetal growth factor
The type II IGF receptor is bifunctional target lysosomal enzymes & enhance IGF-II turnover
IGF gene
Regulations
GH is the primary regulator of IGF-I gene transcription
Oestrogen stimulates the IGF-I mRNA expression
Thyroxine
Existence of multiple promoters
Heterogeneous transcription initiation within each of the promoters
Alternative splicing of various exons
Differential RNA polyadenylation
Variable RNA stability
Severe IGF-I deficiency in children due to growth hormone insensitivity
Long-term treatment with recombinant IGF-I


















Public Health
How many Patients with Diabetes are there

v Background
Worldwide trends in diabetes
Since 1980, age-standardized diabetes prevalence in adults has increased, or at best remained
unchanged, in every country
In 2015 1 in 11 adults has diabetes
In 2040 1 in 10 adults will have diabetes
Together with population growth and ageing, this rise has led to a near quadrupling of the
number of adults with diabetes worldwide
The burden of diabetes, both in terms of prevalence & number of adults affected, has increased
faster in low-income and middle-income countries than in high-income countries
Diabetes epidemic in China and Hong Kong
The MOST in the world in terms of absolute number, and among the HIGHEST as a percentage of
total population (prevalence)
2nd India
3rd USA
Crude prevalence of 11.6% among Chinese adults equates to 113.9 million cases
1980 <1%
2000 5.5%
Hong Kong 10.3% in 2014 (pre-diabetes 8.9%)
The outlook
In recent years age-adjusted incidence has beginning to stabilize in many high-income countries
USA, UK, Denmark, Korea, Hong Kong
However prevalence still increasing and number of people with diabetes increasing because
Population ageing
Population growth
Urbanization
Chronic incurable disease
v Data and health care information
Overview
Real world collecting & coding data
Data processing, analysis, interpretation & presentation information
Information judgment & conclusions knowledge
Knowledge politics & commitment decision & ACTION
Key issues of data
Validity
Reliability
Completeness
Timeliness
Analysis
Confidentiality and information governance
Type & sources of data for practitioner
Routine data (routinely collected) tip of clinical iceberg
Pros Cons
v Readily available, low cost v May NOT be up-to-date, may be less complete (except census)
v Useful for initial assessment v Collected for a different purpose so may not include specific
(baseline of expected levels of variables of interest
health or disease), identifying v May NOT be reliable e.g. political influences & manipulation
hypotheses v Data linkage may NOT be possible
 Demographic data
Census
Conducted every 10 years (latest one in 2011)
Gold standard in terms of completeness
Problems
Self-reported
Under-reporting of certain groups
Outdated
Expensive
Vital statistics (event)
Systematically tabulated information concerning births, marriages, divorces,
separations, and deaths based on registrations of these vital events
(Health) event data
Diagnosis coding
Standardized codes of diagnoses for comparison
Categorized for analysis Includes diseases, disorders, symptoms, injuries
Examples
ICD-9, ICD-10 (International Classification of Disease Version 9/10)
ICPC-2 (Primary care)
DSM (Psychiatry)
SNOMED CT (Medical terms)
Uses
Interventions and procedures (ICD-9, ICD-10)
Medical terms (SNOMED CT)
Epidemiology clinical burden of disease, identify risk factors
Financing, reimbursement
Health service planning/resource allocation
Evaluation
Limitations
Those who have a disease & use health care services X full picture of morbidity
Depends on accuracy and completeness of coding
Differing coding practices
Expensive and time-consuming
Changes in case definitions across time and place
Historical comparisons mapping to ICD version 10
Hospital utilizations
Clinical laboratory and pathology
Prescribed medications
HA Clinical Management System (CMS)
Disease registers
All cases of a particular disease/health-relevant condition in a defined population
E.g. Hong Kong Cancer Registry
Statutory notifications
Useful for incidence rates, information on remission, prevalence & survival
But expensive to maintain & requires linkage of multiple data sources
Health periodic surveys
Self-reported
Generalizability depends on representative sample
Thematic Household Surveys
Health-related themes chronic disease, insurance, service utilization
Behavioural Risk Factor Surveillance System (BRFSS), e.g. smoking, alcohol
 Research studies and commissioned studies
Ecological studies
Cross-sectional surveys
Cohort
Children of 1997 Birth Cohort
UKPDS (UK Prospective Diabetes Study) T2DM
DCCT (Diabetes Control and Complications Trial) T1DM
Other commissioned studies
Applications how many diabetics in Hong Kong?
Examples of data
Lab HbA1c, OGTT, fasting glucose, random glucose results
Diagnosis coding ICD-9, ICPC-2
Diabetic medication prescriptions
Self-reported diagnoses
Attendances at diabetic specific clinics diabetic retinopathy
Published studies by academia, government, NGOs
Denominator census, population projections
Limitations of data
Completeness undiagnosed cases, private healthcare system (most GPs)
Data linkage (double counting of patients)
Matching numerator and denominator across different time periods, geographical area,
populations, e.g. district council vs HA clusters
Information governance
Patient confidentiality
Personal data (privacy) ordinance
Data security
Consent
Ethical approval
v Clinical, social and economic burden of disease
Economic aspect of ill-health
Overview
Direct impact on health such as suffering and spending on care
Indirect impacts on consumption of non-health related goods and services
Loss of leisure time
Reduced productivity, loss of wages
Scarcity of resources & unlimited wants
Utility represents relative satisfaction from consuming a good or service
Determined from preferences
Cost of illness
Direct costs
Expenses incurred because of the illness, e.g. medical care, drugs, travel costs
E.g. diabetes
Direct annual cost of diabetes in the world is $825 billion
China ($170 billion)
USA ($105 billion)
Nearly 60% of the global costs are borne by low-income and middle-income countries,
where substantial parts of treatment costs are paid out-of-pocket
Indirect costs
Value of lost production reduced working time X wage rate
What if unemployed?
 Problems
Intangible costs
Costs of pain and suffering, changes in health status
Measureable?
Economic growth
From lower savings, lower investments in human and physical capital, changes in
labour supply
Leisure time
Perspective individual, household, government, societal?
Other approaches alternatives
Value of a statistical life
Statistical method to value a life using observed trade-offs between risks and money
People make these choices
E.g. wage premium for someone to accept a job with a high risk of injury or death
Value of lost (economic) output
Societal perspective
Measured by Gross Domestic Product (GDP)
GDP is a partial measure of overall economic impact
Sum of household consumption, government expenditure & investment by firms
X include non-market consumption, the value of leisure or the value of health itself
Health expenditure also forms part of GDP
Social burden
Definition is elusive is it cost to society?
Differences between societies, cultures, individuals
Many outcomes
Violence, abuse, public disorder, lost productivity, vandalism, public disarray
Familial problems such as marital conflicts and divorce, interpersonal problems, child abuse
Measureable and quantifiable? $?
Economic efficiency Social welfare (and public health)
v Maximize overall output/benefits v Also concern about equity & fairness
v Minimize resource use to produce a given level of output v How are the benefits distributed?
Clinical burden
Mortality and morbidity
Measuring mortality
Numbers of deaths e.g. 5 million adults die from diabetes, 1.5 million adults die from
HIV/AIDS &TB, 0.6 million adults died from malaria
Total life-years
Bias towards young because of longer life expectancy
Morbidity weighting
Is morbidity comparable across different conditions, individuals?
Is chronic/severe morbidity comparable to death?
Measure of clinical burden
Disability life-years (DALYs)
DALYs = YLL + YLDs (Years of life lost + Years living with disability)
e.g. Global Burden of Disease (GBD) study
Potential years of life lost (PYLL)
Death at an earlier age contributes more PYLLs
Life expectancy
Average number of years an individual is expected to live based on existing mortality rates
Disability-Free Life Expectancy (DFLE)
Quality-adjusted Life Years (QALYs)
Taking Care of the Patients with Diabetes

v Diabetes epidemiology
Type 2 diabetes is the most common form of diabetes in adult
Prevalence in Hong Kong adults 10.2%
Prevalence in Chinese adults 11.6%
About 50% of cases are undiagnosed
Major burden of disease on health and health system
Associated with many other comorbidities
E.g. hypertension, dyslipidaemia, cardiovascular disease, cancer, infections etc.
Wide range of microvascular and macrovascular complications
Expensive and difficult to treat
Require long-term care and follow-up

v Care for chronic disease
Chronic diseases, e.g. hypertension and diabetes, are a major burden to health care systems
Associated with wide range of complications, requiring long-term follow-up and repeated
hospitalizations
Increasing burden with population ageing, epidemiological shift, and raising health care costs
About 43% of patients attending general out-patient clinks (GOPCs) in Hong Kong have hypertension
and/or diabetes
Care of the patient with diabetes
Patient education and empowerment
Glycaemic control
Pharmacological oral medications +/- insulin
Non-pharmacological dietary modifications, physical activity & smoking cessation
Monitor glycaemic control
Prevention of microvascular and macrovascular complications
Screening, monitoring & management
Management of associated risk factors and comorbid conditions
E.g. hypertension, dyslipidaemia, depression
Challenges in delivery of diabetes care
Time-demanding for busy clinicians
Large amount of clinical information
Unique risk profile for each patient
Non-compliance to treatment
Non-attendance or loss to follow-up
Organization of care for diabetes
v Organization of care
Models of care
Chronic Care Model
Evidence-based synthesis of system changes to guide quality improvement in chronic disease
management
Acknowledges that substantial portion of chronic care takes place outside formal health care
settings
Suggests 6 components to improve outcomes of chronic care
Health system
Creating a culture, organization and mechanisms that promote safe, high quality care
Patient self-management
Empowering and preparing people to management their health and health care
Decision support
Delivering effective, efficient care and self-management support
Delivery system design
Promoting care consistent with research evidence and patient preferences
Clinical information systems
Organizing patient and population data to facilitate effective and efficient care
Tracking progress through reporting outcomes to patients and providers
Community resources and policies
Mobilizing community resources and health
policy to meet the needs of patients with
chronic disease
How effective is CCM?
One of the most widely used care models in care
of diabetes
E.g. Canada, United States
Improvement in some clinical outcomes in
diabetes control observed in the US
Health system
Support from health care leaders and redefinition of team roles (e.g. nurses
instead of physicians to conduct foot examinations)
Patient self-management
Individual and group interactive sessions, weekly telephone calls, use of
email/smartphone, computer-based training
Decision support
Support for health care providers by telephone/email, problem-based learning
meetings, evidence-based guidelines
Delivery system design
Streamlining services to provide services exclusively for diabetes, e.g. diabetes
days
Clinical information systems
Disease/patient registries, electronic medical records
Community resources and policies
Collaboration between physicians and community leaders, physicians & hospitals
Limitations
Uncertain which component of CCM is most effective
Single component unlikely to change outcomes
Uncertain how CCM compares to other models in effectiveness
High quality evidence from randomized controlled trials is lacking
Broad chronic care programmes had little effect on mortality, QoL or cost-effectiveness
 Innovative Care for Chronic Conditions Model
CCM adapted by WHO focus more on community
& policy aspects of improving chronic care
Suggests 3 levels for improving chronic care
Micro individual and family
Meso health care organization & community
Macro policy
Limitation
NO rigour evidence on effectiveness
Public Health Model
Suggests 3 levels of intervention to improve
burden of chronic conditions
Population-wide policies
Community activities
Health services
Preventive services
Ongoing care for patients
Limitation
No evidence on effectiveness
Continuity of Care Model
Outlines how chronic disease develops in response to risk factors in the population
Track disease pathway from general
population to patient with terminal disease
Suggest points at which to target interventions,
including prevention, medical therapy,
treatment, rehabilitation & palliative care
Limitation
NO rigours evidence on effectiveness
Life Course Model
Based on Continuity of Care Model
Risk of developing chronic diseases (e.g.
diabetes) are influenced by factors acting at all
stages of life
Suggests different strategies for the prevention
and control of chronic diseases according to
needs & risk specific to each stage of life
E.g. Hong Kong Reference Framework for
Diabetes A Life Course Approach
Primary care
Level of health care
Primary
1st point of contact for patients in health system
Secondary
Services provided by specialists that do not typically have 1st contact with patients
Tertiary
Specialized consultative health care, usually provided by hospitals or facilities for
advanced investigations and treatment




 What is primary care?
Essential health care based on practical, universally sound, and socially acceptable methods
and technology made universal accessible to individuals and families
An integral part of both the countrys health system of which it is the central function and
the main focus of the overall social and economic development of the community
1st level of contact of individuals, families and the community with the national health system,
brining health care as close as possible to where people live and work and constitutes the 1st
element of a continuing health care process
Focus of primary care
People at the centre of health care
Deals with the health of everyone in the community
Aims for universal access and social health protection
Comprehensive response to peoples expectations and needs, spanning the range of risks
and illnesses
Not just the antithesis of the hospital
Investing in primary care is not cheap
But provides better value for money than its alternatives
Attributes of primary care
Accessible 1st contact care that is comprehensive, continuing, coordinated and person-
centred, in the context of family and community
Covers a wide range of services including
Health promotion
Prevention of acute and chronic diseases
Health risk assessment and disease identification
Treatment and care of chronic diseases
Self-management support
Rehabilitative, supportive and palliative care for disability and end-stage diseases
Functions
Gatekeeping
To directly provide services for common needs, and act as agent for coordinating services
for other more specialized needs
Preventing unnecessary escalation of care and misuse of scarce resources
Delivering of continuous or longitudinal care
Sustained relationships between patient and doctor over time
Treating the patient as a whole person whose values and preferences are taken into
account increasing patient satisfaction
How effective is primary care?
Associated with improvements in various population health outcomes
All-cause mortality, cardiovascular disease mortality, cancer mortality, infant mortality,
life expectancy, self-rated health
Less disparities in health outcomes
Reduces total cost of health services
Reduces unnecessary use of specialist care
May improve quality of health care
Improves adherence to guidelines and emphasizes patient as a person
May improve preventive health care and early management of health problems





 Providers of primary care in Hong Kong
Public
Hospital authority
General out-patient clinics (GOPCs)
Chinese Medicine out-patient clinics
Community Nursing Service
Community Geriatric Assessment Team
Department of Health
Family Health Service
Woman Health Service
Maternal and Child Health Centres (antenatal care and child health)
Student Health Service
Elderly Heath Service
School Dental Care Service
Primary care services for civil servants and dependents
Families Clinics
Government Dental Clinics
Private
Solo clinics
Health maintenance organisations
Non-government organizations
Hospitals
Physicians (western or Chinese medicine) MacroHorganisation'of'the'Hong'Kong'health'system'
Dentists Public Health Personal Health Care

Nurses System Public

(Food and Health Bureau)
Private

Chiropractors Financing
sources
Government
general revenue
Employers Individuals

Physiotherapists Department of Health

Minimal
out of
pocket

Occupational therapists & Centre for Health Hospital fees

Purchasers Protection Authority (waived for Private
Disease prevention and the insurers/
Clinical psychologists control (communicable and
non-communicable diseases)
38 hospitals
GOPCs,
indigent) MCOs

Dietician
Elderly health SOPCs
Providers Health education Private providers
HIV/AIDS service (predominantly Western Chinese Dental Laboratories

Pharmacists
Maternal and child health Western allopathic medicine medicine (4%)
Port health allopathic medicine (10%) (12%)
Student health medicine) (73%)

Optometrists Tobacco control

)
Tuberculosis service

Speech therapists Consumers General population

)
Universal
coverage
Mostly individuals from middle and upper socioeconomic
strata (except for Chinese medicine use)

Podiatrists
Market Inpatient (bed-days) 90% 10%
share
(admission) 80% 20%

Others Overall outpatient incl. TCM

Specialist
30%
50%
70%
50%
GP 30% 70%
Challenges to primary care in Hong Kong
Population ageing
Increasing epidemic of non-communicable chronic diseases
Higher expectations form the public and consumers
Rising health care costs
Compartmentalization of health system
Lack of functional primary care network
70% of clinic consultations & ambulatory care mostly carried by solo practitioners in
private sector with patients paying out of pocket
Little gatekeeping
Patient do not need referrals to see specialists in private sector
Many primary care physicians have NO formal training in Family Medicine
Other specialists in private sector simultaneously provide primary care services
HA & DH both carry out primary care functions but have little sharing of information
Doctor shopping and excessive use of ambulatory care
Over-reliance on hospital & specialist care for management of common chronic diseases
 Strategies to strengthen primary care in Hong Kong
Development of reference frameworks and Primary Care Directory
Pilot projects to improve chronic disease management
General Out-Patient Clinical Public Private Partnership Programme (GOPC PPP)
Shared care programme by Hospital Authority
Targeting clinically stable patients at GOPCs with hypertension and/or diabetes
Aims at enhancing primary care of patients and managing demand for GOPC services
Patients receive up to 10 subsidized visits/year to private doctors in the same district
Private doctors providing medical consultations & medications and HA providing
investigations
Patient pay GOPC fee of $45/consultation to receive private doctor consultation
Private doctors to be reimbursed by HA
Multi-disciplinary Risk Assessment and Management Programme (RAMP)
Platform of multi-disciplinary teams set up at GOPCs, including doctors, nurses and
allied health professionals
Aims at providing structured risk assessment and targeted interventions for patients
with diabetes and hypertension
Community and health centres and networks
Primary dental care
Community mental health care
Electronic health recording (eHR) sharing system
Currently enables one-way sharing of information from HA to private sector
Participating private doctors can access (limited data regarding) their patients
medical records health by HA upon patients consent
Aims at improving sharing of clinical information between public and private sectors
Strengthening primary care-related research
Establish of Primary Care Office
Focused factories
In manufacturing, a plant established to focus the manufacturing system on a limited, concise,
manageable set of products and technologies precisely defined by the companys strategy and
economics
In health care, defined as multidisciplinary organizations or teams that work together based on
common objectives, e.g. treatment of specific patient groups
Hospital for hernia surgery
Focused factories for diabetes
Multi-disciplinary team that can treat all problems that patients with diabetes are lively
to have
Primary care physicians
Endocrinologists, ophthalmologists, vascular surgeons, cardiologists, nephrologists,
dermatologists, psychiatrists
Nurses, home care aides
Other eye care professionals, podiatrists, nutritionists, physiotherapists, occupational
therapists etc.
Advantages
Clinical and financial economies of scale may increase efficiency and lower costs
Limitations
Focus on disease rather than patient
Patients may have multiple co-morbidities
May encourage further sub-specialization
Antithesis of primary care?

 Shared care
What is shared care?
Joint participation of sectors in the planned delivery of care
Informed by enhanced information exchange
Over and above routine discharges and referrals
Could be across different interfaces depending on health system
Primary and secondary (specialist) care
Public and private sectors
Used in the management of various choric disease, particularly diabetes
Forms of shared care
Community care
Specialists attend or run clinic in a primary care setting with primary care personnel
Basic model
Specific, regular communication system between primary and secondary care
Liaison
Regular meetings to discuss management of patients
Shared care record card
Communication through shared record card carried by patients
Computer-assisted
Coordinated care through computer database or email
How effective is shared care?
Systematic review of effectiveness of shared care interventions for chronic disease across
primary-secondary care
No consistent improvements in physical and mental health or psychosocial outcomes
Clear improvements in prescribing
But most studies review had suboptimal quality and duration of follow-up (< 2 years)
Limitations
Interventions are contextually specific
Referral system in Hong Kong
Patients can enter health system at multiple points
Public VS private
Primary VS secondary care
Ambulatory VS in-patient
1st point of contact depends on various factors
Disease presentation
Emergency VS non-emergency
Acute VS non-acute
Patient preference
Waiting times
Referral patterns depend on sector or health care providers
Patients typically go through sequential level of care in public sector, e.g. AED secondary
care tertiary care (if necessary)
Some sharing of care from public to private sectors, e.g. PPP
NO formal referral system exists in private sector, e.g. private GP may choose to refer to
private/public specialists care, AED or GOPC






 Application A patients journey into diabetes care

Example 1
Mr Chan, 50 years old, has history of hypertension and hyperlipidaemia, and is followed
up at a GOPC. On a visit to private GP for acute flu-like symptoms, he reveals that he has
had malaise and polydipsia for one month. A Hstix shows blood glucose of 13 mmol/L
What next?
Mr Chan is subsequently diagnosed to have diabetes by his GP but prefers to be followed
up by the GOPC for his chronic conditions. He had also started seeing a TCM practitioner
for his diabetes. 3 years later, he develops numbness in his fingers and toes. He is referred
by the GOPC to the medical SOPC for further workup of suspected diabetic neuropathy
Example 2
Mrs Wong, 70 years old, with good past health, presents at the AED for sudden onset of
weakness in her right limbs. She is diagnosed with ischaemic stroke and is admitted to the
medical ward. On further workup, her fasting glucose if 8.5 mmol/L and she is diagnosed
to have diabetes What next?
After treatment and rehabilitation, Mrs Wong is discharged home. She is followed up at
the general medical SOPC and is paid regular visits by a nurse from the Community
Nursing Service of the hospital. 5 years later, her blood glucose remains poorly controlled
despite oral medications and insulin, and her renal function continues to deteriorate. She
is referred from the general medical SOPC to the endocrine SOPC for follow-up
When should I refer?
Immediate referral to hospital/initiation of insulin therapy
Who is acutely ill
Who have heavy ketonuria
Who have a blood glucose level 25.0 mmol/L
Who present with diabetic ketoacidosis (DKA)
Who present with diabetic hyperosmolar non-ketotic syndrome (HONK)
Referral to specialist
Young patients (age < 30 years) with diabetes
Patients with features suggestive of endocrinopathies, e.g. Cushing syndrome
Heavy proteinuria or presence of haematuria in the absence of other complications
Presence of complications
Women who are pregnant
v Summary
As medical doctors, you should
Recognize the importance of chronic non-communicable disease sand models of care
Appreciate the role and functions or primary care, especially in the care of chronic diseases
Provide the best possible care to each of your patients, including appropriately referring them for
specialist care
Champion for improvement in the organization of care for patients with diabetes and other
chronic disease










The Origins of Diabetes

v Overview of diabetes
Type 1 diabetes
Characterized by deficient insulin production and requires daily administration of insulin
The cause of type 1 diabetes is not known and it is not preventable with current knowledge
Type 2 diabetes
Results form the bodys ineffective use of insulin
Comprises 90% of people with diabetes around the world and is largely the result of excess body
weight and physical inactivity
Symptoms may be similar to those of Type 1 diabetes, but are often less marked. As a result, the
disease may be diagnosed several years after onset, once complications have already arisen
v Global and ethnic patterns of diabetes and its risk factors

Epidemiological trends
ORIGIN OF DIABETES 6

(Xu et al, JAMA 2013)
revalence of diabetes, 1980-2014
v Life course perspective on health
Background
Prevalence of NCD (e.g. diabetes, coronary heart disease) rapidly rising (why?)

NCD Risk Factor

Collaboration
(NCD-RisC),
Lancet (2016)
9
Genetics ORIGIN OF DIABETES 10

Plays a role in determining body weight

Correlation between biological twins VS correlation in adoptive siblings
CANNOT be the ONLY reason for the rise in prevalence
Not enough change in the genome over a biologically short period of time
Attention was directed to the environment
Until recently, research into the aetiology of non-communicable diseases tended to
concentrate on the identification of risk factors in adult life (adult risk factor approach)
The impact of lifestyle and behaviours on the onset and progression of diseases including
smoking, diet, exercise & alcohol consumption
One disease may have multiple risk factors, and one behaviour may be a risk factor for
multiple diseases
The relative contributory effects of different risk factors can be assessed using multiple
regression analysis
Explained in part the rise in prevalence BUT limited success in explaining origins of
diabetes at both the individual & population level, e.g.
WHO MONICA Project 1994
Standardized data from 38 populations in 21 countries
Cross-sectional data on adult risk factors and routine data on mortality from
cardiovascular disorders
Only 25% of the geographical variation in the disease could be explained by
smoking, blood pressure, and total cholesterol
Whitehall study
Examine mortality rate over 10 year among male British Civil Servants aged 20-64
The first Whitehall Study showed an inverse social gradient in mortality from
coronary heart disease, i.e. higher rates in men of lower employment grade
~ of this gradient could be attributed to coronary risk factors obesity, smoking,
less leisure time, physical activity, more baseline illness, higher blood pressure,
and shorter height
In the last decade, however, there has been a shift of focus from adult to early-life risk
factors (moving backwards)

 Thrifty genotype hypothesis
The presence of insulin resistance in obesity & type 2 diabetes theory of the "thrifty" genotype
Insulin resistance might improve survival during states of caloric deprivation but would lead
to diabetes in states of caloric excess or even adequacy
Thrifty genotype might be induced by malnutrition during foetal and early life?
Critical period model (programming) (early life hypothesis)
Hypothesis
Stimuli or insults occurring during critical periods of development in foetal and infant life will
"programme" susceptibility to adult diseases
Emphasize the importance of in utero & early-life factors in determining health status in adult life
Classic example
Barker hypothesis, which states that an effect of in utero malnutrition is an increased risk of
coronary heart disease (CHD) in adulthood
Hypothesis has since been extended to a wide range of chronic diseases, such as type 2
diabetes and hypertension
Criticism of early life hypothesis
Some researchers have suggested that the concept of programming should be broadened to
include adaptive responses to the environment that may occur in infancy, childhood, and
adolescence
Confounding by socio-economic factors
Associations between early life factors and adult diseases may be confounded by the
persistence of such conditions throughout life
Life course model
Attempts to integrate the programming and adult risk factor models into a wider framework
It considers how various biological and social factors throughout gestation and life affect health
and disease in adult life independently, cumulatively & interactively
E.g. a model may propose that different risk factors accumulate throughout life, that they
exhibit a dose-response effect, and that they have long-term consequences
However, few researchers have access to a sufficiently wide range of biological and social data
Life course framework
in large, longitudinal cohorts

Value of life course perspective in risk stratification, prevention & treatment of diabetes
Policy implications
ORIGIN OF DIABETES 29

Necessary and advantageous to adopt an integrated life course approach in the prevention
and control of chronic diseases
Based on the needs and risks of different population subgroups to prevent the onset of
diseases and reduce the rate of disease progression
In other words intervene early in life, interrupt pathways at multiple stages
E.g. Framework for Population Approach in the Prevention and Control of Diabetes across the
Life Course HK Reference Framework for Diabetes Care for Adults in Primary Care Settings

v Economists perspective on health
Undesirable side effect of good things rising obesity prevalence rising diabetes prevalence
Price of food lower food prices
Improvements in the technology of agriculture have made food production substantially
cheaper and driven down price
The law of demand says that a decline in the price of a normal good will be met with an
increase in the quantity consumed of that good and people have responded to these price
decreases just as expected
Price of physical activities labour-saving technological innovations
Sedentary Jobs
The labour economy in the developed world, which previously consisted largely of
agricultural jobs, has become dominated by service and manufacturing jobs, which
require less physical activity
Automobile use
The automobile is credited with dramatically reducing average daily walking exercise in
developed countries
Price of housework (labour force participation) economic opportunities for women
In the Western world, the increase in labour force participation by women, and the
simultaneous decline in the average time spent preparing meals at home, has contributed
to rising body weight
This same force has contributed to the rising share of food dollars spent on restaurant food,
which is often more calorically dense and fattening than food prepared at home
Technological changes that make housework less onerous, e.g. invention and dissemination
of dishwashers and microwaves, have also decreased the relative price of labour force
participation
v Enumerate risk factors for diabetes
Risk factors
Causal (determinants) establish disease aetiology
Predictors (intermediates) risk stratification & early detection
Interested in modifiable risk factors (as doctors)
DM Type 2 most likely represents a complex interaction among many genes and environmental
factors, which are different among different populations & individuals multifactorial disease
Non-modifiable risk factors Modifiable risk factors
v Physical activity
v Genetic susceptibility
v Diet
v Family history
v Obesity
v Ethnicity
v Fat distribution
v Birthweight
v Smoking
v Summary
The risk of developing chronic diseases including diabetes are influenced by factors affecting all
stages of life
The effects of these factors accumulate with increasing age
Major chronic diseases often share common risk patterns, e.g. undesirable environment, social
deprivation, unhealthy dietary habit, physical inactivity, alcohol misuse and smoking
Bio(medical)-psycho-social model for illness
Intervene early in life, and adopt wide-ranging approach to interrupt pathways at many stages