Energy and heat production

The two types of thermogenesis

1. Oligatory associated with resting
metabolic rate
2. Adaptive increased metabolic rate when
there is decreased temperature or
increased food intake

expression (smooth endoplasmic reticula CA2+

atpase)
What is the futule cycle

Regulation of thermogenesis
Conventional view
Hypothalamus SENSORS
Thyroid hormone and sympathetic nervous system
EFFECTOR
Emerging view
Local sensing and effector responses
- Cold stress in FAT induces macrophage
derived cytokines IL4 and IL13
- These cytokines act via local actions in fat
tissue and the sympathetic nerve system
Hormonal control between tissues
- Cold or exercise in muscle induces releases
of peptide = Meteorin-like or Metrnl
- Metrnl = hormonal actions in fat tissue

The other futile reaction = futule cycling of

CA2+ in SER from skeletal muscle cells

What is the role of thyroid hormone?

Involved in BOTH obligatory and adaptive
thermogenesis
Obligatory = control of resting metabolic rate
Adaptive = cold induced (in hypothyroidism, cold
induced thermogenesis is impaired)
This system acts synergistically with the
sympathetic NS
What are the sites of adaptive
thermogenesis?
Brown adipose tissue
- large number of mitochondria
- Mitochondria key site of heat generation
Skeletal muscle
Acute = shivering as ATP breakdown via futile
contractions
Prolonged = changes in muscle fibre phenotype,
enhanced mitochondrial biogenesis and SERCA

Describe heat generation from ion transport

Na+ leak across the membrane and this activates
the Na/K atpase pump to get them out again
The net effect is ATP breakdown and heat
generation
Thyroid hormone increases the membrane Na+
permeability
Revision on the electron transport chain

Electron flow coupled with proton pump

I, III and IV are electron driven proton pumps
Protons in intermembrane space drops the pH to 3
H+ flux through complex V drives ATP synthesis
Heat generation from mitochondria

UCP = heat
Thyroid hormone effect on UCP
Thyroid increases expression of UCP 2 and UCP 3
(found in skeletal muscle)
They also reduce efficiency of mitochondrial
proton pumping
Promote SERCA expression and impairs its
efficiency
What other hormone is involved in heat
production
1. Adrenaline hepatic gluconeogenesis,
vasodilation in skeletal muscle, promote
conversion of T4 to T3
2. Leptin promote Sympathetics
3. Insulin cold exposure increases glucose
uptake and metabolism
4. Glucagon stimulates gluconeogenesis
How is heat production measured?
Direct and indirect calorimetry

Energy and heat production

The two types of thermogenesis
3. Oligatory associated with resting
metabolic rate
4. Adaptive increased metabolic rate when
there is decreased temperature or
increased food intake

Acute = shivering as ATP breakdown via futile

contractions
Prolonged = changes in muscle fibre phenotype,
enhanced mitochondrial biogenesis and SERCA
expression (smooth endoplasmic reticula CA2+
atpase)
What is the futule cycle

Regulation of thermogenesis
Conventional view
Hypothalamus SENSORS
Thyroid hormone and sympathetic nervous system
EFFECTOR
Emerging view
Local sensing and effector responses
- Cold stress in FAT induces macrophage
derived cytokines IL4 and IL13
- These cytokines act via local actions in fat
tissue and the sympathetic nerve system
Hormonal control between tissues
- Cold or exercise in muscle induces releases
of peptide = Meteorin-like or Metrnl
- Metrnl = hormonal actions in fat tissue

The other futile reaction = futule cycling of

CA2+ in SER from skeletal muscle cells

What is the role of thyroid hormone?

Involved in BOTH obligatory and adaptive
thermogenesis
Obligatory = control of resting metabolic rate
Adaptive = cold induced (in hypothyroidism, cold
induced thermogenesis is impaired)
This system acts synergistically with the
sympathetic NS
What are the sites of adaptive
thermogenesis?
Brown adipose tissue
- large number of mitochondria
- Mitochondria key site of heat generation
Skeletal muscle

Describe heat generation from ion transport

Na+ leak across the membrane and this activates
the Na/K atpase pump to get them out again
The net effect is ATP breakdown and heat
generation
Thyroid hormone increases the membrane Na+
permeability
Revision on the electron transport chain

Revision notes on autoimmunity

Electron flow coupled with proton pump

I, III and IV are electron driven proton pumps
Protons in intermembrane space drops the pH to 3
H+ flux through complex V drives ATP synthesis

Mechanism of self tolerance

Central tolerance
- Deletion of autoreactive T cells in the
thymus
- Expression of AIRE in the thymus results =
expression of non-thymic protein antigens
which bind to self reactive T cells
- Gene mutation in AIRE reduces deletion
and results in autoimmune endocrine
disease

Heat generation from mitochondria

Unfortunately there are still some self-reactive T

cells
Peripheral tolerance: anergy
Self peptide/HLA in absence of co-stimulatory
signals leads to anergy

UCP = heat
Thyroid hormone effect on UCP
Thyroid increases expression of UCP 2 and UCP 3
(found in skeletal muscle)
They also reduce efficiency of mitochondrial
proton pumping
Promote SERCA expression and impairs its
efficiency
What other hormone is involved in heat
production
5. Adrenaline hepatic gluconeogenesis,
vasodilation in skeletal muscle, promote
conversion of T4 to T3
6. Leptin promote Sympathetics
7. Insulin cold exposure increases glucose
uptake and metabolism
8. Glucagon stimulates gluconeogenesis
How is heat production measured?
Direct and indirect calorimetry

Autoimmunity in endocrine disease

Co-stimulation requires CD28-B7

Regulatory T cells inhibit auto-reactive T cells
1. CTLA4 and inhibitory cytokines IL10 TGFb
2. Treg expression of FoxP3
Gene mutation of foxP3 = autoimmune endocrine
disease (XPID)

Mechanism of autoimmunity
Combination environmental factors + genetic
susceptibility
1. Infection viral infection of pancreas can
result in self reactive T cell
2. Drug Type I interferon therapy for hep C
induces autoimmune thyroid disease
3. Smoking RA, citrullination of arginine in
Filigranin creates a neo-antigen (a-cyclic
citurllinated peptide or CCP antibodies
What the confirmed known associated genes
for Type 1 diabetes
HLA class II = HLA DQ3.2
PTPN22: poshphatase that reduces signalling in
lymphocytes
CTLA4
IL2 R chain = high affinity IL2 receptor
Interferon induced helicase I protein signals
viral infection

Autoimmune diseases are sometimes

grouped together

Regarding thyroid auto immune diseases,

how is it related to gastric antibodies and
age?
Thyroid antibodies are associated with gastric
antibodies shared by relatives of patients

Describe Hashimoto thyroiditis and primary

myxoedema and graves disease

Which is more likely to occur with age, hyper

or hypothyroidism

Describe the mechanism of graves disease

Auto immune destruction of pancreatic islet

Describe the two auto-immune adrenal
diseases

Thyroid swelling
Opthalmopathy
- periorbital oedema
- chemosis
- scerela injection
- proptosis
- lid retraction (obscured by oedema)
Localised dermopathy

What auto immune disease causes

hypocalcaemia

What are the target antigens for diabetes

mellistus and the mechanism

What autoimmune disease causes

depigmented skin?

Pernicious anaemia

Ipilimumab and nivolumab are used for

melanoma treatment. How do they work?
What complications do they have?

Autoimmune complications can arise due to

blocking of the inhibitory check points in T cell
function (CTLA4 and PD1)
Hypopituitarism
Adrenal insufficiency
Thyroid disease (thyroiditis and then
hypothyroidism)
Hypoparathyroidism
Vitiligo
Auto immune haemolytic anaemia
Immune mediate hepatitis = liver failure
Colitis
Which auto antibodies are associated with
auto immune destruction and which are
RESPONSIBLE for disease?

What is the treatment of auto immune endocrine

disease?

Puberty in females and males

A number of terms is used to defined puberty and
their stages

Describe the major hormones at birth and

how do they change over puberty
All sex hormones are present from birth but at
very low levels.
GnRH comes from the hypothalamis
Pituitary LH and FSH are identical in both male
and female
- Testosterone and oestradiol are the
steroid hormones which increase 20-30 fold
over puberty
- Testosterone = DHT in periphery
- Oestradiol derived from testosterone
Progesterone from ovary matures breast
development
Increase in growth hormone production by
anterior pituitary
- increase in IGF1 from liver and in tissues
Describe the initiation of puberty
-

Increased frequency and amplitude of

GnRH pulses from neurons in
hypothalamus
GnRH stimulates release of pituitary
gondotrophics
Initially its an nocturnal event so
testosterone and oestrogen raised in
morning only in EARLY puberty

Leptin production from adipose tissue has a

permissiverole = measure of energy store
NEEDED for physical growth
What happens in FEMALE puberty?
1. Increased frequency and size of FSH pulses
= ovarian follicles produce increasing
amounts of oestradiol
2. Increased frequency and size of LH pulses
a. Ovarian thecal cells (stromal)
growth = progesterone and
testosterone
Physical changes
- Cervix, uterine muscle and uterine lining
(endometrium) growth under influence of
oestradiol
- Fluctuation in oestradiol = withdrawal
bleed (shedding of endometrium)
Menarche
- HIGH oestradiol = positive feedback on LH
with pre-ovulatory surge
Describe the trend of Mecharche
Mean age in Australia is 12.3
- There has been a falling of this page in
westernised countries
- Percentage of body fat required to achieve
menarche (in evoluntionary terms required
for pregnancy and breast feeding)
What puberty changes happen in males?
Increased frequency and size of LH pulses
stimulate LEYDIG cells testoerone increases
Increases frequency and size of FSH pulses
SEMINIFEROUS TUBULE and SERTOLI cells
increase testicular size
- There is a secular trend for earlier onset of
testicular enlargement over last 30 years
Seminal vesicule and prostate enlargement
Penile growth
Sperm production from about 13.5 years

What factors influence GnRH production?

Kisspeptin1
- Neurons in arcuate nucleus
- Endogenous ligand of the GPR54 receptor
which is a G protein receptor
- The kisspeptin 1 receptor on the GnRHproducing-neuron
Thus if the signalling is absent = no puberty
Other
-

peptides from the arcuate nucleus

neurokini B (TAC 3) = accerelator
Dynorphin pubertal brake
Makorin RING-finger 3 gene (MKRN3)
product is a brake

What are the onset and duration of puberty?

Tanner pubic hair

Describe the height growth in females and

males
Females
- 8-9 cm in a year
- Early puberty there is a growth spurt and is
initiated and maintained by
o Ovarian oestradiol at low levels
o AND pituitary growth hormone/IGF1
- 20 cm average gain
- Stopped by epiphyseal closure when there
is high levels of oestradiol
Males
- 9-11/5cm/year
- Growth spurt is a LATE puberty event
o HIGH levels of testicular
testosterone
o AND pituitary growth hormone IGF1
- 30cm average age
- Halted by closure of epiphyseal from
oestradiol (which is aromatisation from
testosterone)
Describe the body composition change in
puberty

Since there is lots of variety in puberty

there are various tools.
Tanner breast stage

Tanner genital stages male

How is bone /osseous age determined?

Used to as a descriptor of developmental age
X ray of hand and wrist
- Tanner whitehouse
- Greulich Pile
These are TWO grading system which the
individual Xray is compared with radiographic
pictures
What are secondary sexual characteristics
What do the numbers mean?
1. Female growth spurt Breast 2/3 (based on
the bone age from those two systems)
2. Mecharce Breast
a. 95% of heigh complete
b. bone age is around 13.5 years
3. Male growth support Genital
4. Voice break
a. Vocal cord length, larynx and
cricothyroid cartilage increases
b. Laryngeal muscles enlarge
5. Body and facial hair
a. Dependent on sensitivity of
androgen receptor
6. Acne
a. Result of increasing testosterone
What are the factors that increase bone
mass
GH/IFG1, oestradiol OR testosterone, dietary
calcium nd Vitamin D, physical activity
What are the end points of puberty?

Due to the change in balance between

Testosterone and oestrogen
Generally requires no treatment (but may required
surgical removal or aromatase inhibitors)
IF prolonged consider secondary causes
- drugs
- Thyrotoxicosis
- Klinefelter syndrome 47XXY
- Feminising tumours (rare)
What is Adrenarche?
-

Maturation of adrenal zona reticularis

o Independent of gonadal puberty
and biochemically starts before
gonal maturation
o Clinically detected as pubic hair,
seborrhoea of hair and skin and
increased body odor
o ACTH trigger (possibly)

What factors will vary the timing of the

ONSET of puberty
Endogenous
1. Genetics
2. Birth circumstances (earlier puberty)
3. Obesity (earlier in girls)
4. Malnutrition or excessive exercise
(delayed)
5. Chronic illness (delayed)
6. Visual impairment (earlier)
7. Overseas adoptee (earlier)
Exogenous
1. Chemical pollutants (which are endocrine
disruptors)
a. Delayed or advancement of puberty
b. Earlier breast development in
females
c. Hypospadia and lower sperm count
in developed countries
2. Westernised environment = earlier
a. Change in nutrition and physical
activity
b. Changes in body composition
c. Reduced childhood infections
3. Absent biological fathers = earlier in girls
What age is still considered NORMAL range
for puberty in females and males
- 8/13 years in females
- 9 /14in males
More common in females to be EARLY and easier
to detect
Based on early rises in Testosterona and oestrodiol
Delay difficult to differentiate extreme delay
from absent puberty
- BONE age is always delayed
What is gynaecomastia?
Male breast occurring in over 80% of males in
tanner stage G3/4

What is hirsutism
- Increase in terminal hair due to increased
androgen sensitivity
- Exclude endocrine disorders if menstrual
disturbances and acne
o Polycystic ovaries
o Adrenal gland disorders
These are generally benign but may need
endocrine assessment as they may indicate
abnormal early puberty
Premature adrenarche
- Present earlier than expected with
o Secondary sexual hair
o Acne and seborrhea
o Increased body odour
- Low birth weigth children has increased
frequency
- Some advancement of bone age
- Mild increase in plasma adrenal androgens
Important to exclude adrenal or gonadal
pathology
Treatment
- Females may present later with polycycstic
ovaries
Premature thelarche
- Breast development BEFORE 8 with NO
other pubertal signs
- Diagnosis = must have prepubertal
oestradiol levels
Important to exclude
- Ecogenous oestrogen source
- True precocious puberty with advanced
bone age and elevated oestradiol
Treatment = none, may regress
OTHER pathological variations in puberty
that require evaluation
- Vaginal bleeding but absent or early breast
development
- Small testicles, young age and penile
enlargement
What conditions can cause absent puberty
and what can cause early puberty

Absent puberty due to primary gonadal

failure
- High FSH and LH and low oestradiol
o Sex chromosome abnormality with
gonadal damage
o Premature menopause
autoimmune
o Chemotherapy
o Galactosaemia
o Torsion
o Surgical removal
o Irradiation
- Treatment = hormone replacement therapy
required to initiate and maintain puberty

Causes
- Genetic pituitary deficiency
- Tumour replacing normal pituitary tissue
- Trauma = pituitary stalk especially
- Surgery often to remove tumour

Turner syndrome 45 XO and variation

Hypothalamus problem
Low FSH, LH and low oestradiol in females and low
testosterone in males (HENCE it is
indistinguishable on blood test from secondary
gonadal failure. GnRH is NOT measurable in
peripheral blood

What are causes of primary gonadal failure

in males?
High FSH and LH with low testosterone
Causes
- sex chromosome disorders
- chemotherapy
- Trauma and torsion bilaterally
- Crytorchidsm (undescending testicles)
- Radiation damage
- Infection (mumps)
Hormone replacement therapy oral testosterone
then parenteral preparations later
Klinefelter syndrome 47 XXY

What is secondary gonadal failure?

Pituitary failure
- Low FSH and LH with low oestradiol in
females or testosterone in males

Often associated with other hormone deficiencies

Treatment
- Use of oestradiol and testosterone as LH
and FSH can be only given injection as
peptides with a short half life
What is tertiary gonadal failure?

Causes
- Isolated GnRH deficiency or Kallman
syndrome (has anosmia)
- Head trauma
- Iron deposition Iron overload in
thalassemia major
- Tumour
- Raddiation or sugery therapy for tumour
- CHARGE syndrome, Prader Williw syndrome
Again, OFTEN associated with other hormone
deficiencies
GnRH is available as injection and is used in
female infertility
What is primary amenorrhoea?
Absent menarche from 16 years onwards
- Imperforated hymen
- Hypothalamic, pituitary or ovary
disorder
- Mullerian agensis 46XX = normal breast
development with absent uterus, fallopian
tubes and upper 2/3 vagina
- Complete androgen insensitivity
syndrome
o Receptor abnormality, XY
karyotype, femininsed with
endogenous oestradiol from
testosterone
o 46 XY
o Tall stature, female phenotype with
little body hair, inguinal gonads,
lower 1/3 vagina only (upper
structures regress with mullerian
inhibitory factor)
What is precocious puberty?
Puberty occurring TOO early
CCP = central precocious puberty

LH, FSH and oestradiol/testosterone follow

a NORMAL puberty pattern but it is TOO
early
80% is idiopathic in females but 20% in
males
MRI pituitary hypothalamic area

What is considered True CCP that is GnRH

dependent?
Females that present with breast development
with or without vaginal bleeding
Males that present with
- testicular enlargement
- penile enlargement
- voice change
- acne
Treatment is with GnRH agonist
- Continuously as depot injection and to
down regulate pituitary GnRH receptor
- GnRH agonists improve final height and
reduce psychosocial distress
There is also GnRH independent pseudoprecocious puberty
Isosexual (same sex puberty change) form
- Low gondaotrophins but elevated
Oestradiol or testosterone
1. McCune-Albright syndrome in females
a. Instrinsic hyper function of ovarian
FSH receptor
2. Testotoxicosis in males
a. Intrinsic hyperfunction fo testicular
LH receptor
3. Ovarian/testicular tumours
4. Adrenal tumours
5. Exogenous oestrogen/androgens
Contrasexual opposite sex puberty change
Low gondaotrphincs with high oestradiol IN MEN
or HIGH testosterone in FEMALE (opposite)
-

Females: virilisation, acne, deep voice, loss

of body fat, clitoromegaly
o Congenital adrenal hyperplasia
o Adrenal or ovrian tumour
o Exogenous androgen exposure
Male feminisation, breast development,
muscle loss
o Adrenal or ovarian tumour
o Exogenous oestrogen exposure

Steroid biosynthesis
How is cholesterol synthesised from acetyl
CoA

First step in steroid biosynthesis from

cholesterol

Cycle is repeated

Each 17a and progesterone of these have complex

pathways then form cortisol and aldosterone
Cortisol biosynthesis

Synthesis of C10 and C15 is suppressed by Nbiphosphaonates

Major
1.
2.
3.
4.
5.

classes of steroids
Glucocorticoids
Mineralcorticoids
Androgens
Oestrogens
Progestagens

Three major pathways

Glucocorticoids adrenal zona fasciculate
Mineralocorticoids adrenal zona glomerulosa
Androgens Zona retcularis + testis + ovaries

Congenital adrenal hyperplasia

Autosomal recessive where there is deficiency of
the cortisol synthesis pathway
- 21 hydroxylase (mmost common)
- 11b hydroxylase
- others
Symptoms
- Cortisol deficiency
- Mineralocorticoid deficiency salt wasting
- Failure of anterior pituitary feedback
- ACTH

Adrenal hyperplasia
Virilization in girls

21 hydroxylase deficiency risk at birth and

treatment
Salt wasting and hyperkalaemia in neonates
Addisonian crisis after birth is a risk
Treatment
- Glucocorticoid therapy cortisone acetate
- Mineralocorticoid therapy fludrocortisone
Potencies of glucocorticoid and
mineralocorticoids

Describe the adrenal androgen synthesis

Aldosterone biosynthesis

Why are androgens increased in CAH?

Snythesis of testosterone occurs in the testis and
ovaries (NOT in adrenal)

What is the difference between

21hydroxylase and 11b hydroxylase
defincies
11B hydroxylase has accumodation of
deoxycorticosterone which induces salt
retentation
Present with hypertension

Where does testosterone go?

Its converted to active metabolite =
Dihydrotestosterone
Or converted to oestradiol in ovaries
Catabolism

Aromatase inhibits are used clinically

(anastrazole)
CASE
Age 22 women with long term therapy for CAH 21
hydrxylase
Cortisone acetate
Fludrocortisone
ACTH is suppressed
17 hydroprogesterone is suppressed
Clinically
- cushingoid BMI 28
- hypertensive
Treatment
- reduce then stop fludrocortisone 3 months
- Reduce cortisone acetate 12 months
SERUM ACTH, 17a hydroprogesterone and DOC
(deoxycorticosterone) used to monitor therapy

Lipoprotein transport
What is the organization structure of
lipoproteins?

The least dense species are triacylglycerols rich

Most dsense species are cholesterol ester rich

Coat = phospholipids, proteins and unesterified

cholesterol
Core composition transported lipids
- Triacylglycerol/triglycerols
Chylomicrons, VLDLs = These are fatty
acid sources
- Cholesterol esters (ONLY ESTERS)
LDL and HDL = a store for cholesterol for
plasma membrane, bile salts and steroids
What are the sizes of lipoproteins?

What are apoproteins?

These are proteins that are stripped from the
lipids. (coatings on the lipids)
Enzyme activators and tissue targeting
Exchangeable (A1, A2, CII, E) Proteins that move
between particles of same lipoprotein species
Non exchangeable (B48, B100) These stick to
the particles
What do the monoacylglycerol and fatty
acids do?
-

Taken up by cell and used as energy of

stored as TAG

Chlymomicron remnants, where do they

come from?
Lipoprotein lipase depletes TAG and converts
chlymicrons to chlymicrons remnants. Enriched in
CE?
Return to circulation
Taken up by heptaocytes (APO B48 and APO E)

Which lipoproteins species flat? What is the

role of these?
Chylomicron density is <0.95 g ML is LESS than
water which is 1.0g = this one will float.
- TAGs are major forms of dietary fat
- These are broken down in small intestine
and fatty acids and monoacylglycerol (one
fat chain and glycerol) released then
absorbed
- TAG reassembled in small intestinal cells
and packaged into lipoprotein particles
(Chylomicrons)
- These moves to lymph (because they are
too big) then blood
Chylomicrons then immobilized on surface of
capillary endothelial cells and LPL (lipoprotein
lipase) breaks it down. Apoprotein CII on
chylomicrons promite LPL activity

During fasting what do the TAG do?

Tissues that need TAG-derived fatty acid obtain
them from VLDL which are synthesized in liver
using TAG.
TAG synthesized by hepatocytes from free fatty
acids and glycerol (APO B100)
VLDL in circulation and immobilized on surface of
capillary endothelial cells. TAGs converted to
MAGs and FAs by LPL (which is activated apo CII
on VLDLs)
These FA and MAGs are taken up by tissues and
VLDL remnant form is returned to circulation.
- Hepatic uptake APO B100 APO E
- Conversion to LDL in the circulation
What are low density lipoproteins? How is
cholesterol released?
These are rich in cholesterol esters and are source
of cholesterol for tissues. Very small particles and
only one molecule of one apoprotein (ApoB100).

Binding to LDL/APOB100 receptors the free

cholesterol is released

Blood test shows high LDL where did they

come from?
VLDL remnants produce LDL
How can high LDL occur?
Deficiency of LDL receptors 0.2% prevalence
1. Familial hypercholesterolemia
a. Autosomal dominant
b. Heterozygous 2-3x increase of LDLC
c. Homozygous 6-8 fold
Problem: early atherosclerosis and coronary artery
disease
How do LDL cause atherogenic impact? How
do statins work?
ApoB100 is modified by covalent addition,
glycosylation

What is lipoprotein little a?

Lipoprotein (a)
- Modified form of LDL
- These expression apo(a) and ApoB100
Lipoprotein(a) directed to sites of trauma but
Apo(a) levels correlate with increased risk of
atherosclerosis
What is reverse cholesterol transport (HDL
story)
1. Reverse cholesterol transport
a. Defend cells from cholesterol and
relies on production and filling of
HDL
b. ApoA1 provides docking mechanism
c. Recovers cholesterol from cells
(Including foam cells!)
How does this docking mechanism occur?
Cholesterol enter the coat of HDL particles
ApoA1 activates LCAT to convert cholesterol to
cholesterol esters . These enter HDL CORE and
cholesterol is taken up

ROS act on unsaturated fatty acids to generate

reactive aldehydes
Aldehydes (and glucose) modify B100 and these
promote uptake LDL by macrophages (Foam cells)
and smooth cell (scavenger receptors)
Statins are HMG CoA reductase inhibitors which
suppress cholesterol synthesis in liver,
hepatocytes respond with increased expression of
LDL receptors and decreases LDL in plasma

Statins are important in famililal

hypercholesterolemia
In heterozygotes it promotes the normal allele
receptor to promote expression. LDl binds and is
internalized
NOT effective in homozygotes = life threatening,
MI age 2-3
What can be done for homozygote familial
hypercholesterolaemia?
Diet, plasmaphresis = not long term solution
Liver transplantation source of LDL receptor

How does diabetes affect lipoprotein

metabolism
1. Elevated VLDL results in increased serum
TAG
a. Poorly controlled Type II diabetes
b. Increased VLDL synthesis from fatty
acid
c. Reduce VLDL clearance due to
reduced LPL activity
ApoCIII inhibitis LPL which is increased in
hyperglycaemia
2. Enhanced atherosclerosis
a. LDL glycosylation secondary to
hyperglycaemia

b. Enhanced macrophage uptake of

cholesterol
c. Foam cells
How do fibrates work to lower cholesterol?
Fibrates activate PPARa (lipid activated nuclear
receptor)
Suppress VLDL production
Enhance activity of lipoprotein lipase (LPL)
TAG levels falls
Linking up apoproteins to situations
1. APO CII to convert TAG into 2
monoacyglycerol and fatty acids after
eating and during fasting
2. APO B48 and APO E hepatocyte taking
up chylomicron remnants
3. ApoB100 and ApoE = hepatic uptake of
VLDL
4. ApoB100 LDL particle internalization and
free cholesterol is released from
cholesterol esterase
5. ApoB100 modified by reactive aldehyde
and glucose which cause atherogenesis
6. ApoA1 docking mechanism for HDL
7. Apo(a) and ApoB100 expresed by
lipoprptein (a)
8. ApoE involved in hepatic uptake of mature
HDL to liver
9. ApoCIII inhibits LPL in hyperglycaemia
(diabetes problem)

GP and anaesthetics = complications

of obesity

Fatty liver
Steohepatitis/NASH
Cirrhosis
HCC

Renal
- Hypertension
- UTI
- This is via hypertension and
diabetes = risk of renal failure
More overweight men than women
But around the same amount of obese
men and women
Medical complications of obesity

Metabolic
- Diabetes
- T1D
- Vita D deficiency
- PCOS
- Low testosterone
- Poor lipid profile
Cardiovascular
- Coronary artery disease
- MI
- Peripheral vascular disease
- Cardiac hypertrophy
- Cardiac failure
- Arrhythmia
- Hypertension
Neurogenic
- DEMENTIA
- Stroke risk
- Intracranial hypertension
Respiratory
- Infections
- Sleep apnoea
- Obesity hypoventilation syndrome
- Asthma
Gut
- Reflux
- Cholelithiasis
- Colon cancer

Orthopaedic
- Osteoarthritis
- Poorer body quality
- Falls risk
Reproductive
- IVF increased
- Polycystic ovary syndrome
o Complex disorder with
multiple peripheral follicles,
thickened endometrium,
amenorrhea, infertility and
hirsutism
o 5-10% of women
o Associard with central
obeisty,
hypertensinulinaemia,
dyslipidaemia, IHD, diabetes,
endometrial dysplasia
- Pregnancy
o Pre-eclampsia
o Gestational diabetes
o Increased operative delivery
o Wound infection
Limitations of BMI
Ethnicity Australian aborigines and
Pacific islanders
Age extremes
Muscular build
Body fat distribution
- Abdominal fat increases
cardiovasulcar and metabolic risk
- Important to measure central fat
e.g. wasite circumference, hip radio
and sagittal depth
- Women <80cm
- Men <94 cm
Abdominal fat increasing decreases
insulin sensitivity

Compare abdominal vs peripheral

obesity
In Abdominal fat there is large insulin
resistant adipocytes with increased
adrenergic receptors = android obesity
- Increased plasma non esterified
fatty acids
Lipid overload hypothesis
- Designed to store fat in
metabolically active site to supply
muscles
- Fatty acid storage sites are limited
and excess supply leads to ectopic
fat deposition
Adipose tissue expandability
- Ability to expand fat mass to store
lipid important determinant of
obesity related metabolic disease
- Maximal expansion = fat leakage
and ectopic fat deposition
Ectopic fat deposition results in
- Liver insulin resistance
- Muscle inslin resistance
- Impaired insulin secretion
- Atherogenic lipid profile
- Cardiac dysfunction
Peripheral fat have small insulin sensitive
adipocytes with decreased adrenergic
receptors = gynoid obesity
What is non-alcoholic fatty liver
disease
15-20% of adults associated with obesity
and possibly mediated by insulin
resistance
Spectrum disease from bland steatosis to
steatosis with hepatocyte injury,
inflammation and fibrosis (This is Nonalcohol steatohepatitis or NASH)
15-20% will develop fibrosis and cirrhosis
Which cancers do obese people have
increased risk for?

Genetics of obesity
40-70%
Twin studies have shown twin pairs gain
similar amount of weight
Increased number of alleles (identified
obesity related allies) BMI increases

What is the FTO gene?

Brains response to food = commonest
risk factor for overweight and obese
1/16 carry 2 copies of this gene and it
alters the way the brain responds to food
and changes appetite.
What do obesity genes affect?
1. Energy expenditure
a. 60% resting metabolic rate
b. 30% physical activity
c. 10% thermic effect of feeding
2. Energy intake
3. Food preferences
4. Muscle fibre type
5. Physical activity
6. Fat amount/distribution
What is the total energy expenditure
TEE like in an obese patient?
- High TEE due to high lean body
mass
- Resting metabolic rate falls with
energy restruction even before
weight loss has occurred
Microbiota in obese patients
1. Microbiota association studies
reveal microbes differ between fat
and lean

Nutrition obesity management

What are some benefits of weight
loss towards obesity co-morbidity?
Decrease mortality
Decrease obesity related cancer deaths
Decrease fasting glucose
Decrease blood pressure
Decrease lipid and increase HDL
Reduce likelihood of blood clots
Improve back and joint pain
Improve lung function
Reduce sleep apnoea
Improved ovarian function

Presentation of typical patients

- Come in for chronic problem or
other problem
- Need to address these patients
about their weight
- Family history
- Previous weight loss attempts
- Associated co-morbidity
o Diabetes
o Hypertension
o Coronary heart disease
o Stroke
Physical exam BMI, waist, blood
pressure, neck examination, hirsutism,
herniaes, venous stasis
Investigations lipids, glucose, LFT, TSH
(should be tested), reproductive
hormones (if indicated)
What is a diet prescription ?
Calorie reduction and balanced diet
- High intake of fruit, vegetables,
whole grains and fish
- Regular meals
- Watch snacking and poor habits
What diet type?

Low fat (saturated) high carbohydrate

diet
- This is good diet (high carbohydrate
should be low GI food)
More lean protein (satiating)
Diogenes (high protein/Low GI) = least
weight REGAIN
High fat/low carbohydrate diet initial
weight loss easier
Mediterranean diet - Good
Physical activity prescription
- Baseline and aim to increase
- 45-60min walk PER DAY
- Treat musculoskeletal disease and
consider water exercise or cycling
Even if there is no weight loss there is
metabolic improvements e.g. BP, insulin,
lipid profile, glycaemiac control
- Significant decrease in CHD risk
decrease
Practical modification
- Reduce chaos
- Limit eating places
- Regularity in eating
- Do not buy food that will eb
overeaten
- Ready access to low fat snacks
- Reduce portions
- Eat slowly
Sleep and weight problems
Short sleep duration = affects eating and
activity behaviour
Sleep timing sleep deprivation increases
intake post dinner and greater weight
gain
What is very low energy diets?
<800kcal or 3.5MJ/day = mild ketosis and
decrease in hunger
Minimising CHO intake increases ketosis
and effective for rapid weight loss
Indicated for morbid obesity, preparation
for surgery, rapid intervention for comorbidity
Should be medically followed up, but
available over the counter

What drugs are used for weight loss?

All of these drugs must be used along
with lifestyle changes
1. Noradrenergic agents
a. Phentermine (duromine),
diethylpropion
b. Stimulate adrenergic
neurotransmitter
c. Amphetamine derivatives
thus
i. Insomnia
ii. Nervousness
iii. Irritability
iv. Habit forming
v. Increase BP
vi. Possible angina
2. Orlistat (Xenical)
a. Inhibit gastrointestinal lipase
which is required for
absorption of dietary fat
b. Prevent 30% absorption
c. GI consequences usually
result due to EXCESS fat
intake
d. Benefits
i. Moderate reduction in
diastolic BP
ii. Reduction in fasting
insulin
iii. Reduce cholesterol
iv. Improve glycaemic
control
v. Improve insulin
sensitivity
3. Qnexa (los dose phentermine WITH
topiramate)
a.

b. Decrease blood pressure

c. Teratogenic, dry mouth,
constipiation, insomnia,
anxiety and irritability,
abnormal taste, unstable in
cardiac and cerebrovascular
disease
4. GLP1 analogue liraglutide

a. Decrease weight, lower

glucose, less patients
prediabetic
b. Decrease satiety
c. GI side effects (gas) with
some pancreatitis risk
What surgical procedure can be done
for bariatric patients?

Blind loop with possible bacterial

overgrowth

What are the indications for bariatric

surgery
- Class 3 obesity 40 BMI
- Significant co-morbidity BMI >35
- Adequate trial of weight loss
- Ability to lose some weight
- Patient is fit for anaesthesia and
surgery

Biochem genetic predisposition to

disease?
Genetic contribution to disease
- Polygenic + environment
- Environmental factor can play
significant orle in phenotypic
expression
Haemochromatosis
- Phenotype influenced by iron intake
AND iron loss (menstruation)
Haemoglobinopathies
- May be protective against malaria
Compare monogenic disease and
complex diseases in family risk
Monogenic disease
- Genetic risk in 1st degree relatives is
25% AR or 50% AD
- (phenotypic expression can be
variable- depends on penetrate)
Complex diseases
- <5-10% risk in 1st degree relatives
- Disease risk declines rapidly with
genetic distance from index case
What is penetrance and risk?
Penetrant = the likelihood of patients
developing the disease
e.g. Rare mutations can cause <1% of
alzheimers disease and most patients
with these mutations will develop that.
Apolipoprotein E4 allele = less penetrant
and only 8% of heterozygous and 21%
homozygotes will develop disease.
What can cause increase in new
mutations in single genes resulting
in disease?
- Advancing paternal age = new
mutations proportion to impact to
biologic fitness
What methods are used for genetic
diagnosis
DNA analysis direct gene sequencing
and indirect
RNA analysis
Protein analysis (e.g. haemoglobin)
Functional analysis (e.g. sweat test and
lipid studies)

How can DNA testing lead to

individualized medicine?
We now have better diagnostic
applications and can predict, subclassify
and treat diseases differently.
Gene testing can change investigations or
specific treatments early
- Mastectomy BRCA1 BRCA2
- Prenatal testing
- Ferritin in haemochromatosis
- Colonoscopy in familial colon cancer
- BCR-ABL gene causes resistance to
imatinib in CML

Infectious disease
Infective complications of diabetes
What is the impact on intestinal
microbiota in diabetes?
Complex relationship between gut
microflora in response to whats available
to substrate and immune reaction
- Alteration in intestinal microbiota
will DECREASE TLR signalling and
PREVENT autoimmune diabetes

How do infections play a role in

diabetes?
Diabetics are more prone to infections
such as severe influenza.
DKA can be precipitated by infection
Metformin can be presented with lactic
acidosis with UTI
How is cellulitis recognised?
- Limited to SKIN only
- True infection of dermis will present
with
o Skin oedema
o Painful to touch (some
infections can have
underlying area of oedema
that associated with
inflammatory process
underneath it)
o Sharply demarcated from
normal skin
Which bacteria is able to dissect
tissue planes and which is most
common pathogen found on skin?

Staphycoccus aureus = most common

pathogen on skin but not very good at
spreading
Streptococcus pyogenes = dissect tissue
planes using elastase, hyluronidase
- Most common cause of this tissue
plane
- Keep dissecting into the skin
What else can cause this type of
cellulitis?
Opportunistic bacteria via water
injury? Penetrating injury? Wounds
and ulcers? Ischaemia?

Water based
- Aggressive bacteria can cause
shock
- Aeromonas hydrophilia
- Virbrio vulnificus
- Water-borne infection need different
antibiotics = consider
carbapenems and quinolones
Bites
- Cat bite (80% infection
- ANY BITE = Augmentin
consideration
IV therapy for cellulitis
- Clinically stable with cellulitis
severe enough to warrant IV
therapy
- These are unstable for oral
treatment (illness or GI problem)
o With hypotension or
septicaemia
o Can rapidly progress to
extensive/progressive
cellulitis
o Progression despite oral
treatment
o Immobile to go home
- B lactam drugs are commonly used.
These have to be high dose and
difficult for oral high dose due to
absorption and tolerance

Before discharge of infected patient

1. First dose of IV antibiotic in hospital
(ensure no allergy)
2. Script for oral antibiotic
3. Script for analgesia
4. Folow up arrangements and letter
to GP
What factors should a patient be
hospitalized
1. Diabetic feet or iscahemic
extremitis
2. Hand infection
3. Significant trauma
4. Penetrating injury
5. Bite injury or injury in water (see
above)
6. Bone or joint involvement
7. Periorbital cellulitis
Treatment of cellulitis
- Baseline FBC, EUC, FLT and blood
glucose
- Blood culture if fever or abnormal
vital signs (look out for sepsis)
- Culture
- Border should be marked
- Rest and elevate cellulitis in foot or
leg
- Analgesia
- IV
What are common extremities and
facial cellulitis
Extremitis
- Pyogenes >>>> aureus
- CEPHAZOLIN
Facial
- Pyogenes >aeurus (more staph)
- CLINDAMYCIN
- VACOMYCIN
(dont worry so jmuch about antibiotics,
basic principles)
Pneumonia in diabetes
- Increased risk of pneumonia related
hospitalization of >10 years
diabetic

UTI
-

HbA1c is a good marker of risk

Bad management of diabetics =
more infections
More likely to die from pneumonia
too if diabetic
Diabetic type 2 high
Almost double chance of UTI

Diabetic foot
- Poor immunity and poor circulation
o Usually just chronic ulcer until
a significant bacteria gets in
- Neuropathy is predisposition to
injury
- Wound and ulcer suspects = S.
aureus > S pyogenes (cellulitis) +
gram negatives (pseudomonas
aueroginosa and enterics (wet place
bugs)
- Ischaemic elements = anaerobes
Typically ball of foot = pressure necrosis
and unrecognised direct injury
Neuropathy prevents vibration and
pinprick
Vasculopathy
What else to look at for diabetic
foot?
Diabetic complications
- Renal
- Retinopathy
- Macrovascular complications
Control of diabetics
Treatment of cellulitis/avoiding
catastrophe
Misdiagnosis of a rash
Failure of debride
Failure to recognise extension
Failure to recognise ischaemia