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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
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
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
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
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
Thyroid swelling
Opthalmopathy
- periorbital oedema
- chemosis
- scerela injection
- proptosis
- lid retraction (obscured by oedema)
Localised dermopathy
Pernicious anaemia
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
Causes
- Genetic pituitary deficiency
- Tumour replacing normal pituitary tissue
- Trauma = pituitary stalk especially
- Surgery often to remove tumour
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
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
Steroid biosynthesis
How is cholesterol synthesised from acetyl
CoA
Cycle is repeated
Major
1.
2.
3.
4.
5.
classes of steroids
Glucocorticoids
Mineralcorticoids
Androgens
Oestrogens
Progestagens
Adrenal hyperplasia
Virilization in girls
Aldosterone biosynthesis
Lipoprotein transport
What is the organization structure of
lipoproteins?
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
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
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
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
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