Endocrine
1. Diabetes mellitus
2. Complications of diabetes
3. Hyperthyroidism
4. Hypothyroidism
5. Disorders of the adrenal gland
6. Disorders of the pituitary gland
7. Hypercalcemia
8. Hyperlipidemia
Editorial team
Katie Newman, Rebecca Ng, Ashleigh Spanjers
Peer reviewed in 2011 by
Dr Vijay Panicker
Endocrinologist
Diabetes mellitus
Examination1,2
DM I
Weight loss
Tachypnoea
DM II
Signs of hypercholesterolaemia
Xanthelasma, corneal arcus
May show complications of diabetes
Retinopathy
Haemorrhages, vessel narrowing, new vessel
formation on fundoscopy
Cardiovascular:
Carotid bruits, hypertension, absent peripheral pulses
Neurological
Peripheral symmetrical or focal neuropathy with loss
of tendon reflexes, vibration sense, proprioception,
light touch and sharp sensation.
Presentation1,2,4
DM I
Typically
Younger age of onset (<35 years)
Acute (several weeks) onset
Rarely asymptomatic
Classic symptoms
Polyuria
Polydipsia
Polyphagia
Weight loss
Changes to vision (blurring, etc)
Lethargy
Nausea and vomiting (DKA)
Abdominal pain (DKA)
Tachypnoea (DKA)
Coma (DKA)
DM II
Typically
Alder age of onset (increasingly seen in young with
obesity epidemic)
Overweight patients
Gradual onset
Often asymptomatic
History may include
Frequent infections (yeast, skin, UTI)
Slow wound healing
Parasthesia or anaesthesia in extremities
Pruritis
Fatigue
May have symptoms as above for DM type I
Investigations1,2
DM I and DM II
Random plasma glucose
Diabetes: ≥11.1 mmol/L
Fasting plasma glucose
Normal: <5.6 mmol/L
Impaired fasting glucose: 5.6-6.9 mmol/L
Diabetes: >6.9 mmol/L
Oral glucose tolerance test
75g oral glucose. 2 hour post-load monitoring
Normal: <7.8mmol/L
Impaired glucose tolerance: 7.8mmol/L-11.0mmol/L
Diabetes: ≥11.1 mmol/L
Glycosylated haemoglobin (HbA1c)
Diabetes: HbA1c ≥ 6.5%
DM I
Ketones (plasma or urine)
DM I: Medium or high quantity
Fasting C-peptide (in presence of normal or high glucose)
DM I: Typically low/undetectable
DM II: Typically normal/high
Antibodies
Anti-glutamic acid decarboxylase (GAD) antibodies,
islet cell antibodies, insulin auto-antibodies
DM I: Positive in 85%
DM II
Fasting lipids
May have ↑LDL, ↓HDL, ↑triglycerides
Urine microalbumin (ACR)
May have microalbuminuria
U&Es
May have renal insufficiency (↑serum Cr, ↓eGFR)
ECG
May have prior ischaemia.
Classifications/subtypes1,2,4
Diabetes mellitus type I: Absolute insulin deficiency due to auto-immune destruction of pancreatic endocrine beta cells.
Previously known as insulin dependent diabetes mellitus, juvenile onset diabetes mellitus.
Diabetes mellitus type II: Progressive insulin resistance resulting in relative insulin deficiency hyperglycaemia and
metabolic changes, which leads to beta cell failure. Previously known as non-insulin dependent diabetes mellitus
(NIDDM), adult-onset diabetes.
Gestational diabetes: Glucose intolerance that has its onset during pregnancy. Typically resolves post-delivery but
predisposes to onset of diabetes mellitus type II.
Diagnostic criteria1,2
DM I and II
1 of 4 tests should be positive on repeated testing:
1. Fasting plasma glucose >6.9 mmol/L
2. Random plasma glucose ≥11.1mmol/L
3. 2 hour post-load glucose on OGTT ≥11.1mmol/L
4. HbA1c ≥ 6.5%
Differentials1,2
Diabetes mellitus type I
Diabetes mellitus type II
Pancreatitis
Drug-induced glucose intolerance
Aetiology2,4
DM I risk factors
Family history of DM I
HLA risk profile based on
geographic region
Exposure to infectious
agents (rubella,
enterovirus)
DM II risk factors
Older age
Overweight/obesity
Gestational diabetes
Abnormal glucose
intolerance
Family history of DM II
Ethnicity (ATSI,
Polynesian)
Sedentry lifestyle
Polycystic ovarian
syndrome
Hypertension
Hyperlipidemia
Cardiovascular disease
Pathophysiology1,2
DM I
Environmental trigger on background of polygenetic risk factors
o Polymorphisms on MHC and non-MHC genes including HLA-Dqalpha, HLA-
Dqbeta, HLA-DR, preproinslin, PTPN22, CTLA-4 genes.
This results in auto-immune reaction and antibody destruction of pancreatic islet beta
cells resulting in loss of insulin production.
Insulin deficiency results in hyperglycaemia.
o Hyperglycaemia leads to osmotic dieresis which can lead to polyuria, resulting
polydipsia, electrolyte disturbances.
Deficient activity of insulin leads to
o ↓ glucose uptake leading to polyphagia
o Switch to fat metabolism which produces Acetyl CoA which cannot be broken
down and is converted to ketones which can result in diabetic ketoacidosis.
DM II
Insulin resistance (e.g. in overweight patients where adipose tissue is insulin resistant)
and beta cell dysfunction results in ↓ glucose uptake and hyperglycaemia.
Triggers a compensatory ↑ in insulin and as this cycle continues, eventual B cell failure.
Gestational diabetes
Placenta produces TNF-alpha, placental GH which can induce insulin resistance in the
mother (peaks at weeks 24-28 in the third trimester).
Becomes evident in pregnancy due to ↑ insulin requirement
Hyperglycaemia can have adverse neonatal effects including macrosomia,
hyperbilirubinemia, hypocalcemia, neonatal hypoglycaemia and fetal abnormalities.
Epidemiology4,5
3.9% (prevalence of
diabetes in Australia in
2007-8
Estimated 1 undiagnosed
diabetes for every
diagnosed diabetes
88% of diabetes burden
of disease due to DM II in
2007-8
10% of diabetes burden
due to DM I in 2007-8
ATSI 3x as likely as non-
ATSI to be diagnosed
with diabetes
5.5% of total burden of
disease in Australia
attributable to diabetes
8% of total burden of
disease in Australia in
2003 attributable to
diabetes and its
complications
2% ($907 million) of
direct health care
expenditure in 2004-5
due to diabetes
1 in 20 pregnant women
affected by gestational
diabetes
Management1,2,3
DM I
1. Insulin
0.2-1.0 units/kg/day (individualised)
Subcutaneous injections
o Fixed dose insulin (sc insulin bd either 50/50, 75/25 or 70/30)
o Basal-bolus insulin (1-2 basal injections/day of intermediate or long acting
insulin, with bolus short-acting insulin before meals)
Continuous insulin infusion (via pump)
SE: Hypoglycaemia, insulin antibody production, injection site lipohypertrophy
DM II
1. Lifestyle and diet
Low glycaemic index, low saturated fat diet (dietician r/v required)
Exercise (30 minutes, 5/7 days, moderate intensity)
Weight reduction
Smoking cessation, alcohol moderation
2. Oral hypoglycaemics
Co-treatment with multiple oral hypoglycaemics is common
1. Biguanides (Metformin)
o ↑ uptake of glucose to muscles, ↓ gluconeogenesis, ↓ insulin resistance
o Weight neutral
2. Sulphonylureas (Gliclazide, Glibenclamide, Glipizide)
o Insulin secretogogue (requires functional B-cells)
o Weight gain (↑ appetite), risk of hypoglycaemia
3. Thiazolidinediones (Rosiglitazone, Pioglitazone)
o PPARy agonists increase insulin sensitivity in liver, fat, muscle
o Weight gain, peripheral odedema, heart failure, ↑CVS mortality, atypical reactions
4. DPP4 Inhibitors (Sitagliptin, Vildagliptin, Saxagliptin)
o Inhibition of DPP4 resulting in increased GLP1
o Weight neutral, no risk of hypoglycaemia
3. Insulin (basal or as in DM I)
Monitor complications
Annual cycle of care to be monitored by GP
6 monthly: r/v weight, height, BMI, HbA1c (diabetes control), blood pressure,
examination of feet
Annual: measure cholesterol, HDL, LDL, TG, microalbuminuria, medication r/v,
dietary r/v, physical activity r/v, self-education r/v
Biennial: specialist eye examination
Specialist follow-up as required (endocrinologist, ophthal, cardio, podiatrist, etc.)
Glycaemic goals
HbA1c <7%, pre-prandial
plasma glucose 5.0-
7.mmol/L, post-prandial
plasma glucose (1-2
hours after beginning of
meal) <10.0mmol/L
Management algorithm for DM II
a: Adapted from: Colagiuri R, Colagiuri S, Dickinson S, Girgis S. National Evidence Based Guideline forBlood Glucose Control in Type 2 Diabetes. Canberra: Diabetes Australia
and the NHMRC; 2009.
Complications of Diabetes Non-ketotic hyper-osmolar state (HONK)/
Hyperosmolar hyperglycaemic state (HHS) 2,5
Definition
Profound hyperglycaemia (plasma glucose >33.3mmol/L),
hyperosmolality (serum osmolality >320mmol/L), volume
depletion in the absence of profound ketoacidosis (pH >7.3,
HCO3 >15mmol/L
Presentation
Typically in DM II > DM I
Altered mental state (typically NOT coma)
Symptoms of hyperglycemia
Polyuria
Polydipsia
Polphagia
Weight loss
Weakness
Seizures
Signs of volume depletion
Dry mucous membranes
Poor skin turgor
Hypotension
Tachycardia
Hypovolemic shock
Investigations
Bloods
Plasma glucose: hyperglycaemia
U&Es: ↓ chloride, magnesium, calcium, phosphate.
↑creatinine, urea, sodium, potassium (if mild). ↓ potassium
if severe
Serum osmolality and anion gap
U/A
Glucose, if infection leukocytes and nitrites, ↓/no ketones.
Investigate cause
MI: ECG, cardiac enzymes (troponins, CK-MB)
Infection: Septic screen (CXR, blood and urine culture)
Management
1. IV fluids
2. Supportive care (oxygenation, airway protection, etc)
3. IV potassium replacement if <3.3mmol/L
4. Insulin (bolus insulin followed by continuous insulin
infusion) when potassium >3.3mmo/L
5. Vasopressor, potassium, phosphate therapy as required
Aetiology
Any illness that results in release of counterregulatory
hormones catecholamines (adrenalin, noradrenalin),
glucagon, cortisol, growth hormone or causes dehydration.
o Infection (UTI, pneumonia) – most common
o CVA/AMI
o Post-operative TPN (CABG, neurosurgery)
Treatment non-adherence (insulin, oral hypoglycaemics)
Endocrine abnormalities (hyperthyroidism, acromegaly,
hypercorticolism (Cushing‟s syndrome)
Corticosteroids
Pathophysiology
Relative insulin deficiency results in ↓ insulin concentration
↓ insulin results in ↑ gluconeogenesis, glycogenolysis and
impaired glucose uptake to tissues
Hyperglycaemia results and causes osmotic diuresis
resulting in electrolyte disturbances (hypernatremia) and
net loss of water resulting in hypovolemia.
↓ GFR from hypovolemia as well as effect of counter
regulatory hormones to induce insulin resistance and ↓
insulin production contributes to hyperglycemic crisis.
Diabetic ketoacidosis (DKA)2,5
Presentation
Classic presentation of DM I
Dry mouth, shortness of breath, abdominal pain,
nausea, vomiting, changes in sensation
Investigations
High blood glucose
High ketone level (plasma. Urine)
Metabolic acidosis (anion gap)
Investigate cause (septic screen, ECG, etc)
Management
IV hydration
IV insulin infusion
Correct electrolyte imbalance (potassium replacement,
bicarbonate if ABG pH <6.9)
Pathophysiology
Dehydration and metabolic acidosis → symptoms.
Aetiology
Missed insulin
Physiological stress (infection, AMI)
Hypoglycaemia2,5
Presentation
Warning signs: tachycardia, diaphoresis,
shakiness/trembling, anxiety, hunger, altered mental state
Severe hypoglycaemia: Hypoglycaemia unawareness
(absence of symptoms with hypoglycaemia) may occur
with multiple hypos. Severe hypoglycaemia and
hypoglycaemia unawareness is more common in DM I>II.
Investigations
Plasma glucose <3.9 mmol/L
Management
If possible: oral fluids (coca-cola, fruit juice) or
glucose tablets
IM or SC injection of glucagon
IV dextrose
Aetiology
DM I – more sensitive to insulin
Treatment related (↑ insulin, sulphonylurea dose)
↑ physical activity, ↓ dietary intake
Cardiovascular disease2,5
(macrovascular)
Presentation, Examination, Investigations, Management
See „angina‟, „myocardial infarction‟, „stroke‟
Aetiology
Diabetic nephropathy Hypertension
Hyperlipidemia Smoking
Obesity Physical inactivity
Pathophysiology
Diabetes accelerates rate of atherosclerosis which causes
accumulation of plaques on vessel walls obstructing flow.
Occlusion of coronary vessels results in angina (ischaemic
pain) if partial occlusion resulting in reduced blood supply,
myocardial infarction (death of myocardium) if
complete/total reduction. Embolisation of plaque to
cerebral vessels can result in occlusion of blood flow and
cerebrovascular accident (stroke).
Epidemiology
CVD and CVA account for 65% of all diabetes deaths
2x risk of CVD event with diabetes
Retinopathy2,5
(microvascular)
Presentation
Typically asymptomatic until severe
Changes to vision (blurring, floaters, loss of vision)
Examination
Microaneurysms, cotton wool spots (white elevations of
nerve fibre), intra-retinal haemorrhage (flame), lipid
exudates, macular thickening, neovascularisation of
optic disc and retina, retinal detachment
Investigations
Fundoscopy
Optical coherence tomorgraphy scanning
Fluorescein angiography
B scan ultrasonography
Management
Screening (biennial specialist eye examination)
Laser therapy (macular, pan-retinal)
Vitrectomy
Aetiology
Hyperglycaemia, genetics, hypertension, renal disease
Pathophysiology
Hyperglycaemia →changes to Virchow‟s triad → leaky
capillaries and ↓ perfusion.
Non-proliferative retinopathy occurs earlier with blood
vessel swelling and leakage → blurred vision.
Progressive proliferative retinopathy occurs later →
neovascularisation of new, delicate blood vessels that
haemorrhage easily →↓vision, retinal scarring.
Epidemiology
Lifetime risk is 5% in diabetics
Leading cause of blindness in Australians aged 20-74
17% of all vision loss/impairment in Australia
Peripheral vascular disease2,5
(macrovascular)
Presentation
Often asymptomatic
5 P‟s of acute limb ischaemia: pain, paralysis,
parasthesia, pulselessness, pallor
Most commonly: intermittent claudication in calf,
buttocks, thigh (pain on claudication distance, relieved
by rest) and reduced or absent peripheral pulses
Examination
Buerger‟s test: positive (foot pallors on elevation, turns
blue (deoxygenated blood) then red/purple (reactive
hyperemia) on dependence) = critical limb ischaemia
Investigations
Ankle-brachial pressure index: <0.90
Duplex and/or Doppler U/S: ↓ pulsatility index
CT angiogram/angriography: stenosis
Management
Thrombolysis: Urokinase (acute limb ischaemia)
Endovascular revascularization: Angioplasty (balloon),
atherectomy (core out plaque), stent, bypass (vein,
PTFE)
Amputation (above knee/below knee, prosthesis)
Control CVD risk: ACEi, ARBs, Ca-ch blocker, statins,
aspirin (cease beta-blockers)
Aetiology
Hyperglycaemia, hyperlipidemia, hypertension,
smoking, age >40, physical inactivity
Pathophysiology
↓ blood supply due to atherosclerotic plaques
Can result in poor wound healing and amputation
Epidemiology
2-4x ↑ risk of PVD with diabetes
Nephropathy2,5
(microvascular)
Definition
Macroalbuminuria (ACR >34mg/mmol) OR
Microalbuminuria (ACR 3.4-34mg/mmol) with
retinopathy (DM I or II) and/or >10 years of DM I.
Presentation
Progressive course (>10 years)
Classical: Hypertension, albuminuria, falling GFR,
oedema
Severe disease: Pallor (↓Epo production) and platelet
dysfunction (bleeding gums, bruising, epistaxis),
constitutional symptoms (fatigue, anorexia), uremic
symptoms (nausea, vomiting, altered taste)
Investigations
U/A: Proteinuria, albuminuria
Urine albumin/creatinine ratio (ACR)
U&Es: ↑ serum creatinine and urea, ↓ eGFR
Kidney U/S: normal/↑ size, ↑echogenicity
Kidney biopsy: definitive Dx, usually not performed
Management
Establish/maintain glycaemic control
Control hypertension: ACEi, ARBs, B-blocker, Ca-ch
blocker
Lower CVD risk: statins
Lifestyle: smoking cessation, low protein diet
Aetiology
Hyperglycaemia, hypertension, hyperlipidemia, poor
diet/exercise, obesity, smoking
FMH of hypertension, kidney disease
Epidemiology
Lifetime risk is 40% in diabetics
Diabetic nephropathy most common cause of ESKD in
Australia
10% estimated prevalence of diabetic nephropathy in
Australians with diabetes
CKD responsible for 13% of all deaths in diabetes
Neuropathy2,5
(microvascular)
Presentation
Typically lower (feet, legs) can be upper (hands, arms)
Sensory neuropathy: pain, parasthesia, anaesthesia
Motor neuropathy: weakness, loss of coordination
Autonomic neuropathy: dizziness, fainting, nausea,
vomiting, diarrhoea, constipation, urinary incontinence,
sexual dysfunction
Investigations
Nerve conduction study:↓conduction velocity,
↓amplitude
Electromyography
Quantatitive sensory testing: deficits in vibration, thermal
Other tests as required (e.g. gastric emptying studies, etc)
Management
Glycaemic control
Observation and regular follow-up
Symptomatic treatment for autonomic dysfunction/pain
Referral to podiatrist
Aetiology
Hyperglycaemia
Pathophysiology
↓ of sensation and motor control predisposes to
unrecognized foot trauma →deformation, infection
Epidemiology
Lifetime risk is 50% in diabetics
10.3% (M) and 8.6% (F) prevalence
Hyperthyroidism Definition1,2,6
Excess thyroid hormone production.
Examination1,2,6
Vital signs: Tachycardia, Irregularly irregular pulse, wide
pulse pressure, hypertension
General inspection: Dyspnoea, weight loss, fine tremor
(balance paper on dorsum of hand), proximal myopathy
(difficulty standing from sitting position, etc.)
Skin changes: hyperpigmentation, warm, moist smooth
skin, dermopathy (myxoedema)
Nail changes: onycholysis: separation of nail from nail bed
Ophthalmopathy: Lid lag (delay in lid following eye when
asked to follow examiner‟s finger), Lid retraction (results in
hyperthyroid stare), Exophthlamus (eyes bulge out of orbit,
can see sclera inferiorly and superiorly)
Neck: Diffusely enlarged, smooth, firm thyroid (Grave‟s),
firm, tender thyroid (thyroiditis)
Retrosternal goitre: Positive Pemberton‟s sign (thoracic
inlet obstruction from retrosternal goiter), dull percussion
across manubrium (retrosternal goiter)
Auscultation: cardiac flow murmur, thyroid bruits
Presentation1,2,6
General:
Sweating, heat intolerance
Skin, hair, nails:
Hyperpigmentation, pruritis, onycholysis, loss of hair
Eyes
Lid lag, lid retraction, hyperthyroid stare, ocular muscle
dysfunction (e.g. diplopia)
Cardiovascular:
Tachycardia, palpitations, atrial fibrillation
Respiratory:
Dyspnea
Gastrointestinal:
Weight loss with hyperphagia
Diarrhea
Genitourinary:
Urinary frequency, nocturia, oligomenorrhoea,
amenorrhoea, infertility
Neuropsychiatric:
Anxiety, agitation, psychosis, depression, restlessness,
emotional lability, insomnia, cognitive impairment
Grave‟s clinical triad (rare)
1. Goitre
2. Eye changes: proptosis (exophthalmos), peri-orbital
oedema, ocular muscle dysfunction (e.g. diplopia)
only in Grave‟s disease. Also, lid retraction and lid lag
3. Dermopathy: pre-tibial myxedema, peri-orbital
myxoedema dermopathy only in Grave‟s disease
Thyroid storm (life-threatening hyperthyroidism)
Hyperthermia >40ºc
Tachycardia
Arrhythmia
Investigations1,2,6
Thyroid function tests
Normal values (lab dependent: Pathwest values provided)
TSH: 0.4-4.0 mU/L
Free T4: 9.0-19.0pmol/L
Primary hyperthyroidism:
Mixed
o ↑T3, ↑T4, ↓TSH (negative feedback)
T3 toxicosis (Grave‟s disease, nodular goiter)
o ↑T3, ↓TSH (negative feedback)
T4 toxicosis (exogenous, ectopic sources)
o ↑T4, ↓TSH (negative feedback)
Subclinical hyperthyroidism:
N T4, ↓TSH
Secondary and tertiary hyperthyroidism:
↑T4, ↑TSH
Thyroid scintigraphy
Measures uptake of Technetrium-99 or radioiodine in
thyroid gland indicating level of activity
Diffusely ↑ activity: Grave‟s disease
Diffusely heterogenous activity: toxic MN goiter
Focally ↑ activity: toxic adenoma
„Hot‟ nodules can be Rx medically/surgically
“Cold' nodules require U/S +/- FNA(malignancy risk)
Imaging
CT or U/S +/- FNA if malignancy is suspected
Diagnoses malignancy
*See Investigations for Hyperthyroidism algorithm
Management1,2,6
Anti-thyroid drugs
Thionamides
Carbimazole (inhibits thyroperoxidase enzyme)
Propylthiouracil (inhibits thyroperoxidase enzyme
and peripheral deionidases)
Block synthesis of thyroid hormone
Onset of action 3-4 weeks (hormone stores)
Steady state peak in 12 weeks
2-4x daily dosing (1-9 hour half life)
12-18 month treatment regimen
Assess TFTs at 2 and 4 weeks, then monthly
Indicated to achieve euthyroid function before
definitive treatment
SE: pancytopenia, agranulocytosis, liver toxicity
(requires LFT monitoring)
Non-selective beta blockers
Propanolol (specific for tremor)
Indicated as adjunct for symptomatic relief of
sympathetic symptoms (tachycardia, sweating,
tremor, etc) before definitive therapy
Sodium iodide
Oral administration in glass of water
Suppresses release of stored thyroid hormone and
inhibits peripheral deiodination of T4 to active T3
Rapid onset of action (12 hours) and rapid offset
of action (few days)
Indicated for temporary suppression of
hyperthyroidism (e.g. thyroid storm) or pre-op
Thyroidectomy
Types: hemi-thyroidectomy, total thyroidectomy
Performed following achievement of euthyroidism
Risks: recurrent laryngeal nerve injury (voice
changes), general surgical risks (infection, etc)
Radio-iodine ablation
Iodide-131 irradiation causing selective death of
thyroid tissue resulting in hypothyroid state
75% success rate but repeated doses often required
in 10-15%
Thyroxine replacement
Usually required following surgery/ablation
(especially in Grave‟s disease)
Diarrhoea/vomiting
Dehydration
Coma
Aetiology1,2,6
Primary causes of hyperthyroidism
Grave‟s Disease (most common cause)
Autoimmune disorder where auto-antibodies are produced
against the TSH receptor (TSHr-ab) act to continually
stimulate the TSH receptor and increase thyroid hormone
production. No negative feedback occurs. IgG antibodies
(TSI, TGI) also promote thyroid epithelium growth
resulting in epithelial hyperplasia.
Associated with haplotypes HLA-B8, DR3
Hashitoxicosis
Auto-immune thyroiditis with anti-thyroperoxidase
antibodies causes initial increase in thyroid hormone
production before thyroid gland failure leading to
hypothyroidism
Autonomous thyroid tissue
Toxic thyroid adenoma
Toxic multi-nodular goiter
Ectopic thyroid tissue
Thyroid carcinoma (rarely functional)
Thyroid hypertrophy
Iodine sufficiency after iodine deficiency
Subacute de Quervain‟s thyroiditis
Self-limiting, post-viral goitre
Exogenous thyroid hormone
Excessive thyroxine replacement
Secondary causes of hyperthyroidism
Pituitary disease (TSH producing adenoma)
Tertiary causes of hyperthyroidism
Hypothlamic disease (TRH producing adenoma)
Risk factors for automimmune thyroid disease
Female gender
Increasing age
Smoking
Pathophysiology1
Warm skin due to ↑ blood flow.
Smooth skin due to decrease in keratin layer
Heat intolerance and sweating due to ↑ calorigenesis
Hyperpigmentation due to ↑ cortisol metabolism resulting
in ↑ ACTH secretion
Sympathetic overactivity results in hyperthyroid stare and
lid lag.
↑ cardiac output due to ↑ oxygen demand and cardiac
contractility
Tachycardia from ↑ sympathetic activity
Thyroid hormone stimulates bone resportion resulting in ↑
bone turnover/osteoporosis
Weight loss caused primarily by hypermetabolism and
secondarily by ↑ gut motility and the associated diarrhea
and malabsorption.
Hyperphagia due to ↑ demand of body
Grave‟s disease ophthamlmopathy, exopthlamos,
impairment of eye muscle function, periorbital and
conjuctival oedema from inflammation of extraocular
muscles, orbital fat and connective tissue. This can
progress to corneal ulceration from proptosis and lid
retraction and optic neuropathy and blindness may occur
from severe proptosis.
Signs and symptoms of hyperthyroidism
b: Joyce DA. Thyroid and Anti-Thyroid Drugs [unpublished lecture notes].
University of Western Australia; notes provided at lecture given 2010 Sep 24.
Epidemiology6
5x more common in F > M
1.3% overall prevalence of hyperthyroidism
4-5% prevalence in older F
Grave‟s disease more common in younger F
Toxic nodular goiter more common in older F
Personal or family
history of auto-immune
disease or MEN
syndrome
Algorithm for investigation of hyperthyroidism
c: Government of Western Australia Department of Health. Diagnostic Imaging
Pathways – Hyperthyroidism [Internet]. East Perth, WA (Australia): 2009
[updated 2009 Sep; cited 2011 Aug 26]. Available from:
http://www.imagingpathways.health.wa.gov.au/includes/dipmenu/hyperthy/char
t.html
Hypothyroidism Definition1,2,6
T4 and T3 thyroid hormone deficiency.
Examination1,2,6
Vital signs: Bradycardia, Hypothermia
Hair: Dry, coarse hair. Alopecia (loss of lateral 1/3 of eyebrow,
axillary hair)
Skin: dry, pallor, cool, cyanosis, hypercarotenaemia (yellow-
orange discolouration of skin), vitilgo (patches of de-
pigmentation), thickened
Face: Macroglossia, xanthelasma
Neck: Goitre, hard rubbery thyroid (Hashimoto‟s)
Oedema: peri-orbital oedema, pre-tibial (non-pitting)
Tendon reflexes: Slow/increased return phase
May also have associated signs of:
Carpal tunnel
Anaemia
Cardiomegaly
Pericardial effusion
Pleural effusion
Cerebellar ataxia
Presentation1,2,6
Typically:
Female
Middle age (30-50 years)
Gradual onset
Sudden onset with severe symptoms if acute event
(e.g. thyroidectomy)
Presentation:
Lethargy
Cold intolerance
Weight gain
Depression
Difficulty concentrating
Menorrhagia
Infertility
Weakness
Myalgia
Hoarse, deepened voice
Dysphagia
Dry, coarse skin
Coarse hair
Hair loss
Constipation
Oedema of face, eyelid (puffy eyes, etc.)
Bradycardia
Goitre
Myxoedema coma (life-threatening hypothyroidism)
Hypothermia <30 degrees
Altered mental state (stupor, coma)
Occurs from acute event (infection, MI, opiate or
hyponotic use) on background of severe
hypothyroidism
Fatal if untreated
Differentials1,2,6
Anemia
Pregnancy
Adreno-cortical insufficiency
Liver failure
Investigations1,2,6,7,8
Thyroid function tests (Free T4, TSH, typically not T3)
Normal values
TSH: 0.4-4.0 mU/L
Free T4: 9.0-19.0pmol/L
Primary hypothyroidism:
↓T4, ↑TSH
Subclinical hypothyroidism:
N T4, ↑TSH
Secondary and tertiary hypothyroidism:
↓T4, ↓/N/↑ TSH
TRH stimulation tests (now rarely performed)
If secondary hypothyroidism suspected, TSH is N
Autoimmune antibodies
Anti-thyroid peroxidase antibody (anti-TPO)
Anti-thyroglobulin antibody
Ultrasound (not required in most cases)
If thyroid nodule present U/S for response to treatment.
U/S (+/- FNA) can also be used to screen for DDx of
malignancy
Management1,2,6
T4 Thyroxine replacement
Levothyroxine/L-thyroxine (synthetic)
Half life: 6 days
Once daily dosing
Oral preparation
Dosing 1.6mcg/kg/day, typically 50-200mcg/day
Indicated in long term management: T4 preferred to T3
as longer half life allows for more constant level in the
body to allow physiological deiodination of T4 to
active T3 to mimic endogenous thyroid hormone
process
Typically symptoms resolve in 3 weeks, steady state
achieved in 6 weeks
T3 replacement
Half life: 2 days
IV or oral preparation
T3 more rapidly effective than T4 but also more rapidly
eliminated due to half life
Indicated in short term management of life-threatening
hypothyroidism:
Side effects (if excessive replacement):
Arrhythmias, angina, restlessness, tremor
Monitoring treatment
TSH (typically)
T4 (if TSH is unreliable marker due to
hypothalamic/pituitary disease)
Classifications/subtypes1,2,6
Primary hypothyroidism (95%): Pathology in the thyroid gland resulting in ↓ thyroid hormone production
Secondary and tertiary hypothyroidism (5%): Pathology in the hypothalamus or pituitary gland resulting in downstream decrease
in thyroid hormone production.
Subclinical hypothyroidism: Elevated TSH in presence of normal T4 (thyroxine) hormone. Typically asymptomatic.
Aetiology1,2,6
Causes of primary hypothyroidism
Autoimmune thyroiditis
Hashimoto‟s thyroiditis (deficient suppressor T cells results in
auto-immune anti-thyroid peroxidase antibodies which result in
inflammatory destruction of the thyroid gland)
Primary idiopathic hypothyroidism
Iatrogenic
Thyroidectomy
Radioablation (e.g. for treatment of Grave‟s disease)
Radiation therapy (e.g. to neck for Hodgkin‟s lymphoma)
Iodine
Iodine deficiency
o <100mcg/day
o Iodine required for thyroid hormone production
o E.g. developing countries, inland, mountainous areas:
China, Switzerland
Iodine excess
o Excess iodine causes Wolff-Chaikoff effect (inhibits
thyroid)
o Hormone production and can increase thyroid antigenicity
Goitrogens
Dietary: calcium, brassicaceae vegetables (cabbage, broccoli0
Drugs: anti-thyroid drugs (methimazole, prophylthiouracil),
lithium (direct toxic effect and promotes development of
auto-antibodies), amiodarone
Congenital
Hypoplasia, aplasia
Infiltrative disease
Sarcoidosis, amyloidosis
Pathophysiology1
Lack of thyroid hormone results in hypometabolic state causing fatigue,
weight gain, cold intolerance, slow tendon reflexes, bradycardia.
Mucopolysaccharide accumulation in interstitial spaces causes
myxoedema in face and eyelids (puffiness) and vocal cords (hoarse,
deep voice), macroglossia, coarse hair and skin.
Epidemiology6
0.1-2.0% prevalence of overt hypothyroidism
4-10% prevalence of subclinical hypothyroidism
↑ prevalence in older patients
5-8x ↑ prevalence in females > males
Signs and symptoms of hypothyroidism
f: Joyce DA. Thyroid and Anti-Thyroid Drugs [unpublished
lecture notes]. University of Western Australia; notes provided at
lecture given 2010 Sep 24.
Causes of secondary hypothyroidism
Pituitary disease
Failure to produce TSH (thyroid stimulating
hormone)
E.g. Hypopituitarism from pituitary
adenoma, Sheehan‟s syndrome from post-
partum pituitary necrosis
Causes of tertiary hypothyroidism
Hypothalamus
Failure to produce TRH (thyrotropin
releasing hormone)
E.g. Obstruction to hypothalamic-pituitary
portal system, mutation to TRH receptor
Risk factors
Female
Middle age (30-50 yaers)
Family history of hypothyroidism
History of autoimmune disease
Grave‟s disease
Hemithyroidectomy
Post-partum (post-partum thyroiditis)
Past radiation to head and neck
Iodine deficiency or excess
Turner‟s syndrome
Down‟s syndrome
Use of amiodarone, lithium
Thyroid hormone production
d: Brandt E. Thyroid Hormone Replacement Therapy
[Internet]. Victoria, BC (Canada): Rinfocan –
Prescription Drug Information for Canadians; 2011
[cited 2011 Aug 26]. Available from:
http://www.druginformation.bc.ca/thyroid.htm
Thyroid hormone feedback
e: Hill RN, Crisp TM, Hurley PM, Rosenthal SL,
Singh DV. Risk Assessment of Thyroid
Follicular Cell Tumours. Environ Health
Perspect. 1998 Aug;106(8):447-57.
Disorders of the adrenal gland
Conn’s Syndrome (Primary Hyperaldosteronism)1,2
Presentation
Typically in those aged 20-70 years
Common presentation:
o Hypertension (most common), polyuria, nocturia
o Lethargy, neuropsychiatric (irritability, anxiety,
depression, poor concentration)
If hypokalemia:
o Parasthesia, muscle cramps and weakness, muscle
weakness, palpitations
Investigations
Tests
Plasma potassium: low/normal
Aldosterone/renin ratio: >30 (lab and unit dependent)
Fludrocortisone suppression test: suppression failure
Oral salt loading: ↑ (failure to suppress aldosterone)
Imaging
Adrenal MRI or CT: lesion
Adrenal venous sampling: lateralises to one adrenal in
adenoma/carcinoma/unilateral hyperplasia, bilateral in
bilateral hyperplasia
Adrenal selenocholesterol scanning: adenoma isotope
uptake
Management
Medical:
Spironolactone (aldosterone inhibitor, first line)
Amiloride (aldosterone inhibitor, second line)
Potassium replacement
Anti-hypertensives
Surgical:
Adrenalectomy
Aetiology
Causes:
Unilateral adrenal adenoma (85%)
Bilateral adrenal adenoma (<5%)
Bilateral adrenal hyperplasia (10-40%)
Adrenal carcinoma (rare)
Glucocorticoid hyperaldosteronism (rare)
Familial hyperaldosteronism type I
Risk factors:
Family history of primary hyperaldosteronism, early onset
hypertension, early onset stroke
Pathophysiology
Autonomous production of excessive mineralocorticoid
aldosterone results in unregulated action of aldosterone on
the renin-angiotensin system resulting in
o ↑ sodium reabsorption in the distal renal tubules of
kidney (hypertension, suppression of renin-
angiotensin)
o ↑ potassium and hydrogen ion loss due to pump
exchange (hypokalemia, metabolic acidosis).
Cushing’s Syndrome (Hypercortisolism)1,6
Presentation
Simultaneous onset and progressive severity of Sx
Duration and intensity of exposure to ↑glucocorticoid
determines presentation (subclinical→overt)
Most specific presentations: Supraclavicular fat pads ,
skin atrophy, skin striae, proximal weakness
Catabolic effects: Poor wound healing, bruising,
proximal muscle wasting
Obesity: Buffalo hump - dorsocervical fat pad, short
fat neck supraclavicular fat pads, central obesity,
moon facies, skin striae (purple streaks -trunk,
breasts, abdomen)
Other: Facial plethora (flushing), hypertension,
osteoporosis, glucose intolerance, menstrual
irregularities (oligomenorrhoea, amenorrhoea,
menorrhagia), fatigue, hyperpigmentation (↑ ACTH),
fungal infections, neuropsychiatric (lability,
depression, agitation, anxiety, paranoia, insomnia)
If concomitant androgen excess: Hirsutism (face, lip,
chin), virilzation (deepening voice, male body
habitus, balding), acne (face, neck, shoulders)
Investigations
Confirm hypercortisolism: 24 hour urine free cortisol
Establish cause
g: Nieman LK. Trying to establish the diagnosis of Cushing‟s syndrome. In:
Lacroix A, Martin KA, editors. UpToDate. Waltham: UpToDate; 2008.
Imaging: CT (adrenal, abdo/pelvis), MRI: (pituitary)
Management
Iatrogenic: gradual glucocorticoid withdrawal
(periodic HPA axis insufficiency will occur)
Ectopic ACTH/CRH production: tumour excision
Pituitary lesion: transsphenoidal microadenoctomy,
pituitary irradiation, bilateral adrenalectomy
Adrenal adenoma: unilateral adrenalectomy
Adrenal carcinoma: unilateral adrenalectomy,
irradiation, chemotherapy
Adrenal hyperplasia: bilateral adrenelctomy
Lifelong glucocorticoid and mineralocorticoid
replacement: if bilateral adrenalectomy
Medical treatment: Ketoconazole or Metyropone
Aetiology
Secondary to pituitary disease (Cushing disease)
Adrenal tumours (hyperplasia, adenoma, carcinoma)
Ectopic ACTH secretion
Ectopic CRH secretion (small cell lung carcinoma)
Iatrogenic (glucocorticoid Rx)
Physiological (stress, obesity, chronic alcoholism) =
“Pseudo-Cushing‟s”
Adrenal gland9
Paired exocrine glands, located supra-renal. Structure is
90% outer cortex, 10% inner medulla.
Adrenal cortex:
Produces cholesterol-derived hormones from three zones:
zona glomerulosa (mineralocorticoids – aldosterone), zona
fasciculata (glucocorticoids – cortisol), zona reticularis (sex
steroids – ostrogen, androgen).
Mnemonic for adrenal cortex structure and function: “The
deeper you go, the sweeter it gets – salt, sugar, sex”
Adrenal medulla:
Neuroendocrine cells produce catecholamines
(noradrenalin, adrenalin), peptides, amines.
Addison’s disease (Primary adrenal insufficiency)1,6
Definition
Insufficient production and secretion of glucocorticoid
(cortisol) and mineralocorticoid (aldosterone) hormones
from the adrenal cortex.
Presentation
Addisonian crisis (severe adrenal insufficiency)
Shock (profound hypotension, dehydration), fever,
hyponatremia, hyperkalemia, hypercalcemia,
hyopglycaemia, nausea, vomiting, anorexia, abdo pain
Chronic primary adrenal insufficiency:
Malaise, lassitude, fatigue, weakness, anorexia, weight
loss, nausea, vomiting, constipation, abdominal pain,
salt craving, postural hypotension, arthralgia, myalgia,
Hyperpigmentation
Other symptoms of
Glucocorticoid, mineralocorticoid, androgen deficiency
(F only, as M produce majority of androgens in testes)
Investigations
Establish adrenal insufficiency
Serum cortisol (morning) – low
Salivary cortisol (morning) – low
Establish type of adrenal insufficiency
h: Nieman LK. Diagnostic approach to suspected adrenal insufficiency. In: Lacroix A,
Martin KA, editors. UpToDate. Waltham: UpToDate; 2011.
Establish cause of primary adrenal insufficiency
Abdominal CT: adrenals may be enlarged, calcified, TB
CT guided percutaneous FNA: adrenal glands
Antiphospholipid antibodies: if haemorrhage
TB testing: CXR, urine culture, tuberculin skin test
Management
Addisonian crisis:
IV fluid hydration: 5% dextrose or 0.9%isotonic saline
(0.2% not hypotonic saline as worsens hyponatremia)
Correct electrolyte balances
Glucocorticoid: dexamethasone 4mg IV bolus
Long term management:
Glucocorticoid replacement: short acting
hydrocortisone bd or tds, or long acting prednisolone,
dexamethasone od
Mineralocorticoid replacement: fludrocortisone
Androgen replacement (female): DHEA (controversial)
Aetiology
Causes:
Auto-immune: 80-90%
Infection: adrenal TB, others in immunocompromised
Infiltrates: amyloidosis, sarcoidosis,
Secondary mets: lung, breast, kidney, gut, lymphoma
Acute causes:
Adrenalectomy
Adrenal haemorrhoage or necrosis: sepsis, Waterhouse-
Friderichsen syndrome/haemorrhoagic adrenalitis
Familial: congenital adrenal hyperplasia,
adrenoleukodystrophy, adrenomyeloneuropathy, etc
Drugs: heparin, warfarin, TK inhibitors, azole anti-
fungals, phenobarbital, phenytoin, rifampcin
Idiopathic
Phaeochromocytoma2,6
Definition
Tumour of the chromaffin cells of the adrenal medulla
resulting in overproduction of catecholamines.
Presentation
Typically episodic and progressive.
Classical triad:
o Headache
o Diaphoresis (generalized)
o Tachycardia
Typically also have:
o Palpitations
o Hypertension (sustained, paroxysmal, hypertensive
crisis)
Other presenting complaints may include:
o Hypertensive retinopathy, pallor, dyspnea, impaired
glucose tolerance, panic attacks
Investigations
24 hour urine catecholamines and total metanephrines
(98% sensitivity and specificity)
Positive test is 2x elevation about normal upper limit
(noradrenalin >170mcg/day, adrenalin >35mcg/day,
dopamine >700mcg/day, normetanephrine >900mc/day,
metanephrine >400mcg/day
Plasma fractioned metanephrines
96-100% sensitivity, 85-89% specificity, high rate of false
positives, used if high index of suspicion
Clonidine suppression test
Confirmatory test.
Oral administration of adrenergic receptor agonist with
measurement of plasma cateholamines/fractioned
metnephrines at time 0 and time 3 hours.
If >50% decrease is not phaechromocytoma (normal
suppression), if levels remain raised is phaechromocytoma.
Other markers
↑Chromogranin A, ↑ Neuropeptide Y,
Imaging
CT abdo and pelvis, nuclear med MIBG and PET scans
Management
Initial medical treatment
Alpha receptor blockers (Rx hypertension)
Beta-blockers (Rx tachycardia, arrhythmias)
Calcium channel blocker (if hypertension persists)
IV hydration (normal saline)
Benign
Surgical excision (if benign, can be laproscopic or open)
Malignant
Surgical debulking (if malignant, ↓hypertensive Sx)
Chemotherapy
Aetiology
Risk factors
MEN syndrome, von Hippel-Lindau syndrome,
neurofibromatosis type I
Pathophysiology
Uncontrolled growth of chromaffin cells results in
excessive production of catecholamines
Catecholamines over-stimulate adrenergic receptors
resulting in sympathetic symptomatology.
Phaeochromocytomas are generally
o Benign rather than malignant
o Intra-adrenal (90%) rather than extra-adrenal
(paragangliomas, typically abdominal)
o Sporadic (typically large with ↑ catecholamine
secretion) rather than familial (20%, MEN, VHL
syndrome, typically smaller with ↓ catecholamine rel)
Disorders of the pituitary gland Pituitary adenoma1,2,9
Presentation
Symptoms typically gradual onset and progressive.
Local compression effects:
Headache, bitemporal hemianopia (compression of
optic chiasm), cranial nerve palsies (diplopia, facial
numbness)
Loss of hormone production:
Due to destructive compression effects on pituitary
tissue. Can result in hypogonadism, hypothyroidism,
adrenal insufficiency, etc.
Excessive hormone production:
Functional adenoma can result in symptoms of
hypersecretion specific to hormone being secreted.
Prolactinoma/PRL (most common):
Galactorrhoea, gynaecomastia and inhibition of
GnRH resulting in hypogonadism (amenorrhea,
breast atrophy, erectile dysfunction, testicular
atrophy, impotence, loss of libido, infertility)
Somatotrophic/GH (common):
Gigantism if before closure of epiphyseal plates
(dramatic onset of linear growth, height >2 standard
deviations above mean)
Acromegaly if after closure of epiphyseal plates.
Presentation: tall stature, obesity, macrocephaly,
coarse facial features, soft tissue hypertrophy, thick
fingers and toes, frontal bossing, osteoarthritis, carpal
tunnel, cardiac hypertrophy, hypertension.
Pituitary apoplexy:
Haemorrhage into pituitary tumour resulting in sudden
increase in size anda cute onset symtoms of raised ICP:
Headache, vomiting, papilloedema, altered mental
state, altered consciousness, coma, death.
Also ophthalmoplegia, acute adrenal insufficiency
crisis (hypotensive shock).
Investigations
Bloods
Pituitary hormones (PRL, LH, FSH, TSH, ACTH)
Target hormones (IGF-1, T4, testosterone, estradiol,
morning cortisol)
FBC (anemia)
U&Es (hyponatremia in adrenal insufficiency)
Stimulation tests
GH stimulation tests, ACTH stimulation test
Imaging
Contrast CT: Sellar mass
Gadolinium enhanced MRI: sellar mass
Management
Pituitary apoplexy: IV fluids, IV analgesia, IV corticosteroids
hydrocortisone or dexamethasone (acute adrenal insufficiency)
Hormone replacement
Transsphenoidal surgery
Aetiology
Risk factors: MEN-1, familial isolated pituitary adenomas
(FIPA), Carney complex
Pathophysiology
Benign pituitary tumour, but has capacity to be locally
aggressive (compression of vital structures in skull). May be
functional (hormone producing resulting in endocrine and local
effects) or non-functional (only has local effects)
Epidemiology
Accounts for 10-15% of all intracranial neoplasms.
Pituitary gland9
Anatomy:
Located in sella turcica of sphenoid bone, closely
related to cavernous sinus (carotid artery, CN III, IV,
V, VI), optic chiasm, hypothalamus, third ventricle.
i: Moore KL, Dalley AF. Clinically Oriented Anatomy. 5th ed. Baltimore: Lippincott
Williams & Wilkins; 2005.
Anterior lobe:
Larger lobe, embryologocally derived from
pharyngeal Rathke‟s pouch.
No direct blood supply, only portal vessels from
capillaries of hypothalamus and posterior pituitary as
part of hypophyseal portal system.
Hormonal control by releasing/inhibiting factors
from hypothalamus via hypophyseal portal system
and negative feedback from target organs.
Produces FSH, LH, ACTH, TSH, PRL, GH.
Posterior lobe:
Smaller lobe, embryological outpouching from floor
of third ventricle, neural connection persists in life.
Produces vasopression/ADH and oxytocin which are
stored in secretory granules.
Clinical syndromes from pituitary dysfunction:
HORMONE PITUITARY
HYPERSECTION
(hyperplasia,
neoplasia, etc.)
PITUITARY
HYPOSECRETION
(surgery, ischaemia,
inflammation, etc)
GH Acromegaly
Gigantism
Dwarfism
PRL Amenorrhea
Galactorrhoea
Impotence
ACTH Cushing‟s disease Hypoadrenalism
FSH, LH Silent.
May have menstrual
irregularities
May have testicular
enlargement
Hypogonadism
TSH Hyperthyroidism Hypothyroidism
Plurihormonal Panhypopituitism
(Simmond‟s disease)
ADH Syndrome of
Inappropriate ADH
secretion (SIADH)
Diabetes insipidus
Hypopituitarism1,2,6
Definition
Deficiency of one or more pituitary hormones.
Presentation
GH deficiency (childhood): failure to thrive, short stature
GH deficiency (adulthood): insulin resistance, obesity,
hyperlipidemia, hypertension
FSH, LH deficiency (childhood): failure of puberty (absent
facial or pubic hair, testicular atrophy)
FSH, LH deficiency (adult): Infertility, amenorrhea, erectile
dysfunction, loss of libido, testicular atrophy, breast atrophy
ACTH deficiency: hypoglycaemia, hypotension, vomiting,
fatigue, weakness, dizziness
TSH deficiency: weight gain, intolerance to cold,
constipation, dry skin and hair, ↑ relaxation phase of tendon
reflexes
ADH deficiency: polyuria, nocturia
Other: headache, visual defects (e.g. diplopia)
PRL: Galactorrhoea, gynaecomastia (unlike other hormones
which receive releasing factors from hypothalamus,
dopamine inhibits PRL, thus stalk compression results in
↑PRL secretion)
Investigations
Test each hormone separately for secondary hypofunction
ACTH: ↓Serum morning cortisol (<3mgc/dL),
inappropriately ↓/N ACTH, inadequate cortisol response on
cosyntropin/tetraconsactide stimulation test
TSH: ↓ serum T4 and T3, inappropriately N/↓ TSH
LH, FSH (male): ↓Total morning testosterone, N/↓ LH, FSH
LH, FSH (female): Oestradiol, N/↓ LH, FSH
GH: ↓ serum IGF-1, ↓ response to arginine-GHRH
stimulation
PRL: ↑/N
Other
U&Es: ↑Na (diabetes inspidus), ↓Na (ACTH deficiency)
Imaging:
MRI pituitary: sellar or parasellar lesion
CT pituitary: Calcification in craniopharyngioma
Management
Treat any correctable underlying cause (e.g. surgery)
Hormone replacement
ACTH deficiency: po/IV/IM corticosteroids
TSH deficiency: Levothyroxine
LH, FSH deficiency (female): oestrogen, progesterone
LH, FSH deficiency (female): urofollitropin, human
chorionic gonadotropin/hCG (preserves fertility)
LH, FSH deficiency (male): testosterone, hCG
GH deficiency: recombinant human growth hormone
ADH deficiency: desmopressin
Aetiology
Neoplastic: pituitary adenoma, craniopahrygioma
Vascular: pituitary apoplexy (haemorrhage/infarction of
adenoma), Sheehan‟s syndrome (postpartum haemorrhage
resulting in pituitary infarction), intrasellar carotid aneurysm,
subarachnoid haemorrhage, ischaemic stroke
Infiltrative: lymphocytic hypophysitis, haemochromatosis,
sarcoidosis, histiocytosis X, TB
Congenital: transcription factors PROP1 (most common),
Pit-1, HESX1, LHX3, LHX4
Iatrogenic: Radiotherapy, pituitary surgery
Traumatic: traumatic brain injury
Other: Empty sellar syndrome
Hypothalamic: Mass lesion, radiation
Diabetes insipidus (central)1,2,9
Definition
Central diabetes insipidus is insufficiency of
antidiuretic hormone/ADH/vasopressin from
dysfunction in the hypothalamic-pituitary axis
Results in inability to concentrate urine resulting in
dilute urine, dehydration and hypernatremia.
Nephrogenic diabetes inspidus is inability of kidney
to concentrate urine in presence of ADH.
Presentation
Symptoms of dehydration:
Polyuria (most common presenting symptom),
nocturia polydipsia, shock
Symptoms of hypernatremia:
Irritability, restlessness, spasticity, lethargy
Signs of severe hypernatremia:
Delirium, seizures, coma
Aetiological symptoms:
Sensorineural deafness (Wolfram‟s syndrome)
Focal motor defects (lesions, head injury, infection)
Ophthlalmic defects (pituitary lesion)
Examination
Dehydration:
Dry mucous membranes, poor skin turgor,
tachycardia, hypotension
Hypernatremia:
Hyperreflexia
Investigations
Urine osmolality: ↓ <300mOsm/kg
Predicted serum osmolality: N/↑
Serum sodium: N/↑
Urine dipstick (rule out DM): no glycosuria, ketones
24 hr urine: ↑ hypotonic urine (may be >3->20L)
Water deprivation test (confirms DI): urine
osmolality < serum osmolality after fluid deprivation
for 8 hours/5% of body weight lost
AVP desmopressin stimulation test (differentiates
central and nephrogenic DI by stimulation with
synthetic vasopressin): central DI >50% increase in
urine osmolality post-desmopression, nephrogenic
DI <50% increase in urine osmolality post-
desmopression
Management
Correct hypernatremia: Oral/IV fluids (hypotonic
5% dextrose/0.45% sodium chloride), repeated
U&Es
Desmopressin: Oral/IV DDAVP with titration from
low dose to target dose.
Aetiology
Idiopathic (30-50%)
Hypophyseal stalk trauma (trans-sphenoidal pituitary
surgery, post-traumatic head injury)
Hypophyseal stalk lesion (infiltrative conditions,
mets)
Congenital (pituitary, hypothalamus)
IC neoplasm (craniopharyngioma, pituitary
adenoma)
CVA (subarachnoid haemorrhage of anterior
communicating artery)
Infection (meningitis, encephalitis)
Auto-immune
Familial (Wolfram syndrome/DIDMOAD)
Drugs (Phenytoin)
Hypercalcaemia Measurements7
Ionised calcium: N: 1.12-1.32 mmol/L. The level of free, ionized calcium in the serum.
Total calcium: N: 2.15-2.60 mmol/L. The sum of free and bound calcium in the serum.
Adjusted calcium: Total calcium, adjusted for albumin due to albumin binding of calcium where
hypoalbuminemia would result in falsely high calcium and vice versa.
Differentials1,6
PTH dependent causes
Primary hyperparathyroidism (PHPT) (most common)
o ↑ PTH results in ↑ bone
resorption, ↑ renal calcium absorption,
↑ vitamin D activation which all act
to increase serum calcium
o Causes include:
Parathyroid hyperplasia
Parathyroid neoplasia
MEN I or MEN IIa
Familial
Tertiary hyperparathyroidism
o Renal failure is the most common cause where
persistent ↑phosphate and ↓vitamin D results
in ↑ PTH
Drugs
o Lithium (calibrates PTH release set point to
higher serum calcium concentration resulting in
inappropriately ↑PTH release)
Familial hypocalciuric hypercalcemia (FHH)
o Genetic mutation in CASR gene
Presentation6
Mild (2.6-3.0 mmol/L): Asymptomatic or have non-specific
symptoms (constipation, fatigue, depression).
Acute moderate (3.0-3.5 mmol/L): Marked symptoms
Chronic moderate (3.0-3.5 mmol/L): May be tolerated
Severe (>3.5 mmol/L): Marked symptoms→ to coma.
Musculoskeletal:
Muscle weakness
Bone pain
Osteopenia/osteoporosis
Neurological:
Confusion
Fatigue
Poor concentration
Stupor
Coma
Cardiovascular:
Short QT interval
Bradycardia
Hypertension
Investigations1
Bloods
Hypercalcemia Calcium Phosphate PTH
PHPT ↑ ↓ ↑
Malignancy ↑ N ↓
Serum total calcium: >2.63 mmol/L
Ionised calcium: >1.4mmol/L
Adjusted calcium: ↓ total calcium by 0.2mmol/L for
every 1g/L ↑ in albumin above normal.
Always do:
Calcium, phosphate, PTH, ionized calcium, albumin,
adjusted calcium
Consider:
LFTs, U&Es, Vitamin D, PTHrP
Fasting morning spot urine calcium
(Spot urine Ca/urine Cr) x serum Cr = <30umolL GFR in FHH
24 hour urine calcium creatinine clearance ratio
(24 hour urine Ca/urine serum Ca) x (serum Cr/urine Cr) = <0.01
in FHH, >0.02 in PHPT
Serum and urine electrophoresis
Bence-Jones protein in multiple myeloma
Imaging
Renal U/S (renal calculi: 90% visible on imaging)
DEXA scan (BMD T score for osteoporosis)
T/L spine x-ray (pathological fractures)
Algorithm:
1. Measure calcium: ↑ = hypercalcemia
2. Measure PTH:
3. ↑/N PTH: check 24 hour urine calcium ratio (↓ = FHH, ↑N =
hyperparathyroidism)
4. ↓ PTH: assess for malignancy
5. Assess for other endocrine disease (adrenal, thyroid, etc.)
Definition1
↑ calcium in the serum: total
calcium >2.63mmol/L
Non-PTH dependent causes
Malignancy (most common)
o Bony metastases resulting in lytic lesions
o Production of humoral agents (PTHrP)
Multiple myeloma
o ↑ osteoclast activity
Drugs
o Thiazides (↓ renal calcium excretion)
o Calcitriol (active form of vitamin D which acts to
increase serum calcium)
o Antacids (calcium carbonate, resulting in Milk-Alkali
syndrome – hypercalcemia, metabolic acidosis, renal
insufficiency)
Hyperthyroidism
o ↑ bone remodeling
Hypoadrenalism
o Loss of calcium excretion in urine
Vitamin D intoxication
o ↑calcium reabsorption and bone resorption
Vitamin A intoxication
o ↑ bone resorption
Granulomatous disease (sarcoidosis, tuberculosis)
o Results in activation of Vitamin D
Paget‟s disease of the bone
Immobilization
o Abnormal bone remodeling
Renal:
Polydipsia
Nephrolithiasis
Nephrocalcinosis
Distal renal tubular acidosis
Diabetes insipidus
Renal insufficiency
Gastrointestinal:
Anorexia
Nausea and vomiting
Constipation, hypomotility
Pancreatitis
Peptic ulcer disease
Examination6
Typically non-specific findings
Altered mental state (confusion, stupor, coma)
Hypertension
Dehydration (↓ skin turgor, ↓ capillary refill, dry
mucous membranes, etc.)
Features of underlying disease (cancer, etc.)
Rarely
Band keratopathy (subepithelial corneal calcium
phosphate deposits) seen on slit-lamp examination
Pathophysiology1
Calcium exists in the body
primarily in the skeleton (98%).
Serum calcium (2%) is either
bound, typically to albumin
(50%) or free ionized (50%).
Calcium homeostasis is tightly
regulated by three hormones:
Parathyroid hormone
o Produced in
parathyroid glands
o Increases serum
calcium and decreases
serum phosphate
Calcitriol (active 1,25,-OH2
Vitamin D)
o Produced in the
proximal tubules of
the kidneys
o Increases serum
calcium and increases
serum phosphate
Calcitonin
o Produced in
parafollicular C cells
of thyroid gland
o Decreases serum
calcium and decreases
serum phosphate (only
active in
hypercalcemia)
Acute management1,6
Asymptomatic or mild hypercalcemia:
No treatment is required.
Markedly symptomatic hypercalcemia or hypercalcemia >3.5 mmol/: requires IV hydration, bisphosphonates, (calcitonin).
IV hydration
Iso-osmotic fluid (normal saline)
Corrects volume depletion due to renal salt wasting, vomiting and prevents further hypovolemic-induced hypercalcemia
due to ↑ renal excretion of calcium.
Correct only to euvolemia as fluid overload may occur due to underlying renal, cardiac failure.
Biphosphonates
Decreases serum calcium by decreasing bone resorption
E.g. IV Zoledronic acid (most rapid and potent), IV Pamidronate,
Calcitonin (rarely used now)
Decreases serum calcium by increasing renal calcium excretion and decreasing bone resorption
Faster onset of action than bisphosphonates but effect only lasts 48 hours.
Loop diuretic
Traditionally used to increase calcium excretion
Now typically only used where fluid overload from IV hydration is suspected
Investigate and treat cause
Other treatments may include:
Gallium nitrate
Decreases serum calcium by decreasing calcitriol production in patients with granulomatous disease, lymphoma
Glucocorticoids
Decreases serum calcium by inhibiting bone resorption in PTHrP and non-PTHrP malignancy
Algorithm for investigation of hypercalcemia
j: Shane E. Diagnostic approach to hypercalcemia. In: Rosen CJ, Mulder JE, editors. UpToDate. Waltham: UpToDate; 2010.
Hyperlipidemia
Examination1,2,10
General
Large/overweight body habitus (esp central obesity)
Hypertriglyceridemia
Lipaemia retinalis (pale retina and white retinal vessels on
ophthalmoscopy)
Eruptive xanthoma
o Papules on pressure areas (elbows, buttocks) from
chylomicron deposition in cutaneous tissue histeocytes
Hypercholesterolaemia
Xanthelasma (yellow plaque at inner canthus of eye)
Tendinous xanthomas (subcutaneous nodules causing
thickening on tendons, ligaments, typically Achilles)
Corneal arcus (white ring around corneal margin of eye,
pathological in <45 years, senile arcus may be normal >45)
Tuberous xanthomas (firm, painless, red-yellow nodules in
pressure areas, extensor surfaces– knees, elbows, buttocks)
Presentation1,2,10
Hyperlipidemia is typically asymptomatic.
History taking should include:
Past medical history
Obesity
Insulin resistance/diabetes mellitus
Cardiovascular disease (coronary artery
disease/coronary heart disease, angina, intermittent
claudication)
Hypothyroidism
Liver disease
Renal disease
Medications
Thiazides
Glucocorticoids
Oestrogens
Family history
Early onset coronary heart disease
Early onset hyperlipidemia
Social history
Diet (high in saturated and trans fat, cholesterol)
Exercise
Alcohol
Smoking
Typical presentation of familial hypercholesterolaemia
Heterozygous
o Symptoms (Achilles xanthomas, coronary
artery disease, etc) present in adulthood
typically >20-30 years
Homozygous
o Symptoms (xanthomas, atherosclerosis, etc)
present in childhood
Differentials1,2,10
Obstructive liver disease Nephrotic syndrome
Renal insufficiency Hypothyroidism
Diabetes
Investigations7
Lipid profile
Fasting sample, plasma (preferred) or serum
Normal values (Pathwest)
TC: <5.5mmol/L
HDL-C: >1.0mmol/L
TG: <2.0mmol/L
LDL-C (NHFA target): <2.0mmol/L
LDL-C (low risk): <3.0mmol/L
LDL-C (high risk): >4.0mmol/L
Chol/HDL ratio (below average risk): <3.0
Chol/HDL ratio (average risk): 3.0-5.0
Chol/HDL ratio (above average risk): >9.0
Hypertriglyceridemia: ↑TG
Hypercholesterolaemia: ↑LDL, ↑TC, ↓HDL, ↑Chol/HDL
Aetiological investigation for secondary causes
Fasting blood glucose levels
Thyroid function tests
Liver function tests
Renal function tests
Management1,10
k: Burnett JR. Lipids and Lipoproteins [unpublished lecture notes]. University of Western
Australia; notes provided at lecture given 2011 Jul.
Lifestyle modification
Smoking cessation, weight loss, dietary modification
(decrease in total fat to 25-35%, decrease in saturated fat to
<75%, decrease in trans fat to <1% of total daily intake,
addition of plant sterols), aerobic exercise
Medications
Statins (HMG CoA Reductase inhibitors) recommended
for all patients with coronary heart disease unless
contraindicated Efficacy Tolerability
1st line Statins Statins
2nd line Nicotinic acid and/or
bile acid sequestrants
Ezetimibe
3rd line Fibrates Fibrates
4th line Ezetimibe Nicotinic acid and/or bile acid
sequestrants
Lipid goals
LDL-C <2.0mmol/L
HLD-C >1.0mmol/L
TG <1.5mmol/L
Classifications/subtypes1,2,10
Dyslipidemia: Serum total cholesterol, LDL cholesterol, trigylercides, apolipoprotein B or lipoprotein A concentration
>90th
percentile or HDL cholesterol or apolipoprotein A-I concentration <10th
percentile.
Hypercholesterolaemia: Raised serum total and/or LDL cholesterol.
Hypertriglyceridemia: Raised trigylcerides.
Familial hypercholesterolaemia: Significant raised total and LDL cholesterol in the presence of normal triglycerides due
to a genetic mutation/s. Can be heterozygous or homozygous.
Anabolic steroids
Atypical anti-psychotics
Anti-retrovirals
Aetiology1,2
Risk factors for hypertriglyceridemia:
Family history of hyperlipidemia
Family history of diabetes
Overweight/obesity
Diet high in saturated fat, carbohydrates
Insulin resistance
NASH
Hypothyroidism
Nephrotic syndrome
Chronic renal failure
Excessive alcohol use
Anti-retroviral therapy (e.g. HIV)
Cystic fibrosis
Drugs (glucocorticoids, oestrogens,
hydrochlorothiazide, non-selective beta
blockers, anti-retrovirals, interferons, Tamoxifen)
Cushing‟s syndrome
Sarcoidosis
SLE, Myeloma
Pathophysiology2,9
Lipid metabolism
l: Pinniger G. Plasma Lipoproteins [unpublished lecture notes]. University of Western Australia; notes provided at
lecture given 2009 Mar.
Disease process
Hypercholestserolaemia results from elevated LDL
Elevated LDL causes downregulation of LDL receptors in the liver
resulting in decreased LDL catabolism and increased LDL in the
circulation
LDL in the circulation is oxidized
Oxidised LDL is then taken up by macrophages to create foam cells
Foam cells can progress to form atherosclerotic plaques which can
o Damage to the endothelial surface
o Promote thrombus formation
o Embolise to distant sites
o Cause narrowing of blood vessel lumen occluding blood flow
Epidemiology11
50% (>6 million) of
Australians >25 have blood
total cholesterol levels
>5.5mmol/L
7% (1.3 million) of Australians
self-report high blood
cholesterol
High cholesterol is the 10th
most commonly reported
condition (6%) in males and
15th
most common (5.4%) in
females in 2007-8
Peak high cholesterol in males
aged 55-64 and females aged
65-74
Risk factors for hypercholesterolemia:
Family history of familial hypercholesterolaemia
Insulin resistance
Overweight BMI >25
Hypothyroidism
Cholestatic liver disease
Cigarette smoking
Nephrotic syndrome
Drugs (thiazides, oestrogens, glucocorticoids, anabolic
steroids, atypical anti-psychotics (Olanzapine,
Clozapine), protease inhibitors, isotrentinoin)
Familial hypercholesterolaemia
Autosomal dominant mutation to LDL receptor
o Heterozygous (He-FH): mutation to part of
LDL receptor genes resulting in impaired
activity resulting in elevated LDL
o Homozygous (Ho-FH): mutation to LDL
receptor gene resulting in absence of LDL
receptor and total loss of function resulting in
markedly elevated LDL
Reference List: Endocrine
References
1. DynaMed Editorial Team. [See title of relevant document] [Internet]. Ipswich (MA): Ebsco Publishing; 2011 [cited 2011 Jun].
Available from: DynaMed
2. BMJ Editorial Team. [See title of relevant document] [Internet]. BMJ Evidence Centre: BMJ Publishing Group Limited; 2011 [cited
2011 Jun]. Available from: BestPractice
3. Matthews J, Sanders A. Demystifying the annual cycle of care: The importance of the annual cycle of care in diabetes management
[Internet]. Buranda, QLD (Australia): The Royal Australian College of General Practioners; 2009 [updated 2009 Jul; cited 2011 Aug
26]. Available from: http://www.racgp.org.au/2009GPReview/July/072009annualcycleofcare.p
4. Australian Institute of Health and Welfare. Australia‟s Health 2010 [Internet]. 2010 [cited 2011 Aug 26]; AIHW cat. no. AUS 122.
Available from: http://www.aihw.gov.au/publication-detail/?id=6442468376&tab=2
5. Australian Institute of Health and Welfare. Diabetes: Australian facts 2008 [Internet]. 2008 [cited 2011 Aug 26]; AIHW cat. no.
CVD 40. Available from: http://www.aihw.gov.au/publication-detail/?id=6442468075
6. UpToDate Editorial Team. [See title of relevant document] [Internet]. Waltham (MA): UpToDate, Inc; 2011 [cited 2011 Jun].
Available from: UpToDate.
7. PathWest. Laboratory Reference Intervals: For Biochemistry, Haematology, Immunology and Toxicology [Internet]. Nedlands, WA
(Australia): 2007 [updated 2007 Nov; cited 2011 Aug 26]. Available from:
http://www.pathwest.com.au/pdf/2007%20Reference%20Range%20Book%20Nov%202007.pdf
8. Government of Western Australia Department of Health. Diagnostic Imaging Pathways – Goitre [Internet]. East Perth, WA
(Australia): Government of Western Australia Department of Health; 2009 [updated 2009 Sep; cited 2011 Aug 26]. Available from:
http://www.imagingpathways.health.wa.gov.au/includes/dipmenu/goitre/chart.html
9. Medscape (US). [See title of relevant document] [Internet]. New York, NY: WebMD LCC; 2011 [updated 2011; cited 2011 Jun].
Available from: http://emedicine.medscape.com/
10. Heart Foundation (AU). Reducing Risk in Heart Disease 2007 [Internet]. Deakin, ACT (Australia): Heart Foundation (AU); 2007
[updated 2008; cited 2011 Aug 26]. Available from: http://www.heartfoundation.org.au/SiteCollectionDocuments/Reducing-risk-
heart-disease-summary.pdf
11. Australian Institute of Health and Welfare. Australia‟s Health 2010 [Internet]. 2010 [cited 2011 Aug 26]; AIHW cat. no. AUS 122.
Available from: http://www.aihw.gov.au/publication-detail/?id=6442468376&tab=2
Figures
a. Adapted from: Colagiuri R, Colagiuri S, Dickinson S, Girgis S. National Evidence Based Guideline forBlood Glucose Control in
Type 2 Diabetes. Canberra: Diabetes Australia and the NHMRC; 2009.
b. Joyce DA. Thyroid and Anti-Thyroid Drugs [unpublished lecture notes]. University of Western Australia; notes provided at lecture
given 2010 Sep 24.
c. Government of Western Australia Department of Health. Diagnostic Imaging Pathways – Hyperthyroidism [Internet]. East Perth,
WA (Australia): 2009 [updated 2009 Sep; cited 2011 Aug 26]. Available from:
http://www.imagingpathways.health.wa.gov.au/includes/dipmenu/hyperthy/chart.html
d. Brandt E. Thyroid Hormone Replacement Therapy [Internet]. Victoria, BC (Canada): Rinfocan – Prescription Drug Information for
Canadians; 2011 [cited 2011 Aug 26]. Available from: http://www.druginformation.bc.ca/thyroid.htm
e. Hill RN, Crisp TM, Hurley PM, Rosenthal SL, Singh DV. Risk Assessment of Thyroid Follicular Cell Tumours. Environ Health
Perspect. 1998 Aug;106(8):447-57.
f. Joyce DA. Thyroid and Anti-Thyroid Drugs [unpublished lecture notes]. University of Western Australia; notes provided at lecture
given 2010 Sep 24.
g. Nieman LK. Trying to establish the diagnosis of Cushing‟s syndrome. In: Lacroix A, Martin KA, editors. UpToDate. Waltham:
UpToDate; 2008.
h. Nieman LK. Diagnostic approach to suspected adrenal insufficiency. In: Lacroix A, Martin KA, editors. UpToDate. Waltham:
UpToDate; 2011.
i. Moore KL, Dalley AF. Clinically Oriented Anatomy. 5th ed. Baltimore: Lippincott Williams & Wilkins; 2005.
j. Shane E. Diagnostic approach to hypercalcemia. In: Rosen CJ, Mulder JE, editors. UpToDate. Waltham: UpToDate; 2010.
k. Burnett JR. Lipids and Lipoproteins [unpublished lecture notes]. University of Western Australia; notes provided at lecture given
2011 Jul.
l. Pinniger G. Plasma Lipoproteins [unpublished lecture notes]. University of Western Australia; notes provided at lecture given 2009
Mar.