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.