Endocrine Flashcards
What are the 3 main classes of hormones?
Glyoproteins and peptides (amino acid chains of variable length)
Steroids (derived from cholesterol)
Tyrosine and Tryptophan (Amine) derivatives
Give an example of a glycoprotein or peptide
Oxytocin
Insulin
Give an example of a steroid
Cortisol
Testosterone
Give an example of a Tyrosine or Tryptophan derivative
Adrenaline
Thyroid hormones
Melatonin
How are amines synthesised, stored and released?
Pre-synthesised
Stored in vesicles
Released in response to Ca2+ dependant exocytosis
How are peptides and proteins synthesised, stored and released?
Pre-synthesised (usually from a longer precursor)
Stored in vesicles
Released in response to Ca2+ dependant exocytosis
How are steroids synthesised?
Synthesised and secreted upon demand
What increases steroid synthesis and secretion?
cellular uptake and availability of cholesterol
rate of conversion of cholesterol to pregnenolone
What type of hormone is not transported freely in plasma and relies on carrier proteins?
Steroids (+thyroxine)
As well as increasing the amount transported, what other effect do carrier proteins have with steroids?
Prevent Filtration at the kidney
What is CBG?
Cortisol-binding globulin
What is TBG?
Thyroxine-binding globulin
What is SSBG?
Sex steroid-binding globulin (testosterone and oestrodiol)
Name 2 general carrier proteins
Albumin
Transthyretin
What are the 3 classes of hormone receptors?
GPCRs
Receptor Kinases
Nuclear Receptors
What are GPCRs activated by?
amines and some proteins/peptides
Give an example of a receptor kinase
Insulin receptor
Name the 3 classes of nuclear receptor and give an example of which each can be activated by
Class 1 - steroid hormones
Class 2 - Lipids
Hybrid Class - T3
What do alpha cells in pancreatic islets do?
secrete glucagon
What do beta cells in pancreatic islets do?
secrete insulin
What do delta cells in pancreatic islets do?
secrete somatostatin
What do PP cells in pancreatic islets do?
secrete pancreatic polypeptide
Where in the beta cells in insulin formed
RER
Apart from an insulin molecule, what other 2 components make up a molecule of prepoinsulin
signal peptide
C-peptide
How many phases does insulin release occur in? How long does each phase last for?
2
1st phase = 10-15minutes
2nd phase = 1-2 hours
What is KATP inhibited by (drug)
Sulphonylureas
Give examples of sulphonylureas
tolbutamide
glibenclamide
What is KATP stimulated by
Diazoxide
What other function does Diazoxide do? (Other than KATP stimulation)
Inhibits insulin secretion
A mutation in which protein of the KATP channel can lead to neonatal diabetes?
Kir6.2
What are the 2 proteins of the KATP channels?
Kir6.2 and SUR1
What does MODY stand for?
Maturity Onset Diabetes of the Young
What is MODY?
Monogenic diabetes with a genetic defect in beta cell function
In MODY, what can a glucokinase mutation cause?
BG threshold for insulin increases
MODY is not best treated with insulin in most cases, what other drug class is better indicated in MODY?
Sulphonylureas
Define Type 1 Diabetes
Loss of insulin secreting beta cells
Define Type 2 diabetes
Initially hyperglycaemia with hyperinsulinaemia.
Decreased insulin sensitivity in the tissues.
What is the insulin receptor?
Dimeric tyrosine kinase
What is the insulin receptor made up of?
2 extracellular alpha subunits
2 transmembrane beta subunits
alpha and beta subunits linked by disulphide bonds
Insulin binds to the alpha subunits of the receptor, what does this cause the beta subunits to do?
autophosphorylate to activate the receptors catalytic activity
Name 3 biological effects of insulin
Amino acid uptake in muscles DNA synthesis Protein synthesis glucose uptake in muscle and adipose tissue lipogenesis in adipose tissue and the liver glycogen synthesis in liver and muscle gene expression lipolysis gluconeogenesis in the liver
What are the causes and symptoms of Leprechaunism (Donohue Syndrome)?
Caused by a rare, autosomal recessive genetic trait causing mutations in the gene for the insulin receptor.
Causes severe insulin resistance and developmental abnormalities.
What is the cause and the symptoms of Rabson-Mendenhall syndrome?
Rare, autosomal recessive genetic trait causing severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia, developmental abnormalities and more.
Where are ketone bodies formed?
Liver mitochondria
Is ketoacidosis more associated with type 1 or type 2 diabetes?
Type 1
Define Diabetes mellitus (DM)
A group of metabolic diseases characterised by hyperglycaemia, resulting from defects in insulin secretion, insulin action or both.
What is the HbA1c diagnostic criteria for DM?
above 48mmol/mol
What is the fasting glucose diagnostic criteria for DM?
above 7mmol/l
What is the random glucose diagnostic criteria for DM?
above 11.1mmol/l
Give 2 tests used to descriminate between T1DM and T2DM
GAD/anti-islet cell antibodies (T1DM)
Ketones (T1DM)
What does LADA stand for in an endocrine setting?
Latent Autoimmune Diabetes of Adulthood
What is monogenic diabetes? Give 2 examples of types of diabetes in which this can occur
When diabetes is caused by a mutation in a single gene.
MODY and Neonatal diabetes can be monogenic
If a mother has T2DM, what is the chance that her daughter will develop it at some point in her life? (%)
40%
What percentage of T2DM patients are overweight or obese?
90%
As well as being overweight, what other factor must an individual have to develop T2DM?
vulnerable beta cells
As well as insulin resistance and T2DM, what other factors must a person have 2 of before they are considered to have metabolic syndrome?
Dyslipidaemia
Hypertension
Obesity
Microalbuminuria
What is the 1st line treatment for an overweight individual with T2DM?
Metformin
What is the 1st line treatment for an individual of normal weight with T2DM?
Sulphonylureas
Give an example of a thiazolidinedione used in T2DM
Pioglitazone
When is pioglitazone contraindicated?
Heart Failure
If oral therapy is ineffective, or if the HbA1c is deemed to high to justify adding another oral drug, what treatment is used in T2DM?
Insulin
What HbA1c % is aimed for to decrease risk of complications?
less than 7%
Monitoring of BG is not necessary in all T2DM patients. What 2 drugs indicate BG monitoring?
Insulin + Sulphonylureas
What is the target BP for diabetics?
less than = 130/80mmHg
As well as BG and BP levels, what else should be well controlled in diabetics over 40? And what should be used to control it?
Cholesterol
Simvastatin 40mg
Atorvastatin 10mg
What is the usual staring dose for metformin?
500mg od or bd
What are the main effects of metformin? (4 things)
HbA1c decreased by 15-20mmol/mol
Weight decrease
Prevention of micro and macro vascular complications
Decreased Triglycerides and LDL
Is metformin safe in pregnancy?
Yes
What are the adverse effects of metformin?
GI disturbances
Anaemia - rare
Lactic acidosis - very rare
Liver failure - discontinue if this occurs
What effect does eGFR have on the dose of metformin given?
less than 30ml/min = discontinue drug
30-45ml/min = half dose
Give the names of (and standard doses) of the 3 sulphonylureas which can be given in T2DM
Glicazide (40mg od - 160mg bd)
Glibenclamide (5mg-15mg od)
Glimepiride (1mg-6mg od)
What do sulphonylureas do on the cellular level?
Close the KATP channel, and stimulate insulin release
How much do sulphonylureas generally reduce the HbA1c by?
15-20mmol/mol
Do sulphonylureas prevent macro or micro vascular complications?
Micro
What are the adverse effects of sulphonylureas
Hypoglycaemia
Weight gain
GI disturbances
Headache
What is the standard dose range for pioglitazone?
15-45mg od
What effects does pioglitazone have on a T2DM patient?
HbA1c reduced by 15-20mmol/mol
Improvement in microalbuminurea
Reduced end point mortality
What are the adverse effects of pioglitazone?
Hypoglycaemia (unusual unless in combination with a SU)
Increase in weight
Increased risk of hospital admission with HF
Does not prevent micro or macrovascular complications
Increase hip fracture risk by 20% per year of use
What T2DM therapies work by increasing secretion of insulin?
SUs
GLP-1 analogues
Glinides
DPP-4 inhibitors
What T2DM therapies work by decreasing insulin resistance and decreasing hepatic glucose output?
Biguanides
Thiazolidinediones
What T2DM therapy works by slowing glucose absorption from the GI tract?
alpha-glucosidase inhibitors
What T2DM therapy works by enhancing glucose excretion from the kidney?
SGLT2 inhibitors
What T2DM therapies work via insulin independent actions?
alpha-glucosidase inhibitors and SGLT2 inhibitors
If BG levels rise, what does GLUT2 facilitate?
Increased diffusion of glutamide into beta cells
What is it that stimulates insulin secretion from a cell?
Opening of voltage-activated Ca2+ channels, increasing the level of intracellular calcium
What is formed by a tetramer of Kir6.2 subunits?
Potassium selective ion channel
What causes the opening of the voltage activated Ca2+ channels
Membrane depolarisation from closed KATP channels
How do SUs interact with the KATP channels?
They displace ADP-Mg2+ from the SUR1 subunit, which closes the KATP channel, thus causing insulin secretion independent to BG levels.
Give 2 examples of glinides (meglitinides)
Repaglinide
Nateglinide
What drug class do glinides work similarly to? and how do they differ?
Work similarly to SUs, but act at a distant site to the SUR1 subunit.
They are also less likely to cause severe hypos
What stimulates GLP-1 secretion in an individual?
Ingestion of food
Where is GLP-1 released from?
Enteroendocrine cells in the small intestine (L + K cells)
What effects does GLP-1 have on the pancreatic cells?
Enhance insulin release from beta cells
Decrease glucagon release from alpha cells
What is the main GLP-1 analogue in theraptutic use? why does it differ from the normal physiological response?
Exenatide
The effects last for longer thus lowering BG more steadily
What other beneficial effects do GLP-1 analogues have on the T2DM patient?
Slows gastric emptying and decreases apetite
What new longer acting GLP-1 analogue now exists? How is it given?
Liraglutide
od subcut. injection
What terminates the effects of GLP-1?
DPP-4
How do gliptins (DPP4-inhibitors) work?
Competitively inhibit DPP-4, prolonging the effects of GLP-1
What is the main gliptin agent used? (And what other agents can be used?)
Sitagliptin - orally od
Saxigliptin and vildagliptin
What is the alpha-glucosidase inhibitor in theraputic use?
Acarbose
What is alpha-glucosidase?
A brush border enzyme which breaks down starch and disaccharides to absorbable glucose
What does acarbose do?
Inhibits alpha-glucosidase thus reducing the postparandial (after meal) increase in glucose.
When in acarbose used?
When lifestyle changes and other oral agents are not effective in HbA1c and BG control
What are the adverse effects of acarbose?
GI disturbances and infections
How do biguanides (metformin) work?
Reduce hepatic gluconeogenesis - stimulates AMPK
Increases glucose uptake and utilisation by skeletal muscle
Decreases carbohydrate absorption
Increases fatty acid oxidation
What are TZDs (Glitazones)
Exogenous agonists of PPAR-alpha which associates with RXR
What do TZDs do?
Enhance the action of insulin at target tissues (decrease the amount of insulin needed to maintain a given BG)
Promote fatty acid uptake and storage in adipocytes rather than skeletal muscle and the liver
Decreases the hepatic glucose output
Give an example of a TZD
Pioglitazone
What do SGLT2 inhibitors do?
Selectively block reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron, deliberately causing glucosuria
What other benefit do SGLT2 inhibitors have?
Cause calorific loss and weight loss - glucose voided
What is the currently licensed SGLT2 inhibitor?
Dapagliflozin
What are the highest risk HLA genotypes with development of T1DM? What percentage of T1DM patients have one of these?
DR3-DQ2/DR4-DQ8
95% of patients less than 30 have 1 or both
What autoantibodies are associated with some development in T1DM?
GAD (glutamic acid decarboxylase)
Insulin (IAA)
IA2 (Islet-antigen 2)
ZnT8 (Zinc transporter)
What is the classic triad of symptoms in T1DM?
Polyuria
Polydipsia
Weight loss
What symptoms other than the classic triad can present in T1DM?
Fatigue
Blurry vision
Candidial infection
DKA
Where is insulin secreted into?
Portal vein
When fasting, what is the rate of insulin secretion?
0.25-1.5 units per hour
What type of diabetes are children <6months likely to have?
Monogenic (Neonatal)
How is LADA diagnosed?
Presence of increased pancreatic autoantibody levels in patients with recently diagnosed diabetes not needing immediate insulin therapy
Name 3 conditions associated with diabetes
Cystic fibrosis (25% have DM) DIDMOAD Bardet-Biedl syndrome Addisons disease Thyroid disease Coeliac disease Pernicious anaemia IgA deficiency
What 2 AI conditions are very strongly associated with T1DM?
Thyroid disease (1:50 in normal population; 1:20 in T1DM) Coeliac disease (1:100 in normal population; 1:20 in T1DM)
What is polyglandular endocrinopathy?
A set of multiple endocrine gland deficiences that may or may not be AI
What is the normal age of onset of MODY?
less than 25 years
What is the best treatment for HNF1-alpha mutations?
Gliclazide (an SU)
What is the definition of neonatal diabetes?
Requires insulin treatment within first 3 months of life
What are the 2 types of neonatal diabetes and how are they defined?
Transient - diagnosed less than 1 week and resolves within 12 weeks when insulin can be stopped
Permanent - Diagnosed 0-6 weeks and requires lifelong treatment
If Permanent neonatal DM is caused by mutations in Kir6.2, what can this be treated with rather than insulin?
Glibenclamide (an SU)
What types of insulin are marketed as rapid acting? (last between 4-6 hours)
Humalog
Novorapid
Apidra
What types of insulin are marketed as short acting? (~8 hour duration)
HumulinS
Actrapid
Insuman rapid
What types of insulin are marketed as intermediate acting? (18-20 hours duration)
Humulin I
Insuman basal
What types of insulin are considered as long-acting analogues?
Lantus
Levemir
What are some of the rapid acting/ intermediate acting insulin mixes that are available?
Humalog mix 25/mix 50
NovoMix 30
What are some of the short acting/ intermediate acting insulin mixes that are available?
Humulin M3
Insumancomb 15, 25, 50
What is the advantage of a basal bolus insulin regimen?
Mimics normal endogenous insulin production
What factors can affect the absorption action of insulin?
temperature injection site injection depth exercise pen accuracy leakage
What should a patient with insulin always check for at the injection sites?
Lipohypertrophy
What is HbA1c?
Glycated haemoglobin - formed by non-enzymatic glycation of haemoglobin in exposure to glucose
What HbA1c range is diagnostic for diabetes?
> = 48mmol/mol (6.5%)
What do ketone meters measure?
3betaOH-butyrate
What are some symptoms of hypoglycaemia?
Shaking Sweating Anxiousness Dizziness Headache Irritability Hunger Tachycardia Impaired vision Weakness/fatigue
How is severe hypoglycaemia defined as?
Hypoglycaemia that leads to seizures, unconsciousness or the need for external asistance
How is hypoglycaemia treated?
Consuming 15-20g glucose or simple carbohydrates
Recheck BG and keep rechecking until normal
How would severe hypoglycaemia be treated?
Inject 1mg glucagon
What is hypoglycaemia unawareness?
When BG is 3.5-4mmol/l and the individual has no symptoms
In what groups of people is hypoglycaemic unawareness more likely to occur in?
Frequent low BG levels
Longstanding T1/T2DM
Intensively treated T1DM
In a non-diabetic what changes does the body cause when BG = 3.8mmol/l?
Glucagon and adrenaline kick in
In a non-diabetic what changes does the body cause when BG = 3.0mmol/l?
Symptoms of hypoglycaemia begin to appear
In a non-diabetic what changes does the body cause when BG = 2.8mmol/l?
Cagnitive dysfunction occurs
Why is hypoglycaemia more common in T1DM patients?
Neither insulin or glucagon is present to prevent the hypo so no corrective action can be taken by the body itself
What is DKA?
A disordered metabolic state, usually occurring in absolute or relative insulin deficiency accompanied by an increase of counter-regulatory mechanisms e.g glucagon, adrenaline, cortisol + GH.
How does DKA cause death in adults?
Hypokalaemia
Aspiration pneumonia
ARDS
How can DKA cause death in children?
Cerebral oedema
What are the main pathophysiological points that contribute to DKA?
Hyperglycaemia
Increased ketogenesis
Acidosis
Hyperosmolarity
What can trigger DKA?
Non-compliance with medication (most common)
Infections
Illicit drugs and alcohol
Newly-diagnosed diabetes (on no treatment)
What biochemistry results can be used to diagnose DKA?
Ketonaemia >3mmol/l or significant ketonuria
BG >11mmol/l or known diabetes
Bicarbinate less than 7.3 (attempt to compensate for acidosis)
What typical symptoms are associated with DKA?
Thirst, polyuria, dehydration
Flushing, vomiting, abdo pain, tenderness, breathlessness, ketones (pear drops) on breath
Other than ketones, what other biochemistry results may be raised?
Amylase + WCC
How is DKA treated?
Fluid - initially with 0.9% NaCl, then when BG falls <15, switch to 10% dextrose
Insulin
Potassium
What is the normal range for lactate?
0.6-1.2mmol/l
Where does lactate come from?
RBCs, skeletal muscle, brain and renal medulla
What causes type A lactic acidosis?
Tissue hypoxaemia
What causes type B lactic acidosis?
Liver disease
Diabetes (occurs in 10% DKA episodes)
Metformin
How does lactic acidosis present clinically?
Hyperventillation
Mental confusion
Stupor or coma if severe
How does lactic acidosis appear in biochemistry results?
Low bicarb
Increased anion gap
Glucose often high
High phosphate
How is lactic acidosis treated?
Fluids and antibiotics
Withdrawal of any causative medications
How does hyperglycaemic hyperosmolar syndrome present?
incresed refined carbohydrates before the event BG very high ~60 Significant renal impairment increased osmolarity Less ketonaemia/acidotic than DKA
How is hyperglycaemic hyperosmolar syndrome different from DKA?
More common in older T2DM patients Caused by undiagnosed DM, diuretics, steroids, fizzy drinks Often a infection predisposing event Much higher mortality More liklely to have comorbidities
How is hyperglycaemic hyperosmolar syndrome treated differently from DKA?
Fluids are given slower due to higher risk of cerebral oedema
Insulin given slower
Avoidance of rapid sodium fluctuations, may need to use 0.45% saline
LMWH
What are the main macrovascular complications of diabetes?
IHD
Stroke
What are the main microvascular complications of diabetes?
Neuropathy
Nephropathy
Retinopathy
Other than micro/macrovascular complications, what other complications can occur in diabetes?
Erectile dysfunction
Psychiatric
What are the different types of neuropathy which can occur in diabetes?
Peripheral - pain/loss of feeling in feet/hands
Autonomic - bowel/bladder function changes, hypoglycaemic unawareness
Proximal - pain in thighs, hips or buttocks
Focal - Sudden weakness in one nerve causing muscle weakness and/or pain
What symptoms may be associated with diabetic neuropathy?
Numbness, pain, tingling Ulcers Muscle wasting Indigestion, NV Dizziness Urination issues
What increases the risks of developing diabetic neuropathy?
Duration of diabetes Poor control T1DM High cholesterol Smoking/Alcohol Genetics Mechanical injuries
What are the symptoms of a distal symmetric or sensorimotor neuropathy?
Numbness Tingling/burning Sharp pains/cramps Sensitivity to touch Loss of balance/coordination
What complications may arise as a result of distal symmetric or sensorimotor neuropathy?
Infection/ulceration
Deformities (hammer toe/collapse of midfoot)
Amputations
How is painful neuropathy treated? (list with increasing amounts of pain)
Simple analgesia TCAs Gabapentin Duloxetine/Pre-gabalin Stronger opiods - oxycodone/tramadol
What topical treatment can be used for painful neuropathy?
Capsaicin cream
How can autonomic neuropathy affect the digestive system?
Gastric slowing - constipation
Gastroparesis (slow stomach emptying) - N+V, bloating and loss of appetite
Can make BG levels fluctuate greatly
Oesophageal nerve damage - swallowing is difficult
How can autonomic neuropathy affect the sweat glands?
Body temp is not regulated
May sweat profusely at night or when eating
Autonomic neuropathy may cause hypoglycaemic unawareness, what is this?
Symptoms of hypos may not occur
How can autonomic neuropathy affect the CVS?
Postural hypotension
HR may stay high despite normal body functions
How can autonomic neuropathy affect the eyes?
Pupils have decreased responsiveness to changes in light
This makes driving in the dark difficult
How can neuropathy be diagnosed?
Nerve conduction studies/EMG HR variability in response to changes to BP, stance and breathing etc. US Gastric emptying studies Foot screening once per year
What types of nephropathy may occur in diabetics?
Kimmelsteil-Wilson syndrome
Nodular GN
Angiopathy of capillaries
Between 1-5% diabetics are found to have CKD, what are the consequences of this?
Hypertension
Decline in renal function
Accelerated vascular disease
What screening program exists for diabetic nephropathy?
All patients >12 have urinary ACR testing done once a year
Dipstick testing is also done
What are the risk factors for progression on nephropathy?
Hypertension High cholesterol Poor glycaemic control Smoking Albuminuria
What should all patients with microalbuminuria/proteinuria be commenced on and why?
ACEI Dilates renal arteries Lowers filtration pressure Reduces proteinuria Reduces GFR (upto 20%)
What eye pathologies can diabetics get?
Diabetic retinopathy
Cataract
Glaucoma
Acute hyperglycaemia (visual blurring)
What do cotton wool spots suggest when seen on the fundus?
Ischaemic areas
What do hard exudates suggest when seen on the fundus?
Lipid breakdown products
What would a retinopathy of grade R0 suggest?
No diabetic retinopathy - rescreen in 12 months
What would a retinopathy of grade R1 suggest?
Background diabetic retinopathy (BDR) - rescreen in 12 months At least 1 of the following anywhere: Dot haemorrhages Microaneurysms Hard exudates >2DD Cotton wool spots Superficial/flame shaped haemorrhages
What would a retinopathy of grade R2 suggest?
BDR - >=4 blot haemorrhages in 1 hemi-field only
Rescreen in 6 months
What would a retinopathy of grade R3 suggest?
BDR with 1 of the following:
4 or more blot haemorrhages in both hemi-fields
Venous bleeding
Intra-retinal microvascular abnormalities
Refer to ophthalmology
What would a retinopathy of grade R4 suggest?
Proliferative diabetic retinopathy:
Active new vessels
Vitreous haemorrhage
Refer to ophthalmology ASAP!
What would a retinopathy of grade M1 suggest?
Lesions within a radius of >1 but <2 disc diameters(DDs) from the fovea
Rescreen in 6 months
What would a retinopathy of grade M2 suggest?
Lesions less than 1DD from the fovea
Refer to ophthalmology (does not need ASAP treatment but does need close surveillance)
What other complications can arise from diabetic retinopathy?
Secondary glaucoma
Retinal detachment
How is retinopathy treated?
Laser therapy
Vitrectomy
Anti-VEGF injections
How common is erectile dysfuction in males with diabetes?
affects 50% of diabetic men, and 55% of those >60y/o
How can erectile dysfuction caused by diabetes be treated?
improve glycaemic control/lose weight/improve lipids
Lower alcohol intake
Withdrawal of causative drugs where possible
What oral medication can be given to men with erectile dysfunction?
sildenafil (viagra)
vardenafil (levitra)
tadalafil (cialis)
What are the contraindications to taking medications for erectile dysfunction?
If the patient is on nitrates, nicorandil
Stroke/MI in past 3 months
Hypotension
Severe hepatic dysfunction
Hereditary degenerative retinal disorders
What vascular disorders does having diabetes increase the risk of?
Stroke
Peripheral vascular disease
Coronary artery disease
Why does diabetes increase the risk of developing vascular disease?
Dyslipidaemia Endothelial dysfunction Platelet aggregation Thrombogenesis Inflammation/increased oxidative stress
What psychiatric disorders can come from diabetes?
Depression
Eating disorders
Bi-polar disorder
Schizophrenia
What does the thyroid gland tissue secrete?
Thyroxine (T4)
Tri-iodothyronine (T3)
Calcitonin
What do the 4 parathyroid glands secrete?
PTH - parathyroid hormone
How does the thyroid tissue appear histologically?
Colloid-tyrosine containing thyroglobulin filled spheres enclosed by follicular cells
Surrounding the follicles lies the parafollicular C cells which secrete calcitonin
How are the thyroid hormones created and stored?
Iodine is taken up into follicle cells where it is attached to tyrosine residues on thyroglobulin to form MIT (monoiodotyrosine) and DIT (Di-iodotyrosine)
MIT+DIT = T3 2*DIT = T4
T3 and T4 are then stored in colloid thyroglobulin until required
What is T4?
Thyroxine - approx 90% of thyroid hormones secreted
Converted to T3 by the liver and kidney
What is T3?
Triiodothyronine - approx 10% of thyroid hormones secreted
4x more potent than T4
Is the major biologically active thyroid hormone
What does carbimazole and propythiouracil inhibit?
Iodine attaching to tyrosine residues to form T3 and T4
How and to where are T3 and T4 released?
TSH acts upon the follicular cell and T3T4 are secreted from the colloid, through the follicular cells, and into the blood, where T3 is turned into T4
What happens when T3 reaches its target cell?
T3 acts upon the nuclear receptors of the target cell, which then produces mRNA proteins and then a biological response.
T3 + T4 are hydrophobic/lipophilic so to be transported they must bind to plasma proteins. What are these plasma proteins?
Thyroxine binding globulin (TBG) = 70%
Thyroxine binding prealbumin (TBPA) = 20%
Albumin (5%)
T3 and T4 are only biologically active when UNBOUND from these plasma proteins
What can caused Increased TBG levels?
Pregnancy Newborns Oestrogen levels Hep A/Active hepatitis Billiary cirrhosis Genetics Heroin
What can cause decreased TBG levels?
Androgens Large doses of glucocorticoids Acromegaly Systemic illness Chronic liver disease Genetics Pheytoin, carbamzepine
How do the thyroid hormones affect BMR?
Increased number and size of mitochondria
Increased oxygen use and rates of ATP hydrolysis
Increased synthesis of resp. chain enzymes
How do the thyroid hormones affect thermogenesis?
approx 30% thermoregulation due to thyroid hormones
How do the thyroid hormones affect carbohydrate metabolism?
Raised BG - due to stimulation of glycogenolysis and gluconeogenesis
Insulin-dependent glucose uptake into cells
How do the thyroid hormones affect lipid metabolism?
Mobilises fats from adipose
Fatty acid oxidation in tissue
How do the thyroid hormones affect Protein metabolism?
Stimulates protein synthesis
How do the thyroid hormones affect growth?
Causes GHRH production and secretion
Glucocorticoid-induced GHRH release
GH/somatomedins
All require thyroid hormones in order to happen
How do the thyroid hormones affect the development of the fetal and neonatal brain?
Myelinogenesis and axonal growth requires thyroid hormones
How do the thyroid hormones affect normal CNS activity?
Hypothyridism = slow intellectual functions Hyperthyroidism = nervousness, hyperkinesis and emotional instability
How do the thyroid hormones affect permissive sympathomimmetic actions?
Increased responsiveness to adrenaline and NA
CV responsiveness also increased (increased force and rate of contraction of the heart)
Beta-blockers are initially used in hyperthyroidism to prevent this
How are thyroid hormone levels regulated?
Thyrotrophin releasing hormone (TRH) stimulates TSH.
T3 + T4 exert a -ve feedback control of TRH and TSH
Low temps causes TRH release in young children and babies
Stress inhibits TRH and TSH release
Thyroid hormones are higher at night and lower in the morning.
What is hypothyroidism?
Deficiency of T3 and T4 levels
What causes primary hypothyroidism?
Thyroid gland failure - may be associated with goitre
What causes secondary hypothyroidism?
TRH or TSH abnormalities - no goitre
What are the symptoms of hypothyroidism?
Low BMR Slow pulse Fatigue, lethargy, slow response times, mental sluggishness Cold intolerance Put weight on easily
What signs may indicate hypothyroidism in only adults?
Myxoedema - puffy face, hands and feet
What signs may indicate hypothyroidism in only babies?
Cretinism - dwarfism + limited mental functioning
What is the most common cause of hyperthyroidism?
Grave’s disease
What is the pathology behind grave’s disease?
AI condition where TSI (thyroid stimulating immunoglobulin) acts like TSH but goes unchecked by T3 + T4
What symptoms and signs are associated with Grave’s disease?
Exopthalmos - water retaining carbohydrate build up behind eyes Goitre High BMR V. fast pulse Nervousness and emotional instability Insomnia Sweating and heat intolerance Tendency to lose weight easily
What is the commonest type of thyroid cancer?
Papillary (76%)
What is the second commonest type of thyroid cancer?
Follicular (17%)
What varients of thyroid cancer are diffentiated?
Follicular and Papillary
How do most differentiated thyroid cancers (DTCs) act physiologically?
Take up iodine and secrete thyroglobulin
Are driven by TSH
How do DTCs present?
Palpable thyroid nodules
5% will have have local or disseminated metastases
How does Papillary TC spread?
via lymphatics
via blood to lungs, bone, liver and brain
What thyroid disease is papillary TC associated with?
Hashimoto’s thyroiditis
What is the general prognosis of papillary TC?
10 year mortality less than 5%
Where is there increased incidence of follicular TC?
Areas where iodine deficiency is common
How does follicular TC spread?
Via the blood
What investigation is usually done for a neck lump suspected to be associated with the thyroid?
US-guided FNA
Potentially excision biopsy of the lymph nodes
What clinical features would suggest a thyroid lump is more likely to be malignant?
New thyroid nodule in those 50 Male sex Nodule growing >4cm diameter History of head/neck irradiation Vocal cord palsy
What is the treatment of choice for DTC?
Surgery
Thyroid lobectomy with isthmusectomy
Sub-total thyroidectomy
Total thyroidectomy
What does the risks of surgery depend on?
AMES
A = age M = metastases E = extent of primary tumour S = size of primary tumour
What is the 20 year survival rate for those who have low AMES scores?
99%
What is the 20 year survival rate for those who have high AMES scores?
61% (with surgery alone)
When is thyroid lobectomy with isthmusectomy indicated?
Papillary microcarcinoma (<1cm)
Minimally invasive follicular tumour
AMES low risk
When is sub-total/total thyroidectomy indicated?
DTC with extra-thyroidal spread Bilateral/multifocal Distant mets Nodal involvement AMES high risk
What is involved in the post-op care of a thyroidectomy of any sort?
Calcium checked within 24hours
Calcium replaced if less than 2mmol/l
When is whole body iodine scanning used?
3-6 months post-op of a sub-total or total thyroidectomy
What must be done before a whole body iodine scan is performed?
T4 stopped 4 weeks before scan
OR
T3 stopped 2 weeks before scan
Why does the whole body iodine scanning take a full week?
Injections to raise TSH given on mon and tues
Radioactive iodine capsule administered on wed
Patient returns for the imaging process on Friday
What happens if following a whole body iodine uptake scan the uptake in the thyroid bed is found to be >0.1% of the ingested activity?
Patient will undergo thyroid remnant ablation (TRA) the following Tues
What happens to the patient when receiving TRA?
Admitted to a lead lined room with mains sewarage
Given 2/3GBq capsule of radioactive iodine
Patient uses disposable utensils for the duration of stay
Discharged when count rate <500cps at 1m. on T4
What can Thyroglobulin (Tg) be used as?
A tumour marker post TRA
If a child has a high BG, but no ketones and is clinically well, how soon should they get a paediatric clinical review?
24-48hours
If a child has high BG, ketones, but is clinically well, how soon should they see a paediatrician?
Within the same day
How is DKA treatment different in children?
Fluid resus is based on weight
Risk of cerebral oedema is highlighted
Insulin in commenced 1 hour after IV fluids are started
What are the signs of early vascular disease in children?
Microalbuminaemia CV autonomic neuropathy Sensory nerve damage Retinopathy Thickened skin and limited joint mobility of hands and fingers Skin vascular changes
What is primary congenital thyroid disease?
Dysplastic gland +/- an abnormal site e.g. sublingual
What is secondary/tertiary congenital thyroid disease?
Congenital pituitary disease
Usually associated with hypopituitarism
What are the clinical symptoms of congenital thyroid disease?
Delayed jaundice
Poor feeding but “normal” weight gain
Hypotonia
Skin and hair changes
How is congenital thyroid disease screened for?
Capillary blood spot in blotting paper at 5 days to measure TSH and/or T4 levels = Guthrie test
If a child is found to have congenital thyroid disease when should therapy be commenced?
within 2 weeks of birth
2-3 month window where protected by placental thyroid hormones
If a child with congenital thyroid disease is not treated within 3 months and thyroxine is absent, then what will happen?
Child will develop cretinism - permanent developmental delay
How does hypothyroidism present in children?
slow progress Growth retardation and delayed puberty poor general health educational difficulties Goitre TFTs = high TSH and low free T3/T4 High thyroid cell antibody titres
How is hypothyroidism in children treated?
Thyroxine replacement for life
Dose is dependent on the size of the child
How does hyperthyroidism present in children?
Behavioural problems, sleep disturbance, eating difficulties Goitre, high PR Precocious puberty TFTs = low TSH and high Free T3/T4 High thyroid cell antibody titres
How is hyperthyroidism treated in children?
Initially = beta-blockers
Suppressant for at least first 2 years = carbimazole +/- thyroxine
Permanent cure = Radio-iodine + surgery
What causes primary underactive adrenal disorders in children?
(low steroid production)
Adrenal hyperplasia
Inborn error of metabolism
CAH
What causes secondary underactive adrenal disorders in children?
Pituitary disease
Suppression secondary to steroids
What does overactive production of steroids cause in children?
Cushing’s disease
Primary = Adrenal cause
Secondary = Pituitary cause
What does 21-alpha-hydroxylase deficiency lead to?
No aldosterone or cortisol production
High testosterone conversion
= Fetal virilisation
What happens to the body when there is no cortisol or aldosterone?
“Addison crisis” - hyponatraemia, hyperkalamia and hypotension
How is an addison crisis managed?
Urgent therapy with salt and cortisol
What does virilisation in females cause?
ambiguous genitalia
What does virilisation in males cause?
Precocious puberty
What conditions may lead to ambiguous genitalia?
CAH or other steroid abnormalities
Gene and/or chromosomal abnormalities
Congenital defects
What conditions may lead to ambiguous genitalia?
CAH or other steroid abnormalities
Gene and/or chromosomal abnormalities
Congenital defects
What would the TFTs show in primary hypothyroidism?
TSH high
T4/T3 low
What would the TFTs show in primary hyperthyroidism?
TSH low
T4/T3 high
What would the TFTs show in secondary hypothyroidism?
TSH low
T3/T4 low
What would the TFTs show in secondary hyperthyroidism?
TSH high
T3/T4 high
What causes secondary hypothyroidism?
Pituitary gland failure
Hypothalamic problems
What causes secondary hyperthyroidism?
TSHoma (rare)
What is myxoedema?
Severe hypothyroidism leading to a myxoedema coma
What is pretibial myxoedema?
Accumulation of hydrophilic mucopolysaccharides in the ground substance of the dermis leading to a doughy induration of the skin typically in the shins
What thyroid disease can present with pretibial myxoedema?
Grave’s disease (thyrotoxicosis)
What are the 2 main causes of goitrous, primary hypothyroidism?
Chronic thyroiditis (Hashimoto's thyroiditis) Iodine deficiency
What is the main cause of non-goitrous, primary hypothyroidism?
Atrophic thyroiditis
What are the self-limiting causes of hypothyroidism?
Withdrawal of thyroid suppressive therapy
Subacute thyroiditis and chronic thyroiditis with transient hypothyroidism
Post-partum thyroiditis
What are the main causes of secondary hypothyroidism caused by the hypothalamus?
Congeital defects
Encephalitis
Sarcoidosis
Malignancy
What are the main causes of secondary hypothyroidism caused by the pituitary?
panhypopituitarism (trauma. infection, infiltration, neoplasm)
Isolated TSH deficiency
What are the main causes of secondary hypothyroidism caused by the pituitary?
panhypopituitarism (trauma. infection, infiltration, neoplasm)
Isolated TSH deficiency
What hypothyroid disorder is also known as an AI condition?
Hashimoto’s thyroiditis
What is the pathophysiology behind Hashimoto’s thyroiditis?
AI destruction of the thyroid gland causing decreased thyroid hormone production
What investigtions would prove a diagnosis of Hashimoto’s thyroiditis?
Thyroid peroxidase antibodies in the blood
T-cell infiltrate and inflammation on microscopy
What symptoms occur in the hair/skin in hypothyroidism?
Coarse, sparse hair Dull, expressionless face Periorbital puffiness Pale, cool skin that feels doughy to touch Hypercarotenaemia? (yellow skin)
How does hypothyroidism affect thermogenesis?
Become intolerant to cold
How does hypothyroidism affect the body’s fluid status?
Causes pitting oedema
What cardiac symptoms may be present in hypothyroidism?
Low HR
Cardiac dilatation
Pericardial effusion
Worsening of pre-existing HF
How might hypothyroidism affect the metabolism and BMR?
Hyperlipidaemia
Decreased appetite
Weight gain
What GI symptoms may present with hypothyroidism?
Constipation
Megacolon and intestinal obstruction (rare)
Ascites (rare)
What resp. symptoms may present with hypothyroidism?
Deep hoarse voice
Macroglossia
Obstructive sleep apnoea
What neurological/CNS symptoms may appear with hypothyroidism?
Decreased intellectual and motor activities Depression Muscle stiffness/cramps Peripheral neuropathy Carpal tunnel syndrome Decreased visual acuity
What gynaecological/Repro symptoms may present with hypothyroidism?
Menorrhagia Hyperprolactinaemia (high TSH = high prolactin)
What lab results will show with hypothyroidism?
Macrocytosis (large RBCs)
High creatinine kinase
High LDL cholesterol
Hyponatraemia - decreased renal tubular water loss
What lab results will show with hypothyroidism?
Macrocytosis (large RBCs)
High creatinine kinase
High LDL cholesterol
Hyponatraemia - decreased renal tubular water loss
What thyroid antibodies (and what percentage of people) are present in Grave’s disease?
Anti TPO (70-80%)
Anti-thyroglobulin (30-50%)
TSH-receptor (70-100%)
What thyroid antibodies (and what percentage of people) are present in AI hypothyroidism?
Anti TPO (95%)
Anti-thyroglobulin (60%)
TSH-receptor (10-20%)
How is hypothyroidism managed?
Thyroxine od before breakfast
Restoration of normal BMR gradually
When might thyroxine levels have to be increased for a patient with hypothyroidism?
Pregnancy (25-50% increase in dose requirements)
Who is most likely to be affected by myxoedema coma?
Elderly women with longstanding untreated/poorly treated hypothyroidism
How does myxoedema coma present?
ECG - Bradycardia, low voltage complexes, heart block, T-wave inversion, prolonged QT
Type 2 resp failure: Hypoxia, hypercarbia, resp. acidosis
How is myxoedema coma treated?
ABCDE
Slowly rising temp
Close monitoring of ECG, BP, BG, urine output
Fluids and electrolytes - closely monitored
Broad spectrum antibiotics
How does amiodarone affect the thyroid function?
upto 50% have abnormalities
- 2% = thyrotoxicosis
- 13% = hypothyroidism
What are the cardiac symptoms associated with hyperthyroidism?
Palpitations/AF
HF (rare)
What are the cardiac symptoms associated with hyperthyroidism?
Palpitations/AF
HF (rare)
How can hyperthyroidism affect the CNS?
Anxiety, nervousness, irritability, sleep disturbance
How can hyperthyroidism affect the GI system?
Frequent, loose bowel movements
How might hyperthyroidism affect the vision?
Lid retraction
Double vision
Proptosis
How may hyperthyroidism affect the hair and skin?
Brittle, thinning hair
Rapid fingernail growth
How can hyperthyroidism affect the repro system?
Menstrual cycle changes - lighter and less frequent
How can hyperthyroidism affect the muscles?
Weakness esp. in thighs and upper arms
What happens to the metabolism in hyperthyroidism?
Weight loss despite increased appetite
How does hyperthyroidism affect thermogenesis?
Becomes intolerant to heat
What are the causes of hyperthyroidism?
AI - Grave’s
Nodular thyroid - Goitre, toxic nodule (adenoma)
Thyroiditis
Iodine (rare)
Medication (rare) - Lithium, amiodarone, thyroxine
Who is most likely to get Grave’s disease?
Women between 20-50 with a +ve FH and increased iodine intake.
At 18 months what happens to those with Grave’s disease?
50% - burn out
50% - relapse
What would investigations show in an individual with Grave’s disease?
High T3/T4
Low TSH
Antibody +ve (TRAbs)
How would a patient with Grave’s disease present?
Smooth symmetrical goitre Lid retraction and lid lag Swellin of conjunctivae Proptosis Visual loss and diplopia
How is Grave’s disease treated?
Lubricants Decompression surgery Radiotherapy Corrective surgery Smoking cessation
What age group is more likely to get nodular thyroid disease?
Older patients
How does Nodular thyroid disease differ from Grave’s?
More gradual onset
Gland may feel nodular and asymmetrical
What would investigations show in an individual with Nodular thyroid disease?
High T3/T4
Low TSH
Antibody -ve (TRAbs)
What would investigations show in an individual with Nodular thyroid disease?
High T3/T4
Low TSH
Antibody -ve (TRAbs)
What is sub-acute thyroiditis/De Quervains?
A potentially virally triggered thyroiditis which affects females between 20-50.
May be associated with a sore throat/fever
Usually self-limiting (few months)
What do the TFTs show in sub-acute thyroiditis/De Quervains?
T4 =high in early stage, low in late, then normal
TSH = low in early stage, high in late, then normal
What is a thyroid storm?
A medical emergency with severe hyperthyroidism, resp and cardiac collapse, exaggerated reflexes and hyperthermia
How is a thyroid storm treated?
Lugols iodine, glucocorticoids, PTU, beta-blockers, fluids, and very close monitoring
How is hyperthyroidism treated?
Carbimazole
Propylthiouracil (PTU) (used in pregnancy)
Beta blockers
Radioiodine or surgery
What is the composition of the thryroid?
Multiple follicles surrounded by flat to cuboidal follicular epithelial cells.
In the centre of each follicle is a dense amorphic pink material containing thyroglobulin
There are scattered C (parafollicular) cells which are slightly larger with a clear cytoplasm, and secrete calcitonin.
How would a thyroid adenoma present?
A discrete solitary mass encapsulated by a collagen cuff.
Composed of neoplastic thyroid follicles
Usually non-functional but may secrete thyroid hormones leading to thyrotoxicosis
How would a thyroid adenoma present?
A discrete solitary mass encapsulated by a collagen cuff.
Composed of neoplastic thyroid follicles
Usually non-functional but may secrete thyroid hormones leading to thyrotoxicosis
What HLA groups is Hashimoto’s thyroiditis associated with?
HLA-DR3
HLA-DR5
What are the genetic features associated with Papillary thyroid carcinomas?
activate the MAPK pathways
rearrangements of RET ot NTKR1
Activating point mutation in BRAF
How does a papillary thyroid carcinoma present?
Usually a solitary nodule in the thyroid sometimes with lymph node mets
What are the genetic features associated with a follicular thyroid carcinoma?
Mutations in P13K/AKT pathway
How does follicular thyroid carcinoma usually present?
Single nodule which slowly enlarges is painless and non-functional
Rarely has lymphatic spread but may have haematogenous spread to bones/lungs/liver
What genetic factors are associated with Medullary Thyroid carcinoma (MTC)?
MEN2 - germline RET mutations
What is MTC derived from?
C-cells (neuroendocrine) and may secrete calcitonin
What does a MTC contain?
Spindle or polygonal cells arranged in nests, trabeculae or follicles
What may the cause of a MTC be?
Sporadic (70%)
Associated with multiple endocrine neoplasia (MEN)
Familial
Amyloid deposition may be associated with a MTC, why?
Amyloid represents deposition of an abnormally folded protein - in this case calcitonin
How does MTC usually present?
Neck mass with local effects
Paraneoplastic symdrome - diarrhoea, Cushings
How does MTC usually present?
Neck mass with local effects
Paraneoplastic symdrome - diarrhoea, Cushings
What is anaplastic thyroid carcinoma?
An undifferentiated, aggressive tumour usually found in older patients
What genetic factors are associated with anaplastic thyroid carcinoma?
Features of both papillary and follicular carcinomas + p53 and beta-catenin mutations
In thyroid cytology what would a specimen with Thy1 results be?
Insufficient/uninterpretable results
In thyroid cytology what would a specimen with Thy2 results be?
Benign
In thyroid cytology what would a specimen with Thy3 results be?
Atypia/probably benign/equivocal
In thyroid cytology what would a specimen with Thy4 results be?
atypia suspicious of malignancy
In thyroid cytology what would a specimen with Thy5 results be?
Malignant
How many parathyroid glands does an individual have?
usually 4
10% populus have 2/3
What do chief cells which make up the parathyroid glands do?
secrete PTH
act on Ca homeostasis
What do chief cells look like histologically?
Round cells with moderate cytoplasm and bland, round central nuclei
What do oxyphil cells do?
Support the chief cells in the parathyroid glands
What do the oxyphil cells look like on histology?
Slightly larger than chief cells
Acidophilic cytoplasm
What are most cases of hyperparathyroidism caused by?
small adenomas on 1 parathyroid gland
What is hyperplasia of the parathyroid glands associated with?
MENI and MENIIa
If one parathyroid gland contains an adenoma, what happens to the other parathyroid glands?
They become atrophic
How does a parathyroid adenoma present microscopically?
Resembles normal parathyroid but may see a fibrous connective tissue capsule with adjacent rim of compressed parathyroid tissue
How does a parathyroid adenoma present microscopically?
Resembles normal parathyroid but may see a fibrous connective tissue capsule with adjacent rim of compressed parathyroid tissue
In hyperplasia of the parathyroid glands how many glands are typically affected?
Usually all of them
What is secondary hyperparathyroidism?
Chronic hypocalcaemia causes compensatory overactivity of the parathyroid glands
What can secondary hyperparathyroidism cause?
Renal failure (low Ca intake, Vit D deficiency) Hyperplasia of parathyroid tissue
What is tertiary hyperparathyroidism?
Parathyrid activity becomes autonomous
Associated with hypercalcaemia
What are the signs and symptoms of hyperparathyroidism?
Bone disease - pain, fracture, osteoporosis
Nephrolithiasis - renal stones
GI complications - constipation, gallstones, nausea
CNS - depression, lethargy, seizures
Neuromuscular - weakness and fatigue
CVS - calcification of aortic and mitral valves
Hypoparathyroidism is very rare, but what can cause it?
Post-op of thyroid
congential absence - DiGeorge
familial - associated with primary adrenal insuffiency and mucocutaneous candidiasis
What can hypoparathyroidism cause?
Tetany
Altered mental state
Basal ganlia calcification, Parkinsonian, Raised ICP
Calcification of lens + cataract
Prolonged QT interval on ECG
Dental abnormalities - if during development
What hormone does the ovum produce?
oestradiol
What hormone is detected on a pregnancy test if fertilisation of the ovum occurs?
hCG
What hormones does the placenta produce?
Human placental lactogen (hPL)
placental progesterone
placental oestrogens
Progesterones + hPL in an insulin resistant mother leads to what?
Increased BG and gestational diabetes
What complications may occur in pregnancy as a result of poor diabetic glycaemic control?
Congenital malformation Prematurity Intra-uterine growth retardation Large birth weight Polyhydramnous (too much fluid around baby) Intrauterine death
What complications may occur in the baby if a diabetic mother has poorly controlled BG levels?
Resp distress due to immature lungs Hypoglycaemia and/or hyperglycaemia = fits Anencephaly + spina bifida caudal regression syndrome ureteric dulplication
What percentage of people who suffered from gestational diabetes will go on to develop T2DM in 10 or so years?
50%
More in obese individuals
What effect does thyroid disease have on pregnancy?
Hyper or hypo thyroidism may cause anovulation
Increased demand on thyroid during pregnancy (thyroxine dose needs to increase)
What effect does hCG have on TFTs in pregnancy?
9% have low TSH
14% have high ft4
What effect does hCG have on TFTs in pregnancy?
9% have low TSH
14% have high ft4
What should be done for pregnant women with pre-existing hypothyroidism?
Increase medication dose
TFTs monthly until 20 weeks, then 2 monthly until term
What are the risks of untreated hypothyroidism during pregnancy?
Increased spontaneous abortion risk Pre-eclampsia Pstpartum haemorrhage Perterm labour Foetal neuropsychological dvelopment (lower IQ)
What can cause thyrotoxicosis in pregnancy?
Grave’s disease
TMNG, toxicadenoma
Thyroiditis
Gestational hCG-associated thyrotoxicosis (resolves by 20 weeks)
What are the risks in pregnancy in a woman with pre-existing hyperthyroidism?
Infertility Spontaneous miscarriage stillbirth thyroid crisis in labour transient neonatal thyrotoxicosis
How is hyperthyroidism managed in pregnancy?
Supportive management for symptoms
Beta blockers in early pregnancy
Low dose antithyroid drugs
What is postpartum thyroiditis?
Occurs in 5% of postpartum women (more in T1DMs)
Can occur upto 1 year postpartum but usually 1-4 months
May have a small, diffuse, non-tender goitre
Transiently thyrotoxic -> hypothyroid
What is the physiology of the posterior pituitary lobe?
ADH and oxytocin are synthesised in the body of the nerve cells within the hypothalamus
The neuron that secretes ADH and oxytocin moves downwards from the axon and gathers at the axon tips
Hormones enter the blood stream from a vessel joining the pituitary and ECF level rises
What does ADH act on?
Urine collection channels in the kidneys
What does oxytocin act on?
Mammary glands and smooth muscles above the uterus
What is the physiology of the posterior pituitary lobe?
ADH and oxytocin are synthesised in the body of the nerve cells within the hypothalamus
The neuron that secretes ADH and oxytocin moves downwards from the axon and gathers at the axon tips where the hormones enter the blood
Hormones exit the pituitary from a vessel joining the pituitary and ECF level rises
What does oxytocin act on?
Mammary glands and smooth muscles above the uterus
What happens in the anterior lobe of the pituitary?
Stimulator and inhibitor hormones are released from the body of the nerve cells in the hypothalamus which are 1st absorbed by capillaries in the hypothalamus base
Blood is then transported to the 2nd capillary network in the anterior pituitary lobe where they can then affect the anterior pituitary cells which secrete hormones.
Hormones leave though small vessels connected to the general bloodstream
What does ACTH act on?
Adrenals
What does TSH act on?
Thyroid
What does FSH and LH act on?
reproductive organs
What does PRL act on?
mammary glands
What does STH act on?
Muscle
What happens in the hypothalamo-pituitary testicular axis?
- Hypothalamus secreted GnRH
- GnRH travels to anterior pituitary
- Pituitary releases LH and FSH in response
- LH and FSH travel to testicles
- LH stimulates Leydig cells in the testicles to produce testosterone
- FSH stimulates sertoli cells to produge ABG and inhibin
- Increased levels of testosterone and inhibin negatively feeback to pituitary and hypothalamus
- Resulting in decreased LH and FSH production
- Testosterone and inhibin levels also decrease
What is the role of ABG in males?
Binds to testosterone and keeps it in the seminiferous tubules
What is the role of inhibin in males?
Supports spermatogensis and inhibits production of FSH, LH and GnRH
What does CRH release from the hypothalamus cause to happen in the pituitary gland?
stimulates ACTH release
What does ACTH release cause to happen in the adrenal gland?
Cortisol release
What does ACTH release cause to happen in the adrenal gland?
Cortisol release
What effects does cortisol have on the body?
Regulates glucose levels
Increases body fat
Defends body against infection
Helps body respond to stress
What dynamic tests can be done to identify whether or not too much or too little hormone is being produces?
Too much hormone = do tests to suppress the hormone
Too little hormone = do tests to stimulate the hormone
What hormone stimulation tests exist to test hormone function?
Synacthen test (synthetic ACTH) - measure cortisol at 0, 30 and 60 minutes
Insulin stress tests - measure cortisol and GH response every 30 mins for 2-3hours
Water deprivation test - check serum and urine osmolarities for 8 hours and then 4 hours after giving desmopressin (tests for diabetes insipidus)
What are the 2 different types of pituitary adenoma?
Microadenoma less than or = 1cm
Macroadenoma >1cm
What effects can a non-functioning pituitary adenoma have on the body?
Compression of optic chiasm Compression of cranial nerves Hypoadrenalism Hypothyroidism Hypogonadism DI GH deficiency
What effects can a non-functioning pituitary adenoma have on the body?
Compression of optic chiasm Compression of cranial nerves Hypoadrenalism Hypothyroidism Hypogonadism DI GH deficiency
What are the physiological causes of increased prolactin levels in the body?
Breast feeding
Pregnancy
Stress
Sleep
What drugs can caused increased body prolactin levels?
Dopamine antagonists Antipsychotics Antidepressants Oestrogens Coccaine
What pathological conditions can cause increased prolactin production?
Hpothyroidism
Stalk lesions
Prolactinomas
What symptoms and signs occur in females with increased prolactin levels?
EARLY presentation Galactorrhoea Menstrual irregulartiy Ammenorrhoea Infertility
What symptoms and signs occur in males with increased prolactin levels?
LATE presentation Galactorrhoea in less than 30% Visual field abnormalities Headache Impotence Anterior pituitary dysfunction
What investigations can be done when suspicions of prolactinoma arise?
Prolactin conc.
MRI pituitary
Visual field testing
Pituitary function tests
How is excess prolactin (prolactinoma) treated?
Dopamine agonists:
- Bromocriptine
- Quinagolide
- Cabergoline
How effective is treatment for prolactin excess?
Prolactin is normalised in 96%
Menstruation regained in 94%
Pregnancy rate 91%
Tumour shrinkage
What causes acromegaly?
GH excess
What re the signs and symptoms of acromegaly?
Thickened soft tissues - skin, large jaw and hands, excessive sweating Hypertension and HF Headaches Snoring/sleep apnoea DM Visual field defects Hypopituitarism Early CV death
How is acromegaly diagnosed?
IGF1 levels - age and sex matches
GTT - GH unchanged after glucose >1microgram/l
How is a glucose tolerance test (GTT) performed?
75g oral glucose bolus is given
GH is checked at 0, 30, 60, 90 and 120 mins
In normal cases GH suppresses to
How is a glucose tolerance test (GTT) performed?
75g oral glucose bolus is given
GH is checked at 0, 30, 60, 90 and 120 mins
In normal cases GH suppresses to less than 0.4micrograms/l after glucose
What is the treatment for acromegaly?
Pituitary surgery
External radiotherapy to the pituitary fossa
Retest GTT - if normal stop here, if still >1 then drug therapy is required:
-cabergoline
-octerotide
-peguisomant
What are the effects of somatostatin analogues in acromegaly?
Reduced GH in most patients
reduces tumour size by 30-50%
useful pre-op to relieve headache in 1 hour and gives an improved op outcome
What are the side effects of somatostatin analogues?
Local stinging
Flatulence, diarrhoea, abdo pains
Gastritis in 50-60%
Gallstones in 60%
What drugs are somatostain analogues?
Octerotide
Sandostatin
Lanreotide autogel
What dopamine agonists is used in acromegaly?
Cabergoline upto 3g weekly
Reduces GH to less than 2 in 15% cases
What drug is a GH anatgonist and used in acromegaly?
Peguisomant
What doe GH antaginists do?
Bind to the GH receptor and block GH activity
Has an 85% response rate
IGF-1 decreases
What is included in the follow-up and long term management of acromegaly?
Achieve clinically safe levels (less than 1) Check for other pituitary disorders Cancer surveillance Manage CVD risk factors Manage sleep apnoea
What is the main cause of Cushing’s syndrome?
Excess cortosol
What are the symptoms of protein loss in Cushing’s
Myopathy
Osteoporosis
Thin skin
What are the symptoms of mineralocorticoid excess in Cushing’s?
Hypertension
Oedema
What are the symtoms of excess androgen in Cushing’s?
Virilism
Hirsutism
Acne
Oligo/amenorrhoea
What does altered carbohydrate/lipid metabolism in Cushing’s cause?
DM
Obesity
What does an altered psyche is Cushing’s cause?
Psychosis
Depression
What does an altered psyche is Cushing’s cause?
Psychosis
Depression
What is the most common clinical presentation of Cushing’s syndrome?
Thin skin Proximal myopathy Frontal balding in women Conjunctical oedema Osteoporosis 'moon face'
What screening tests are available for Cushing’s syndrome?
Overnight 1mg dexamethasone suppression test:
- cortisol less than 50nmol/l next morning = normal
- cortisol >100nmol/l = abnormal
Urine free cortisol (24h urine collection)
- total less than 250 is normal
- Cortisol/creatinine ratio of less than 25 is normal
Diurnal cortisol variation
What definitive test exists for Cushing’s syndrome?
2 day 2mg/day dexamethosone suppression test
A cortisol less than 50nmol/l 6h after the last dose is -ve for Cushing’s
What are the causes of Cushing’s syndrome?
Pituitary >80%
Adrenal adenoma - beign/cancerous
Ectopic - thymus, lung, pancreas
Psuedo - Alcohol and depression, steroid medication
How is Cushing’s caused by a pituitary disease treated?
Hypophysectomy (pituitary removal) and external radiotherapy if recurrance
How is Cushing’s disease caused by adrneal adenoma treated?
Adrenalectomy
How is Cushing’s disease caused by an ectopic cause treated?
Remove source OR bilateral adrenalectomy
What drug treatment is available for Cushing’s syndrome?
Metyrapone - if other treatments fail or while waiting for radiotherapy to work
Ketoconazole
Pasireotide
What drug treatment is available for Cushing’s syndrome?
Metyrapone - if other treatments fail or while waiting for radiotherapy to work
Ketoconazole
Pasireotide
What does pan hypopituitarism cause in the anterior pituitary?
Growth failure
Hypothyroidism
Hypogonadism
Hypoadrenal
What does pan hypopituitarism cause in the posterior pituitary?
Diabetes insipidus (DI)
What causes pan hypopituitarism?
Pituitary tumours Secondary mets from lungs and breast Local brain tumours Granulomatous diseases Vascular diseases Trauma Hypothalamic diseases Iatrogenic AI Infection
What are the signs and symptoms of pan hypopituitarism ?
Mestrual irregularities (F) Infertility, impotence Gynaecomastia (M) Abdo obesity Loss of facial hair (M) Loss of axillary and pubic hair Dry skin and hair Hypothyroid faces Growth retardation (children)
What tests should be done when suspecting pan hypopituitarism in an individual?
fT4, TSH
Oestradiol/testosterone, LH + FSH
GH, IGF-1
Prolactin
How is pan hypopituitarism treated?
Thyroxine Hydrocortisone ADH GH Sex steroids
How do GH injections affect adults?
Improves well-being and QOL Decreased abdo fat Increases muscle mass, strength, exercise capacity and stamina Improves cardiac function Lowers cholesterol and increases LDL Increases bone density
How do GH injections affect adults?
Improves well-being and QOL Decreased abdo fat Increases muscle mass, strength, exercise capacity and stamina Improves cardiac function Lowers cholesterol and increases LDL Increases bone density
What are the risks of artificial testosterone replacement?
Prostate enlargement
Polycthaemia (increased RBCs)
Hepatitis
What are the causes of DI?
Familial = DIDMOAD Acquired = trauma, idiopathic, RTAs, surgery, skull fracture Rare = Tumour, sarcoid, external irradiation, meningitis
How is DI treated?
Desmospray
Desmopressin oral tablets/sublingual tablets/injection
What is the most important thing to remember when thinking about sodium and water balance?
WATER FOLLOWS SODIUM EVERYWHERE
How are sodium levels in the body controlled?
Mineralocorticoid activity - sodium retention in exchange for potassium and/or H+
What steroids have a mineralocorticoid activity?
Aldosterone (main)
Cortisol
What are the effects of too much and too little mineralocorticoid activity?
Too much = sodium retention (+ water)
Too little = sodium loss (+water)
What process brings back sodium and water into the system?
Low BP activating the RAAS system - aldosterone is produced (high BP has the opposite effect)
How are water levels controlled in the body?
By ADH
What does ADH cause to occur in the renal tubules?
Water reabsorption
Antidiuretic effect
What does ADH cause to occur in the renal tubules?
Water reabsorption
Antidiuretic effect
If urine osmolarity is high, what does this do to the urine?
Concentrated urine
What causes increased ADH secretion and hence concentrated urine?
Increased sodium levels in the blood (low sodium causes the opposite)
What causes Decreased sodium concentration in the blood?
Too much water - Decreased excretion (SIAD) or increased intake
Too little sodium - increased sodium loss (kidneys-Addison’s, gut, skin) or decreased sodium intake (v. rare)
What causes Increased sodium concentration in the blood?
Too little water - Increased water loss (DI) or Decreased water intake
Too much sodium - RARE, some IV drugs, near-drowning in the sea.
What is the basis behind Addison’s disease?
Too little sodium due to adrenal insuffieciency
Not enough steroid synthesis and thus sodium not retained in the kidneys so sodium and water are lost from ECF leading to clinical dehydration
What are the common presenting features of Addison’s disease?
Dizziness and hypotension from reduced ECF
Excess pigmentation thus tanned skin from excess ACTH production
What complication of Addison’s disease is associated with Na loss?
K retention and thus hyperkalaemia
What is the basis behind SIAD?
ADH is secreted in response to a non-osmotic stimulus (hypovolaemia/hypotension, pain, N+V), thus causing a slowly-progressing fluid retention (asymptomatic usually)
How is SIAD diagnosed?
Decreased sodium found on U&Es.
How is SIAD diagnosed?
Decreased sodium found on U&Es.
What is the basis behind DI?
Disruption of pituitary or pituitary stalk thus no ADH secreted. Lots of (pure) water lost in urine and sodium conc is high.
When should abnormalities of sodium levels be considered serious?
If {Na} is less than 120mmol/l or >155mmol/l
If patient has altered consciousness, confusion or nausea accompanying sodium disturbance
If {Na} levels have risen or fallen rapidly to reach their current level
What is the basic make-up of the anterior pituitary?
Adenohypophysis
Derived from Rathke’s pouch
Secretes trophic (TSH, ACTH, FSH, LH) and non-trophic (GH, prolactin) hormones
What is the basic make-up of the posterior pituitary?
Neurohypophysis
Extension of neural tissue consists of modified glial cells and axonal processes
Secretes ADH (vasopressin) and oxytocin
What is the basic histology of the anterior pituitary gland?
Islands, cords of cells
Acidophils
Basophils
Chromophobe
What is the basic histology of the anterior pituitary gland?
Islands, cords of cells
Acidophils - Somatotrophs (GH), Mammotrophs (PRL)
Basophils - Corticotrophs (ACTH), Thyrotrophs (TSH), Gondaotrophs (FSH/LH)
Chromophobe
What is the basic histology of the posterior pituitary gland?
Non-myelinated axons of neurosecretory cells
What pathologies affect the anterior pituitary gland?
Hyperfunction = adenoma/carcinoma Hypofunction = surgery/radiation, sudden haemorrhage, ischaemic necrosis, tumours extending into sella, inflammatory conditions
What pathologies affect the posterior pituitary gland?
DI
SIADH
What are pituitary adenomas?
Derived from anterior pituitary cells
Sporadic or associated with MEN1
Micro or macro
Classified by the cell type or type of hormone(s) they produce
What symptoms may large adenomas present with?
Visual field defects
Pressure atrophy of surrounding tissue
Infarction can lead to panhypopituitarism
What symptoms may large adenomas present with?
Visual field defects
Pressure atrophy of surrounding tissue
Infarction can lead to panhypopituitarism
What is a prolactinoma?
The most common type of functional pituitary adenoma
Causes infertility, lack of libido and ammenorrhoea
What is a GH-secreting adenoma?
2nd most common type of functional pituitary adenoma
May cause gigantism or acromegaly
What can an ACTH secreting adenoma cause?
Cushing’s
What causes pituitary hypofunction?
Primary or metastatic tumours Traumatic brain injury Subarachnoid haemorrhage Surgery or radiation Granulomatous inflammation Infarction Hypothalamis lesions
What is a craniopharyngioma?
A tumour derived from the remnants of Rathke’s pouch
A slow-growing, often cystic tumour which may calcify
What symptoms does a craniopharyngioma cause?
Headaches and visual disturbances
What are the adrenal glands?
Bilateral glands around 4-5g each
Sit superior and medial to the upper pole of the kidneys
Composed of an outer cortex and an inner medulla
What are the 3 zones of the adrenal cortex?
Zona glomerulosum - mineralocorticoids and aldosterone
Zona fasciculata - glucocorticoids and cortisol
Zona reticularis - sex steroids and glucocorticoids
What are the 3 zones of the adrenal cortex?
Zona glomerulosum - mineralocorticoids and aldosterone
Zona fasciculata - glucocorticoids and cortisol
Zona reticularis - sex steroids and glucocorticoids
What cells lie in the adrenal medulla?
Neuroendocrine (chromaffin) cells which secrete catecholamines
What is congenital adrenocorical hyperplasia?
A group of AR disorders which have a deficiency of the enzyme required for biosynthesis
Altered biosynthesis leads to increased andrigen production
Decreased cortisol stimulates ACTH release
What is acquired adrenocortical hyperplasia?
Endogenous ACTH production
Bilateral adrenal enlargement
How do adrenocortical tumours present?
Incidental finding
Hormonal effects
Mass lesion
Carcinomas with necrosis leads to fever
What features of a tumour indicate an adrenocortical carcinoma?
Large size >50g or >20cm
Haemorrhage and necrosis
Frequent mets
Lack of clear cells
What are the typical features of an adrenocortical adenoma?
Well circumscribed, encapsulated lesions
Small
Yellow-brown cut surface
Well-differentiated, small nuclei
What is primary aldosteronism also known as?
Conn’s syndrome
What is Conn’s syndrome ususally associated with?
Diffuse or nodular hyperplasia of both adrenal glands
What happens in and what causes secondary hyperaldosteronism?
Increased Rennin
Decreased renal perfusion, hypovolaemia, pregnancy
What happens in and what causes secondary hyperaldosteronism?
Increased Rennin
Decreased renal perfusion, hypovolaemia, pregnancy
What is hypercortisolism also known as?
Cushing’s disease
What are the ACTH dependent causes of hypercortisolism?
ACTH secreting pituitary tumour
Ectopic ACTH - small cell lung cancer
What are the ACTH independent causes of hypercortisolism?
Adrenal adenoma or carcinoma
Non-lesional adrenal gland atrophies
What can cause primary adrenocortical hypofunction?
May be acute or chronic
Many causes and associations
What can cause secondary adrenocortical hypofunction?
Failure to stimulate adrenal cortex
Suppression of the adrenal cortex
What causes acute primary adrenocortical insufficiency?
Rapid steroid withdrawal
Crisis in patients with chronic adrenocortical sufficiency
Massive adrenal haemorrhage
What causes chronic primary adrenocortical insufficiency?
Addison's AI adrenalitis Infections Unusual causes Signs and symptoms occur when >90% gland is destroyed
What causes chronic primary adrenocortical insufficiency?
Addison's AI adrenalitis Infections Unusual causes Signs and symptoms occur when >90% gland is destroyed
What are the symptoms of Addison’s disease?
weakness fatigue anorexia N+V weight loss diarrhoea pigmentation
What happens to the body when mineralocorticoid levels fall?
K+ retention
Na+ loss
Volume depletion and hypotension
What happens to the body when glucocorticoid levels fall?
Hypoglycaemia
What can cause an Addisonian crisis?
Stress, Infection, Trauma, Surgery
What are the symptoms of an Addisonian crisis?
Vomiting abdo pain hypotension shock death
How common are neuroblastomas?
1 in 7000 live births
What percentage of neuroblastomas arise from the adrenal medulla?
40% - the rest arise along the sympathetic chain
What is a neuroblastoma composed of?
Primative appearing cells but may show maturation and differentiation
What is a phaeochromocytoma?
A neoplasm derived from chromaffin cells in the adrenal medulla which secretes catecholamines
A rare cause of secondary hypertension
What complications can arise as a result of a phaeochromocytoma?
HF
Infarction
arrhythmias
CVA
How are phaeochromocytomas diagnosed?
Detection of urinary catecholamines and metabolites
Why are phaeochromocytomas known as the 10% tumour?
10% are extra-adrenal 10% are bilateral 10% are biologically malignant 10% NOT associated with hypertension 25% familial
How do phaeochromocytomas appear macroscopically?
Small to v. large necrotic tumour masses
May see surface adrenal remnants
Yellow, red/brown to to haemorrhagic nature
Potassium dichromate will turn tumour dark brown due to oxidation of catecholamines.
How do phaeochromocytomas appear macroscopically?
Small to v. large necrotic tumour masses
May see surface adrenal remnants
Yellow, red/brown to to haemorrhagic nature
Potassium dichromate will turn tumour dark brown due to oxidation of catecholamines.
Where do phaeochromocytomas typically metastatise to?
Skeletal muscle
Regional lymph nodes
Liver
Lung
What condition is phaeochromocytoma a small part of?
MEN (IIA or IIB)
What is MENIIA?
Phaeochromocytoma (40-50%)
Medullary thyroid cancer (100%)
Parathyroid hyperplasia (10-20%)
Phaeochromocytoma may be bilateral and occur at extra-adrenal sites
What genetic mutation is MENIIA linked to?
Germline gain of function mutation in RET oncogene on Ch10
What is MENIIB?
Phaeochromocytoma, medullary thyroid carcinoma, neuromas or ganglioneuromas
Marfinoid habitus
What genetic mutation is MENIIB linked to?
Germline in RET oncogene - distinct from IIA mutations, almost always activating point mutation in the catalytic domain of the encoded enzyme.
What genetic mutation is MENIIB linked to?
Germline in RET oncogene - distinct from IIA mutations, almost always activating point mutation in the catalytic domain of the encoded enzyme.
What regulates functions of the zona glomerulosa?
Angiotensin II and K+
What regulates the zona fasiculata?
ACTH
What regulates the functions of the Zona reticularis?
ACTH + other unknown factors
What lies in the adrenal medulla?
Chromaffin cells
Medullary veins
Splanchnic nerves
How does RAAS regulate aldosterone?
Activated in response to low BP
Produces angiotensin II which causes direct vasoconstriction and indirect (via aldosterone) methods of BP elevation
What is the mechanism of corticosteroids?
Bind intracellular receptors
Receptor/ligand complex binds DNA to affect transcription
What are the 6 classes of steroid receptor?
Glucocorticoid Mineralocorticoid Progestin Oestrogen Androgen Vit D
How do glucocorticoids (cortisol) affect the CNS?
Mood lability
Euphoria/psychosis
Decreased libido
How do glucocorticoids (cortisol) affect the Bone/connective tissue?
Accelarates osteoporosis
Decreased serum calcium
Decreased collagen formation
Slower wound healing
How do glucocorticoids (cortisol) affect the Immunological system?
Decreased:
- capillary dilataion/permeability
- leucocyte migration
- macrophage activity
- inflammatory cytokine production
How do glucocorticoids (cortisol) affect the Metabolic system?
Increased:
- BG
- Lipolysis
- Proteolysis
How do glucocorticoids (cortisol) affect the Circulatory/renal system?
Increased:
- CO
- BP
- Renal blood flow and GFR
In general what does too much cortisol cause?
AI disease
What are the clinical roles of corticosteroids?
Suppress inflammation
Suppress immune system
Replace treatment
What are the effects of aldosterone via mineralocorticoid receptors?
Sodium/Potassium balance
BP regulation
ECFV regulation
Where are mineralocorticoid receptors (MRs) found?
Kidneys
Salivary glands
Gut
Sweat glands
Where are mineralocorticoid receptors (MRs) found?
Kidneys
Salivary glands
Gut
Sweat glands
What conditions show primary insufficiency of the adrenal glands?
Addison’s
CAH
Adrenal TB/malignancy
What conditions show secondary insufficiency of the adrenal glands?
lack of ACTH stimulation
Iatrogenic - excess exogenous steroid
Pituitary/hypothalamic disorders
How can adrenal insufficiency be tested for?
Low Na or High K levels Hypoglycaemia Short synACTHen test v. high ACTH levels v. high rennin and low aldosterone levels Adrenal autoantibodies
How is a Shory synacthen test performed?
Plasma cortisol is measured before and 30mins after IV ACTH
Normal =
-Baseline >250nmol/l
-postACTH >480nmol/l
How is adrenal insufficiency treated?
Hydrocortisone to replace cortisol
Fludrocortisone to replace aldosterone
Education
What is Addison’s disease?
An AI disease causing destruction of the adrenal cortex thus leading to primary adrenal insufficiency
What other AI conditions is Addison’s associated with?
T1DM
Grave’s disease
Pernicious anaemia
What are the clinical features of Addison’s disease?
Anorexia and weight loss Ammenorrhoea Fatigue/lethargy Dizziness and low BP Abdo pain Vomiting Diarrhoea
What causes the skin pigmentation seen in Addison’s disease?
v. high ACTH levels
What is the commonest cause of secondary adrenal insufficiency?
Exogenous steroid use
Further lowers CRH and aCTH
How does secondary adrenal insufficiency present?
Same as Addison’s
EXCEPT
Skin pale/normal (no excess ACTH)
Aldosterone production is intact
How is secondary adrenal insufficiency treated?
Hydrocortisone (fludrocortisone is unnecessary as aldosterone is normal)
How is secondary adrenal insufficiency treated?
Hydrocortisone (fludrocortisone is unnecessary as aldosterone is normal)
What is iatrogenic Cushing’s syndrome?
Commonest cause of cortisol excess due to prolonged high dose steroid therapy
Causes chronic suppression of ACTH production and adrenal atrophy
What are the implications of an individual having iatrogenic Cushing’s syndrome?
Unable to respond to stress
Needs extra doses of steroid when ill or prior to surgery
Cannot stop treatment suddenly
How is iatrogenic cushing’s syndrome treated?
Gradual withdrawal of steroid therapy
What CVD may be brought on by primary aldosteronism?
LVH
atheroma
Increased BP
What are the common clinical features of primary aldosteronism?
Significant hypertension
Hypokalaemia
Alkalosis
What re the rare causes of primary aldosteronism?
Genetic mutations
Unilateral hyperplasia
K+ channel mutations producing adenomas and hereditary hypertension
What is the 1st step in diagnosis of primary aldosteronism?
Measurement of plasma aldosterone and rennin and express as a ratio(ARR)
If >750 then investigate with the saline suppression tests
Failure of plasma aldosterone to suppress by >50% with 2l normal saline confirms PA
What is the 2nd step in diagnosing primary aldosteronism?
Confirm subtype
What is the 2nd step in diagnosing primary aldosteronism?
Confirm subtype
Adrenal CT or adrenal vein sampling to demonstrate adenoma or adrenal hyperplasia
What is the 2nd step in diagnosing primary aldosteronism?
Confirm subtype
Adrenal CT or adrenal vein sampling to demonstrate adenoma or adrenal hyperplasia
What is the surgical management of primary aldosteronism?
Unilateral laproscopic adrenalectomy
Cures hypokalaemia
Cures hypertension in a good number of cases
What is the medical management of primary hypoaldosteronism?
MR antagonists
- spironolactone
- eplerenone
What is CAH?
Rare condition associated with enzyme defects in the steroid pathway
What is the commonest CAH?
21-alpha-hydroxylase deficiency
What are the 2 variants of 21-alpha-hydroxylase deficiency?
Classical = salt-wasting, simple virilising Non-classical = hyperandrogenaemia
How is 21-alpha-hydroxylase deficiency diagnosed?
Basal 17-OH progesterone
genetic mutation analysis
What does a 21-alpha-hydroxylase deficiency mean for the body?
Cortisol and aldosterone are not produced
Androstenedione and testosterone are produced in excess
How does classical 21-alpha-hydroxylase deficiency present in males?
Adrenal insufficiency
Poor weight gain
Biochemical pattern similar to Addison’s
How does classical 21-alpha-hydroxylase deficiency present in females?
Genital ambiguity
How does non-classical 21-alpha-hydroxylase deficiency present?
Hirsutism Acne Oligomenorrhoea Precocious puberty Infertility/sub-fertility
How is 21-alpha-hydroxylase deficiency treated in children?
Early recognition glucocorticoid replacement mineralocorticoid replacement surgical correction achieve maximal growth potential
How is 21-alpha-hydroxylase deficiency treated in adults?
Control androgen excess
Restore fertility
Avoid over-replacement of steroids
What is the clinical triad of phaeochromocytoma?
Hypertension
Headache
Sweating
What other symptoms does phaeochromocytoma present with?
Palpitations breathlessness constipation anxiety flushing weight loss
If a phaeochromocytoma is found extra-adrenally what is it known as?
Paraganglioma
If a phaeochromocytoma is found extra-adrenally what is it known as?
Paraganglioma
What are the clinical signs associated with phaeochromocytoma?
hypertension pallor bradycardia and tachycardia pyrexia LVF myocardial necrosis stroke shock paralytic ileus of bowel
What biochemical abnormalities may present in phaeochromocytoma?
hyperglycaemia
low K+
Increased haematocrit
Lactic acidosis
What imaging is used to diagnose a phaeochromocytoma?
MRI
PETscan
How are phaeochromocytomas treated?
Full alpha and beta blockade -phenoxymethylbenzamine -atenolol or metoprolol Fluid and/or blood replacement Surgical -total excision wherever possible Chemo if mallignant
What is Von-Hippel-Lindau syndrome?
Mutation in HIF1-alpha
AD
Range of vascular tumours across the body
Associated with phaeochromocytomas.
Other than phaeochromocytomas, what other condition can caused raised catecholamines?
HF
What defines the anterior triangle of the neck?
Bounded by the mandible superiorly
Midline medially
Anterior border of the sternocleidomastoid laterally
What defines the posterior triangle of the neck?
Posterior border of SCM anteriorly
Anterior border of trapezius laterally
Clavicle inferiorly
What defines the posterior triangle of the neck?
Posterior border of SCM anteriorly
Anterior border of trapezius laterally
Clavicle inferiorly
What can cause superficial swellings on the neck?
Sebaceous cysts
Lipomas
Neurofibromas
What can cause midline neck swellings?
Thyroid
Thyroglossal cyst
Dermoid cyst
What can cause swellings in the anterior triangle of the neck?
Lymph nodes
Salivary glands
Branchial cyst
Carotid body tumour
What can cause swellings in the posterior triangle of the neck?
Lymph nodes
Cystic hygroma
What is a cystic hygroma?
Forms when lymph vessels fail to form correctly during foetal development
What is a branchial cyst?
Congenital failure to obliterate 2nd branchial cleft
What is a dermoid cyst?
A cyst containing an array of developmentally mature solid tissues
What is a lipoma?
A small fatty lump that grows beneath the skin
What is a Neurofibroma?
A benign nerve sheath tumour
What symptoms are associated with cervical lymphadenopathy?
Fever weight loss sweats hoarseness cough dyspnoea
What would a brancial cyst show on FNA?
cholesterol crystals
What would a brancial cyst show on FNA?
cholesterol crystals
What is osteoporosis?
A progressive systemic skeletal disease characterised by low bone mass and microarchitechtural deterioration of bone tissue, with a consequent increased in bone fragility and susceptibility to fracture
What are the 2 types of bone making up the human skeleton?
20% trabecular (porous sponge-like)
80% cortical (dense material that provides stiffness and strength
How does bone remodelling occur?
Osteoclasts appear on a previously inactive surface and begin to resorb (gradually breakdown) the bone
Osteoblasts then fill the cavity by putting down osteoid that is mineralised to form new bone.
What happens with bone remodelling in osteoporosis?
There is an increase in resorption over formation leading to increased bone loss
What contributes to an adults peak bone mass?
Genetics - major part Sex hormones Exercise Increased body weight Diet
What factors may contribute to bone loss?
Sex hormone deficiency Genetics Immobility Low body weight Diet Disease Drugs - glucocorticoids + aromatase inhibitors
What endocrine conditions can predispose an individual to osteoporosis?
Hyperthyroidism
Hyperparathyroidism
Cushing’s disease
T1DM
What GI conditions can predispose an individual to osteoporosis?
Coeliac disease
IBD
Chronic liver disease
Chronic pancreatitis
What respiratory conditions can predispose an individual to osteoporosis?
CF
COPD
What direct effects do corticosteroids have on the bone?
Decreased osteoblast activity and lifespan
Suppression of replication of osteoblast precursors
Decrease in calcium absorption
What indirect effects do corticosteroids have on bone?
Inhibition of gonadal and adrenal steroid production causing Increased PTH and decreased bone mass
What indirect effects do corticosteroids have on bone?
Inhibition of gonadal and adrenal steroid production causing Increased PTH and decreased bone mass
What do DEXA scans measure?
BMD (Bone mineral density) against a population mean - predicts fracture risk independently of other risk factors
What is the T-score in DEXA scans?
Young adults female population mean
What is the Z-score in DEXA scans?
Age-matched female population mean
What is normal BMD in DEXA scanning?
BMD is withing 1SD of the young adult reference means
What is osteopenia on DEXA scanning?
BMD more than 1SD but less than 2.5SD below the young adult mean reference
What is osteoporosis on DEXA scanning?
BMD >= 2.5SD below the young adult mean
What is severe osteoporosis on DEXA scanning?
BMD >= 2.5SD below the young adult mean with a fragility fracture
What lifestyle advice is given to patients with osteoporosis?
High intensity strength training
Low impact weight-bearing exercises
Avoidance of excess alcohol and smoking
Fall prevention
What dietary advice is given to patients with osteoorosis?
2-3 portions from milk and dairy for calcium
When should antiresorptive therapy be considered in patients with osteoporosis?
T less than or equal to -2.5
If on steroids or fracture of vertebrae has occured, start at T-1.5
What drug treatments are recommended in osteoporosis?
Calcium for post-menopausal women who do not get enough dietary intake
Vit D supplements for housebound under 60s or anybody over 65
What supplementary treatments are recommended in osteoporosis?
Calcium for post-menopausal women who do not get enough dietary intake
Vit D supplements for housebound under 60s or anybody over 65
What are bisphosphonates?
Analogues of pyrophosphate that adsorb onto bone within the matrix
Anti-resorptive agents used in osteoporosis
How do bisphosphonates work?
Ingested by osteoclasts, leading to cell death, thereby inhibiting bone resorption
How effective are bisphosphonates?
Increases BMD by 5-8%
Reduces fragility fracture by around 50%
How is zoledronic acid used to treat osteoporosis
Once yearly infusion for 3 years
~70% reduction in vertebral fracture risk
~40% reduction in hip fracture risk
What is denosumab?
Fully human monoclonal antibody that targets and binds with high affinity and specificity to RANKL
How does denosumab prevent fractures in osteoporosis?
Prevents RANK, inhibiting development and activity of osteoclasts, reducing bone resorption and increasing bone density
What are the side effects of denosumab?
Eczema
Cellulitis
What are the side effects of denosumab?
Eczema
Cellulitis
What is strontium ranelate?
An anti-resorptive agent which is third line for osteoporosis
What are the contraindications for using strontium ranelate?
history of thomboembolic disease
IHD
Peripheral arterial disease
Uncontrolled hypertension
What is teriparatide?
A recombinant parathyroid hormone which stimulates bone growth
What are the symptoms of acute hypercalcaemia?
Thirst
Dehydration
Confusion
Polyuria
