Endocrinology Flashcards
Where is insulin secreted?
Pancreatic beta cells (islets of Langerhans)
What is the action of insulin? (2)
To increase cellular uptake of glucose, fatty acids and amino acids into the liver, adipose tissue and muscle.
Also promotes storage of nutrients in the form of glycogen, lipids and protein respectively.
Describe the synthesis of insulin (3)
Synthesised form precursor (proinsulin).
Proinsulin is cleaved by the endoplasmic reticulum into active form insulin and a C peptide fragment.
Both are stored in secretory granules in beta cells awaiting release by exocytosis.
What receptor (promoted by insulin) promotes glucose uptake on the cell surface of muscle and adipose tissue cells?
GLUT4
Describe 4 types of glucose transporter proteins. Which is the most common?
GLUT-1 - Allows basal non-insulin stimulated glucose uptake into cells.
GLUT-2 - Transports glucose into beta cells, allowing them to sense serum glucose concentrations (low affinity receptor - so require high conc of glucose)
GLUT-3 - Enables non-insulin mediated uptake of glucose into brain, neurones and placents
GLUT-4 - Mediates majority of peripheral action of insulin, promoting glucose uptake into muscle and adipose tissue (most common)
Where is the majority of insulin extracted and degraded?
In the liver (50%)
Define gluconeogenesis
Glucose synthesis
Describe the impact of insulin on the liver
Acts on hepatocytes to inhibit gluconeogenesis (glucose synthesis) and activate glycogenesis (formation of glycogen), resulting in glycogen storage within the liver.
Define glycogenesis
Glycogen synthesis
Define glycogenolysis
Glycogen breakdown
Describe the impact of insulin on muscle (3)
Post-prandial spike (after eating) in insulin acts on monocytes to increase glucose import and shifts muscle metabolism to primarily use glucose as an energy source.
Promotes amino acid import and protein synthesis in muscle and inhibits protein degeneration and metabolism.
Promotes potassium uptake into cells, thus preventing dangerous hyperkalaemia following a meal.
Describe glycogen
Mainly stored in liver and muscles. Accumulated in response to insulin and broken down into glucose by glucagon
What hormone is released in response to low glucose levels? Where is it released?
Glucagon.
Released by pancreatic alpha cells
Describe glucagon
Peptide hormone produced by alpha cells of the pancreas.
Increase concentration of blood glucose (counteracts insulin) by stimulating hepatic glucose production through the breakdown of glycogen.
Describe the function of glucagon and where it acts. (3)
Acts on the liver to;
Convert glycogen to glucose (glycogenolysis)
Forms glucose from lactic acid and amino acids (gluconeogenesis)
Stimulates lipolysis and muscle glycogenolysis and breakdown (increased ketogenesis)
What are normal blood glucose levels?
3.5-8.00 mmol/L
Define diabetes mellitus (2)
Describes a reduced responsiveness to endogenous insulin.
Described as a syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both
Describe the difference between type 1 and type 2 diabetes
Type 1 - An inability to synthesise insulin
Type 2 - The body becoming resistant to the effects of insulin.
Name 3 microvascular complications of diabetes
Retinopathy (blurred vision, cotton wool sports, macular oedema)
Neuropathy (pain - at night, numbness in feet and hands, paraesthesia)
Nephropathy (microalbuminuria)
Name 3 macrovascular complications of diabetes
Stroke
MI
Limb ischaemia
Give 4 secondary causes of diabetes
Pancreatic pathology (total pancreatectomy, chronic pancreatitis, haemochromatosis)
Endocrine disease (acromegaly, cushing’s disease, hyperthyroidism)
Drug induces (thiazide diuretics, corticosteroids)
Maturity onset diabetes of youth (MODY)
Define MODY. When does it present? (3)
Maturity onset diabetes of youth (MODY)
Describes an autosomal dominant form of type 2 diabetes.
Presents in <25 year olds with a positive family history.
Describe 3 types of MODY
MODY1 - Mutation in HNF4A (presents in neonates - macrosomia and hyperglycaemia)
MODY2 - Mutation in GCK (glycokinase - sensor of pancreatic b-cells)
MODY3 - Mutation in HNF1A (patients respond well to sulfonylurea treatment so don’t require insulin)
Define type 1 diabetes
Describes a disease of insulin deficiency caused by the autoimmune destruction of insulin producing pancreatic beta cells.
Mutations in which HLA genes are strongly linked to type 1 diabetes? (2)
HLA-DR3 and HLA-DR4
Name 4 autoantibodies involved in type 1 diabetes
Anti-GAD (most common)
Pancreatic islet cell Ab
Islet antigen 1Ab
ZnT8 (zinc transporter 8)
When is the peak incidence of type 1 diabetes?
Manifests during childhood, peak incidence around puberty)
<30 years old and tend to be lean
Give 4 risk factors for Type 1 Diabetes
Family history (HLA-DR3/DR4)
Autoimmune disease (autoimmune thyroid, coeliac disease, addison’s disease, pernicious anaemia)
Environmental factors (diet, coxsackie B4, vitamin D deficiency)
Describe the pathophysiology of type 1 diabetes
Autoimmune destruction of insulin producing beta cells > insulin deficiency > glucose cannot be taken up by cells > body resultantly responds as if were hypoglucaemic > liver compensates by increasing glycogenolysis (producing glucose and ketones) > glucose is excreted by kidney leading to glycosuria and ketouria > increase in glucose and ketone excretion pulls more water into urine leading to thirst and polyuria.
Describe symptom triad of type 1 diabetes (3)
Polyuria/nocturia
Polydipsia (thirst)
Weight loss
Give 3 additional clinical signs of type 1 diabetes
Early onset (childhood/adolescence)
Lead body physique/build
Acute onset of osmotic symptoms (polyuria/nocturia/polydipsia/weight-loss)
Name 3 additional presenting features of type 1 diabetes
Hunger (hyperphagia - due to lack of usable energy source i.e glucose)
Pruritis vulvae and balanitis (glucosuria increases infection risk)
Blurred vision (lens swelling due to increased uptake of glucose and water)
Give 6 investigations used to diagnose type 1 diabetes
Urine dipstick for glucose and ketones
Random plasma glucose (>11mmol/L - confirms diagnosis)
Fasting plasma glucose (>7mmol/L)
Oral glucose tolerance test (>11mmol/L)
Autoimmune markers (i.e Anti-GAD)
Fasting C-peptide (Byproduct of insulin generation - Low due to absence of insulin secretion)
Describe the diagnostic criteria for a symptomatic patient with ? Type 1 diabetes
Fasting plasma glucose >7mmol/L
Random plasma glucose >11mmol/L (or after 75g oral glucose tolerance test)
Describe the diagnostic criteria for an asymptomatic patient with ? type 1 diabetes
Fasting plasma glucose >7mmol/L
Random plasma glucose >11mmol/L (or after 75g oral glucose tolerance test)
ON TWO SEPERATE OCCASIONS
What is more common Type 1 Diabetes or Type 2?
Type 2 diabetes
Describe 5 differences between type 1 and type 2 diabetes
Age of onset - Type 1 <20 years, Type 2 >40 years
Speed of onset - Type 1 more acute (hours/days), Type 2 slower (weeks/months)
Weight of patient - Type 1 recent weight loss typical, Type 2 Obesity strong risk factor
Features - Type 1 features of DKA, Type 2 milder symptoms (polyuria, polydipsia)
Ketonuria - Type 1 common, Type 2 rare.
NICE recommend diagnosis Type 1 diabetes on clinical grounds in adults presenting with hyperglycaemia, bearing in mind that Type 1 diabetics also have one or more what features? (5)
One or more of;
Ketosis
Rapid weight loss
Age of onset <50 years
BMI below 25kg/m2
Personal and/or family history of autoimmune disease
What further test is recommended by NICE to diagnose Type 1 Diabetes?
Measurement of C-peptide and/or diabetes specific antibodies
How is type 1 diabetes managed? (4)
Multiple daily subcutaneous insulin injections
Monitor HbA1c every 3-6 months (target of >48mmol/L in adults)
Self-monitor blood glucose 4 times a day (before each meal and before bed)
Metformin (if BMI is >25kg/m2)
Describe the blood glucose targets for those being managed for type 1 diabetes
5-7mmol/L on waking AND 4-7mmol/L before meals at other times of the day
What complications can occur as a result of insulin treatment? And how can these be prevented?
Hyperglycaemia (due to not taking enough insulin)
Hypoglycaemia (due to taking too much)
Can use DAFNE (Dose Adjusted for Normal Eating) - Teaches patients how to adjust insulin doses relative to amount of carbohydrate they’re consuming.
DKA is more common in which form of diabetes?
Type 1 Diabetes
What is the most common management error leading to DKA?
Patients reducing/omitting insulin due to being unable to eat (nausea/vomiting).
Insulin should never be stopped, only adjusted.
Describe the pathophysiology of DKA (3)
Body responds as if were hypoglycaemic, stimulating ketogenesis
Uncontrolled peripheral lipolysis causes increase in free fatty acids > increases in Acetyl CoA results in excess ketone production.
Ketones are strong acids, so lower the pH of the blood, leading to metabolic acidosis.
Increased acidity of the blood impairs the ability of haemoglobin to bind to oxygen.
Give 4 symptoms of DKA
Breath/Urine smells like pear drops
Polyuria, Polydipsia, Dehydration (leading to AKI)
Vomiting/Severe weight loss
Hyperventilation/Breathlessness (Kussmaul’s respiration)
Define Kussmaul’s respiration. What complication of diabetes is it associated with? (2)
Associated with DKA
Describes paradoxical rise in JVP on inspiration or failure for appropriate fall of JVP with inspiration.
Give 3 diagnostic factors for DKA
Hyperglycaemia (blood glucose >11mmol/L)
Raised plasma ketones (Urine >2+ or >3mmol/L in blood)
Metabolic acidosis (plasma bicarbonate <15mmol/L, Blood pH <7.3)
What other features may be present on a blood test in patients with DKA?
Hyperkalaemia (acidosis promotes potassium efflux from cells) (Insulin can promote potassium influx into cells vis Na/H antiporter - sodium influx stimulates Na/K ATPase)
Raised urea and creatinine (renal failure)
How is DKA managed? (3)
Fluids - 0.9% Sodium Chloride +/- Potassium Chloride
Insulin - (IV infusion at 0.1unit/Kg/hour) (once blood glucose is <14mmol/L, 10% dextrose should be started in addition to 0.9% sodium chloride).
Long acting insulin should be continues, short-acting insulin should be stopped
How is DKA resolution defined? (3)
DKA resolution defined as;
pH >7.3 AND blood ketones <0.6mmol/L AND bicarbonate >15mmol/L
Give 5 complications of DKA
Gastric stasis
Thromboembolism (hyperglycaemia causes hyperviscosity -thicker blood)
Cardiac arrhythmias (due to hyper/hypokalaemia)
Acute respiratory distress syndrome
Acute kidney injury
Name 1 common trigger for DKA and how is causes DKA.
Infection
Increases epinephrine release > increases glucagon levels > results in gluconeogenesis and glycogenolysis > hyperglycaemia
Give 1 important complication of fluid resuscitation in DKA (especially in young patients). How may this present and why does this occur?
Cerebal oedema
Presents as; Low GCS, Incontinence, vomiting, resp symptoms; grunting, apnoea, tachypnoea
When fluids are given too quickly, the sudden drop in blood osmolarity can lead water to move into cerebral tissue, causing oedema
Describe type 2 diabetes
Describes diabetes mellitus forming from a combination of insulin resistance and less severe insulin deficiency.
Describe the epidemiology of type 2 diabetes (4)
Age - Patients tend to be > 40
Fitness - Patients tend to be overweight/obese
Ethnicity - Tends to be more prevelent in South Asian, African and Caribbean
Sex - More common in males
Give 4 risk factors for type 2 diabetes
Obesity/lack of exercise/calorie alcohol excess
Increasing age
Family history
Low birth weight (impairs beta cell development and function)
Describe the pathophysiology of type 2 diabetes
Insulin resistance likely occurs due to a defect in the translocation of GLUT4 to the membrane.
Established T2DM leads to hypersecretion of insulin by depleted beta cells. Resulting in high circulating levels of insulin.
Insulin blood levels increase due to increased glucose production from the liver (due to inadequate suppression of gluconeogenesis) and reduced glucose uptake by peripheral tissues (insulin resistance).
Why don’t type 2 diabetics tend to develop DKA?
As even a small amount of insulin can halt the breakdown of fat and muscle into ketones.
Define 2 states of pre-diabetes
Impaired glucose tolerance (IGT) - When blood glucose levels are elevated but they’re not high enough to be classified as diabetes
Impaired Fasting Glucose (IFG) - When blood glucose levels are elevated in a fasting state but they’re not high enough to be classified as diabetes.
Describe 4 macrovascular complications of Type 2 diabetes
Myocardial infarction (4x more common)
Stroke (2x more common)
Atherosclerosis (can lead to stroke, IHD or PVD)
Peripheral Vascular Disease (can lead to amputation)
Diagnostically define Impaired Glucose Tolerance (IGT) (2)
Fasting plasma glucose - <7mmol/L
Oral glucose tolerance test - >7mmol/L but <11mmol/L
Describe 4 symptoms of peripheral vascular disease secondary to type 2 diabetes
Diminished or absent pedal pulses
Coolness of feet
Poor skin and nails
Absence of hair on feet and legs
Diagnostically define Impaired Fasting Glucose (IFG)
Fasting Plasma Glucose - >6.1mmol/L but <7mmol/L
How can peripheral vascular disease be detected?
Detected via doppler ultrasound
How is type 2 diabetes diagnosed? (3)
Fasting plasma glucose >7mmol/L
Random plasma glucose >11.1mmol/L
HbA1c >48mmol/mol (diagnostic)
(must be fulfilled on 2 separate occasions if asymptomatic)
When may HbA1c not be used for diagnosis of Type 2 diabetes? (8)
Increase in HbA1c can be caused by increased red cell turnover, occurring in;
Haemoglobinopathies
Haemolytic anaemia
Untreated iron deficiency anaemia
Gestational diabetes
Children
HIV
CKD
Corticosteroid use
Describe the initial management of Type 2 Diabetes (3)
Assess cardiovascular risk (QRISK >10%)
If QRISK <10% - Metformin
If QRISK >10% or Pt has CVD, or Pt has chronic heart failure - Metformin + SGLT-2 inhibitor (Empagliflozin/Dapagliflozin)
*SGLT-2 inhibitors should be started at any point if patient develops CVD)
Describe risk factor management patient Type 2 diabetes (4)
Lifestyle and dietary changes
Blood pressure control - Ramipril (ACEi) or ARB (in Afro-Caribbean)
Hyperlipidaemia control - Statins (Atorvastatin if QRISK >10%)
Obesity control - Orlistat
When metformin be contraindicated? Why? (3)
Heart failure
Liver disease
Renal disease
Can induce lactic acidosis
Give 4 side effects of metformin
Gastrointestinal upset;
Anorexia
Diarrhoea
Nausea
Abdominal pain
What should be given as an initial management of type 2 diabetes if metformin is contraindicated? (2)
If patient has CVD disease/risk - SGLT-2 monotherapy
If patient does not have CVD disease/risk - DPP-4 inhibitor or pioglitazone or a sulfonylurea
Describe the treatment ladder for Type 2 diabetes (3)
1st line (monotherapy) - Metformin (+/- SGLT-2 inhibitor - depending on CVD risk)
2nd line (dual therapy) - Add; DPP-4 inhibitor OR Pioglitazone OR sulfonylurea OR SGLT-2 inhibitor
3rd line;
- Metformin + DPP-4 inhibitor + sulfonylurea
- Metformin + Pioglitazone + Sulfonylurea
- Metformin + (Pioglitazone or sulfonylurea or DPP-4 inhibitor) + SGL-2 inhibitor
- Insulin based treatment
What is the 4th line treatment for type 2 diabetes?
Glucagon-like peptide (GLP analogues) - Exenatide + Liraglutide
Describe the HbA1c targets for patients on lifestyle or single drug treatments of Type 2 diabetes
Lifestyle - 48mmol/mol
Lifestyle + metformin - 48mmol/mol
Lifestyle + Sulfonylurea (can cause hypoglycaemia) - 53mmol/mol
What is the HbA1c target for type 2 diabetic already on 1 drug but HbA1c has risen to 58mmol/mol?
53mmol/mol
Describe the MOA of metformin (2)
Suppresses gluconeogenesis and glycogenolysis in liver
Increases cells’ sensitivity to insulin
Name and describe MOA of DPP4 inhibitors
Sitagliptin (gliptins)
Dipeptidyl peptidase 4 inhibitors. DPP4 usually breaks down incretin. Incretin stimulates insulin release facilitating decrease in blood glucose levels.
What can DPP4-inhibitors (gliptins) increase the risk of?
Pancreatitis
Name and describe the moa of sulfonylurea
Gliclazide
Stimulates insulin secretion from pancreatic beta cells by binding and blocking K+ channels > stimulates influx of calcium into beta cells > stimulates exocytosis of vesicles containing insulin.
When should sulfonylureas not be used?
In obese patients as can cause weight cain and fluid retention.
Can also cause hypoglycaemia if overused.
Name and describe MOA of SGLT-2 inhibitors
Empagliflozin and Dapagliflozin
Selective sodium glucose co-transporter 2 inhibitor
Blocks glucose reabsorption in the proximal tubule, promoting excretion of glucose in urine
Give 3 side effects of SGLT-2 inhibitors (Empagliflozin/Dapagliflozin)
DKA, Hypoglycaemia, Increased risk of Infection
Describe the MOA of poiglitazone
Increases cellular insulin sensitivity
Give 3 complications of pioglitazone
Increases risk of heart failure, bladder cancer and bone fractures
In who should pioglitazone be avoided? (4)
In patients with history of;
Bladder cancer
Heart Failure
Hepatic Impairment
DKA
How can diabetic nephropathy be diagnosed?
Urine Albimin:Creatinine ratio >3 indicated microalbuminuria
How is diabetic nephropathy treated? (2)
ACEi/ARBs (ramipril/candesartan)
Avoid metformin (contraindicated in renal disease)
Name symptoms of diabetic neuropathy (2-7)
Somatic symptoms;
Pain (worse at night)
Numbness (glove and stocking distribution - hands and feet)
Pareaesthesia
Autonomic symptoms;
Postural hypotension
Gastroparesis
Diarrhoea, constipation, incontinence
Erectile dysfunction
Describe a life threatening emergency associated with uncontrolled type 2 diabetes (3)
Hyperosmolar Hypeglycaemic State.
Characterised by marked hyperglycaemia, hyperosmolality and mild/no ketosis.
Important to distinguish from DKA as insulin therapy (Mx of DKA) can produce adverse effects of HHS
How is diabetic neuropathy managed?
1st line - Amitriptyline, Duloxetine, Gabapentin or Pregabalin
Tramadol can be used as a ‘rescue therapy’ for exacerbations of neuropathic pain
Give 3 risk factors for hyperosmolar hyperglycaemic state
Infection (most common) (particularly pneumonia)
Consumption of glucose rich fluids
Concurrent medications; thiazide diuretics or steroids
In who should amitryptiline be avoided?
In those with urinary retention (i.e BPH)
AmiDRIPtiline
Describe the pathophysiology of Hyperosmolar Hyperglycaemic State
Insulin levels decrease > Hepatic ketogenesis is inhibited but hepatic gluconeogenesis still occurs > Hyperglucaemia > osmotic diuresis > Loss of sodium and potassium > volume depletion and raised serum osmolairy > Hyperviscosity
Describe the clinical presentation of Hyperosmolar Hyperglycaemic State (4)
Osmotic symptoms (polyuria, polydipsia, weight loss)
Severe dehydration
Decreased level of consciousness
Stupor (near unconsciousness) or coma (rare)
What tests may be conducted to investigate ? Hyperosmolar Hyperglucaemic State (5)
Blood glucose - >30mmol/L, no ketones or acidosis (pH >7.3, bicarbonate >15mmol/L)
Hyperosmolality - >320mmol/Kg
Urine dipstick - Heavy glycosuria)
Hypovolemia
Hyperkalaemia/hypokalaemia
How is hyperosmolar hyperglycaemic state managed?
Slow rehydration - 0.9% saline +/- electrolyte replacement over 48 hours
Insulin - only if blood glucose is NOT falling by 5mmol/L following rehydration OR if NO ketonaemia present
Low Molecular Weight Heparin - Enoxaparin
(reduces risk of thromboembolism, stroke, MI)
What is the function of the thyroid?
Controls metabolism, growth and development.
What 3 hormones are produced by the thyroid?
T3 - Most active
T4 (thyroxine) - Less active but more abundant
Calcitonin (produced by parafollicular cells)
What molecule and process is required for the synthesis of thyroid hormones?
Iodine
Iodination of tyrosine molecules AND combination of two tyrosine residues.
Describe the Hypothalamic Pituitary Thyroid Axis
HPT axis regulates thyroid hormone synthesis
Neurones in the paraventricular nucleus of the hypothalamus release Thyrotropin Releasing Hormone (TRH).
TRH stimulates release of Thyroid Stimulating Hormone (THS) from the anterior pituitary.
TSH travels to thyroid gland and stimulates release of T3 and T4.
T3 and T4 negatively feedback to TSH and TRH.
From where is Thyotropin Releasing Hormone released?
Paraventricular Nucleus of the Hypothalamus
From where is Thyroid Stimulating Hormone produced?
Anterior pituitary
Describe the Wolff-Chiakoff effect. When is this useful clinically?
Describes an autoregulatory phenomenon in which thyroid hormone synthesis is inhibited irrespective of serum TSH levels, when excess iodine is ingested.
Useful clinically as pharmaceutical doses of iodine may be used to acutely reduce thyroid activity.
Name 3 types of thyroid disorders
Hyperthyroidism - Graves’ Disease (overactive thyroid)
Hypothyroidism - Hashimoto’s thyroiditis/Iodine deficiency (underactive thyroid)
Thyrotoxicosis (excessive amount of thyroid hormone in in the body)
Describe 2 types of goitre formation and describe when they’re seen?
Diffuse (Entire thyroid gland swells, is smooth to touch)
Associated with; Iodine deficiency, Graves’, Hashimotos, De Quervain’s
Nodular (lumpy - solitary or multinodular)
Associated with: adenoma/cyst, carcionma
What hormone is the basis of screening for possible thyroid disease?
TSH
What will circulating levels of TSH, T4 and T3 look like in primary hyperthyroidism?
Low TSH
High T4
High T3
What will circulating TSH, T3 and T4 levels look like in hypothyroidism?
High TSH
Low T3
Low T4
If TSH is raised, T3 is low and T4 is raised, what is the likely diagnoses? Why?
Deiodinase deficiency or euthyroid hypothyroxinaemia
Because T4 is converted into T3 by deiodinases. If these are deficient then T3 is unable to be generated.
Thyroid function tests - Name 3 antibodies that are useful for diagnosing autoimmune thyroid disease.
Anti-TPO antibodies (Graves’/Hashimoto’s)
Antithyroglobulin antibodies (Graves’/Hashimoto’s/Cancer)
TSH receptor antibodies (Graves’)
Thyroid function tests - What imaging tool is used to investigate thyroid nodules?
Ultrasound (can also be used for guided biopsy)
Thyroid function tests - Describe the use and purpose of a radioisotope scan
Used to investigate hyperthyroidism and thyroid cancers, providing functional information about the thyroid.
Radioactive iodine is given orally/IV. This is taken up by the thyroid.
The more active the thyroid cells, the faster the radioactive iodine will be taken up.
(e.g Graves will show diffuse uptake of radioactive iodine. Toxic multi-nodular goitre will show focal high uptake)
Define primary hyperthyroidism
Describes pathology of the thyroid itself, causing it to produce too much thyroid hormone
Define secondary hyperthyroidism
Occurs when the thyroid is producing too much thyroid hormone due to overstimulation from thyroid stimulating hormone (TSH).
May rise due to an issue with the pituitary or hypothalamus.
Give 5 causes of hyperthyroidism
Graves’ disease
Toxic Multinodular goitre
Solitary toxic adenoma/nodule
Amiodarone
Sub acute de Quervain’s thyroiditis
Describe Graves’ disease
Most common form of hyperthyroidism.
Graves’ disease describes an autoimmune disease characterised by the production of Thyroid Stimulating Immunoglobin (igG) from b lymphocytes.
Thyroid Stimulating Immunoglobin mimics TSH, binds to and activates TSH receptors on the thyroid cell membrane, stimulating synthesis of T3 and T4.
Give 5 risk factors for Graves’ disease
Female (biggest risk factor - common post-partum)
Genetic association (HLA-B8, DR2 and DR3)
Infection - E.coli contain TSH binding sites.
High iodine intake
Autoimmune disease (vitiligo, addisons, pernicious anaemia, myasthenia gravis, Type 1 diabetes)
Name 5 autoimmune diseases associated with Grave’s disease
Vitiligo
Addison’s disease
Pernicious anaemia
Myasthenia gravis
Type 1 diabetes
Give 5 clinical features of Graves’ disease
Sweating, weight loss, irritability
Palpitations/tachycardia/cardiac flow murmur
Diffuse (smooth) goitre
Heat intolerance
Graves orbitopathy (only occurs in Graves’)
How may Graves’ orbitopathy present? (3)
Presents in 25% of Graves’ patients
Results in retro-orbital inflammation and swelling of the extraocular muscles
May present as;
Upper eyelid retraction
Exophthalmos (protruding eye)
Optic neuropathy
Give 2 rare but distinct clinical signs of Graves’ disease
Pretibial myxoedema - Arises from excess hyaluronic acid leading to deposits of mucin under the skin. Presents as swelling and lumpiness in the lower legs (may be red)
Acropachy - Finger clubbing with erosion of the distal phalanges
What will thyroid function tests show in a patient with Graves’ disease?
Free TSH - Low
Serum T4/T3 - High
TSH receptor antibodies - Positive (highly specific)
What test can be used to identify Graves Orbitopathy?
MRI or CT
How is Graves’ disease initially managed?
Symptom control;
Beta blockers - Propranolol
Hydrocortisone (for Graves’ dermopathy)
IV Methylprednisolone (for Graves’ orbitopathy)
Antithyroid drugs;
First line - Carbimazole (continued for 12-18 months)
Second line - Propylthiouracil (used in pregnancy as Carbimazole is teratogenic)
If Graves’ patient relapses following Anti-Thyroid Drug treatment, what treatment is offered?
1st line - Radioiodine treatment
2nd line - Thyroidectomy
Give 1 complication of radioiodine therapy
Can lead to hypothyroidism resulting in patient requiring thyroxine replacement therapy (levothyroxine)
What is the major complication of Carbimazole?
Agranulocytosis (increases risk of sepsis)
Give 3 possible consequences of thyroidectomy
Can risk damaging the recurrent laryngeal nerve
Can cause parathyroidism
Patients become hypothyroid so require life-long thyroid replacement therapy.
Name and describe 2 treatment strategies for hyperthyroidism
Titration Regimen (12-18 months) - Dose of drug is reduced (every 1-2 months) with the aim of keeping the patient on the lowest dose required for normal thyroid function.
Block and replace - Give high dose carbimazole to stop thyroid producing T3/T4. When T3/T4 levels return to normal range, give levothyroxine replacement.
What is the MOA of Carbimazole?
Inhibits TPO from coupling and iodinating tyrosine residues.
In whom is Carbimazole contraindicated?
In pregnancy as it is teratogenic
Describe subclinical hyperthyroidism (2)
Describes a condition where there is low TSH levels but normal T3 and T4.
Most causes are iatrogenic, especially due to over treatment with levothyroxine (T4)
Describe Toxic Multinodular Goitre (4)
Describes hyperthyroidism in which nodules form on the thyroid gland, each producing excessive amounts of thyroid hormone.
2nd most common form of thyrotoxicosis
Primarily seen in elderly and in iodine deficient areas.
1st line - Radioactive iodine therapy (I-131)
Describe De Quervain’s thyroiditis and it’s two phases. How is it treated? (3)
Occurs when a viral infection (i.e URTI)causes pain and inflammation in the thyroid.
Two phases;
A hyperthyroid phase followed by a hypothyroid phase.
(Occurs as TSH levels fall due to negative feedback from the hyperthyroid phase)
Treatment; NSAIDs and Beta blockers for symptomatic relief
Name 3 drugs that can induce hyperthyroidism
Amiodarone (anti-arrhythmic drug) (Can cause both hyper and hypothyroidism.
Iodine
Lithium
What blood results would you expect in a patient with De Quervain’s Thyroiditis? (T4, ESR, Uptake of Iodine-131)
T4 - Raised
ESR - Raised
Uptake of Iodine-131 - Reduced
What effect can amiodarone have on the thyroid? How can each happen?
Can cause Hyperthyroidism (due to high iodine content)
Can cause hypothyroidism (as inhibits conversion of T4 to T3)
Describe a Thyroid Storm (Aka thyrotoxic crisis)
Describes an acute, severe, life-threatening presentation of hyperthyroidism.
Usually precipitated by stress, infection, surgery or radioactive iodine therapy.
How may a thyroid storm (thyrotoxic crisis) present? (3)
Pyrexia (raised body temp)
Tachycardia
Delerium/Coma
How is thyroid storm (thyrotoxic crisis) treated? (4)
Oral Carbimazole
Oral Propranolol
Oral Potassium Chloride (acutely blocks release of T3/T4)
IV Hydrocortisone (inhibits peripheral conversion of T4 to T3)
Describe hypothyroidism
Describes underactivity of the thyroid gland resulting in symptoms associated with a lack of thyroid hormone.
What is the most common cause of hypothyroidism in the developing world?
Iodine deficiency
What is the most common cause of hypothyroidism in the developed world?
Autoimmune/atrophic hypothyroidism - Hashimotos’
Give 5 risk factors for Hypothyroidism
Iodine deficiency (developing world)
Autoimmune diseases (Hashimoto’s is the most common in the developed world)
Female
Turners’/Down’s syndrome
Drugs (amiodarone and lithium)
Give 7 clinical features of hypothyroidism
Tiredness/sleepy/lethargic
Decreased mood/depression
Cold sensitivity
Weight gain
Constipation
Muscle weakness/myalgia
Menorrhagia (menstrual bleeding lasting >7 days)
Using the acronym BRADYCARDIC, give clinical signs of hypothyroidism.
- Bradycardia
- Reflexes relax slowly
- Ataxia (cerebellar)
- Dry thin hair/skin
- Yawning/drowsy/coma
- Cold Hands/Low body temperature
- Ascites (+/- pitting oedema in feet, hands, eye lids) (+/- pericardial or pleural effusion)
- Round puffy face/double chin/obese
- Defeated demeanour
- Immobile
- CCF – Congestive Cardiac Failure
What hand pathology is associated with hypothyroidism?
Carpal Tunnel Syndrome
What antibodies are raised in Hashimoto’s Thyroiditis?
Anti-TPO antibodies (raised in >90% of patients)
How is hypothyroidism treated?
Young and healthy - Levothyroxine therapy
Elderly or Ischaemic heart disease - Low dose levothyroxine (as too much can precipitate angina or MI)
Over-replacement of levothyroxine in hypothyroid patients can increase the risk of developing what?
Osteoporosis and atrial fibrillation
Define Hashimoto’s thyroiditis
Most common cause of hypothyroidism in the developed world.
Characterised by the formation of antithyroid antibodies that attack thyroid tissue, causing lymphocyte infiltration, atrophy and progressive fibrosis, leading to decreased thyroid hormone production.
Hashimoto’s thyroiditis is associated with the development of what?
MALT lymphoma (mucous associated lymphoid tissue)
What will Thyroid Function tests show in a patient with Hashimoto’s thyroiditis?
High TSH
Low T3
Low T4
High Anti-TPO antibodies
Name one complication of giving iodine supplementation to patients with iodine deficiency goitre
Can cause iodine-induced hyperthyroidism (aka Jod-Basedow Effect)
Occurs as some patients Wolff-Chaikoff effect due to impaired autoregulation.
Describe Post-Partum Thyroiditis
Describes a short lasting (transient) episode of thyroid dysfunction occurring within the first year post-partum.
No presence of toxic nodule or TSH receptor antibodies.
Usually follows a pattern of hyperthyroidism/thyrotoxicosis followed by hypothyroid followed by euthyroid.
What would thyroid function tests show in post partum thyroiditis?
Low TSH
High T4
High T3
Negative TSH antibodies
When is it recommended to test TSH levels post partum?
Test 6-12 weeks post-partum, particularly in high risk populations and in patients experiencing postpartum depression, lactation difficulties or hyper/hypothyroidism.
Name 1 complication of hypothyroidism and describe how it is treated
Myxoedema coma
Features;
Confusion/coma
Hypothermia
Cardiac failure
Hypoventilation/Hypoglycemia/Hyponatremia
Treatment;
IV/Oral T3
Glucose infusion
Gradual rewarming
Are features of hyper/hypothyroidism seen in thyroid cancer?
No as they rarely secrete excess thyroid hormone.
Name 5 types of thyroid cancers
Papillary (70%)
Follicular (20%)
Medullary (5%)
Anaplastic (rare)
Lymphoma (rare)
Describe sub-clinical hypothyroidism
No obvious symptoms
TSH is raised but T3 T4 are normal
Describe papillary thyroid carcinomas (3)
Most common type of thyroid carcinoma
Often seen in young females and have a good prognosis
Well differentiated and arise from thyroid epithelium
How is sub-clinican hypothyroidism managed in relation to TSH levels?
If TSH is >10mU/L and T3/T4 is normal = Consider offering levothyroxine if TSH level is >10mU/L on 2 separate occasions 3 months apart.
If TSH is 5.5-10mU/L and T4 is normal =
If <65 consider offering 6 month trial of levothyroxine if; TSH level is 5.5-10mU/L on 2 separate occasions 3 months apart AND there are symptoms of hypothyroidism.
Describe follicular thyroid carcinomas (3)
Usually present as a solitary thyroid nodule
Well differentiated and arises from thyroid epithelium
More likely than papillary to spread to lung/bone but usually has a good prognosis
Describe medullary thyroid carcinoma (2)
Arises from parafollicular (c-cells) and secrete calcitonin
Associated with the hereditary condition (MEN-2) (multiple endocrine neoplasia type 2)
Describe anaplastic thyroid carcinomas (3)
Very undifferentiated and arises from thyroid epithelium
Tend to be aggressive, spreading local quickly and has a poor prognosis.
Management is generally palliative.
Medullary Thyroid Cancer is associated with MEN-2. What type of cancer is this associated with? How may this present?
Phaeochromocytoma
May present as poorly controlled hypertension.
Describe the clinical presentation of thyroid cancer (4)
90% present as thyroid nodules
May present as cervical lymphadenopathy or with lung, cerebral, hepatic or bone metastases
Dysphagia
Hoarseness of voice (due to tumour compressing oesophagus/recurrent laryngeal nerve)
Name 4 diagnostic tests used to diagnose thyroid cancer
Fine needle aspiration cytology biopsy
Thyroid Function tests (to assess hyper/hypothyroid)
Laryngoscopy (may show ispilateral paralysed vocal cord - suggestive of malignancy)
Circulating thyroglobulin (>90% if differentiated thyroid carcinomas secrete thyroglobulin)
What may a fine needle aspiration cytology biopsy show for a papillary carcinoma? (3)
Orphan Annie eyes
Intranuclear holes and grooves
Pasmmoma bodies
What may a fine needle aspiration cytology biopsy show for follicular thyroid carcinoma?
Hypercellularity (excess cells)
Microfollicles
Absence of colloid
In which type of thyroid carcinoma would you see orphan annie eyes on cytology?
Papillary carcinoma
What type of thyroid carcinoma commonly secretes calcitonin?
Medullary thyroid carcinomas
How are papillary and follicular carcinomas treated? (4)
Total thyroidectomy
Node excision
Radioiodine therapy
Levothyroxine (Suppresses TSH which acts as growth factor for cancer)H
How are medullary thyroid carcinomas treated?(3)
Thyroidectomy and lymph node removal
Levothyroxine (for replacement rather than suppression)
Vandetanib (2nd line) - Used for more aggressive cancers
What class of drug is Vandetanib and what is it used to treat?
Tyrosine Kinase Inhibitor
Used to treat more aggressive/metastatic medullary thyroid cancers
Define carcinoma
Describes malignant neoplasms of epithelial origin
Name and define 2 subtypes of carcinomas
Adenocarcinoma - Develops from an organ or gland.
Squamous cell carcinoma - Develops from squamous epithelium
Define sarcoma
Refers to malignant cancer that originates in supportive and connective tissues, such as; bone, tendons, cartilage, muscle or fat
What is the benign and malignant name for Bone cancers
Osteoma and Osteosarcoma
What is the benign and malignant name for cartilage cancers
Chondroma and Chondrosarcoma
What is the benign and malignant name for smooth muscle cancers
Leiomyoma and leiomyosarcoma
What is the benign and malignant name for skeletal muscle
Rhabdomyoma and Rhabdomyosarcoma
What is the benign and malignant name for cancers of the membranous lining of body cavities?
Mesothelioma and mesothelial sarcoma
What is the benign and malignant name for cancers of fibrous tissue?
Fibroma and Fibrosarcoma
What is the benign and malignant name for cancers of blood vessels?
Hemangioma and Angiosarcoma/Hemangioendothelioma
What is the benign and malignant name for cancer of adipose tissue?
Lipoma and Liposarcoma
What is the benign and malignant name for cancer of primitive embryonic connective tissue?
Myxosarcoma
Describe the adrenal glands
Adrenal glands are paired endocrine glands (retroperitoneal) situated over the medial aspect of the upper poles of each kidney.
They consist of an outer connective tissue capsule, a corted and a medulla.
What are the adrenal glands neurologically innervated by?
Coeliac plexus and greater splanchnic nerves (T5 to T8)
From where do the adrenal glands receive their blood supply? (3)
Superior adrenal artery (arises from inferior phrenic artery)
Middle adrenal artery (arises from abdominal aorta)
Inferior adrenal artery (arises from renal arteries)
What veins drain blood from the adrenal glands? (2)
Right adrenal vein = Inferior Vena Cava
Left adrenal vein = Left renal vein
What are the 3 regions of the adrenal cortex (from superficial to deep)
(GFR - Makes Good Sex)
Zona Glomerulosa
Zona Fasciculata
Zona Reticularis
What does the zona glomerulosa produce?
Mineralocorticoids (such as aldosterone)
What does the Zona Fasciculata produce?
Glucocorticoids (cortisol - corticosteroids)
What does the Zona Reticularis produce?
Androgens
What does the medulla of the adrenal gland produce? (2)
Contains chromaffin cells which secrete catecholamines (i.e adrenaline) into the blood in response to stress.
Also secrete enkephalins which function in pain control
Describe the Hypothalamic-Pituitary-Adrenal Axis (4)
Corticotrophin Releasing Hormone (CRH) is secreted by the hypothalamus.
CRH acts on the anterior pituitary, secreting secretion of adrenocorticotrophic hormone (ACTH).
ACTH acts on the adrenal cortex, stimulating production of cortisol (glucocorticoid) and androgens.
Both negatively feed back to inhibit further secretion of CRH and ACTH
Where in the adrenal gland is cortisol produced?
Zona Fasciculata
With regards to cortisol, what happens physiologically in response to stress?
The amygdala sends stress signals to the hypothalamus.
This kickstarts the HPA axis
Leads to cortosol and adrenaline secretion
Name 5 functions of cortisol
Increases blood pressure
Increases insulin resistance
Increases gluconeogenesis, lipolysis and proteolysis
Inhibits bone formation (increases risk of osteoporosis)
Inhibits inflammatory and immune responses
Define Cushing’s Syndrome
Describes a disease of cortisol excess and loss of normal feedback mechanism of the HPA axis.
Define Cushing’s Disease
Characterised by excess cortisol production resulting from inappropriate ACTH secretion from a pituitary adenoma.
Give 2 ACTH dependent causes of Cushing’s
Cushing’s disease - Bilateral adrenal hyperplasia resulting from an ACTH secreting pituitary adenoma
Paraneoplastic Cushing’s Syndrome - Ectopic ACTH secreting tumour (Small lung cancer)
Give 3 ACTH independent causes of Cushings
(More common than ACTH dependent causes)
Iatrogenic (most common cause is oral steroids - prednisolone)
Adrenal adenoma/cancer
Adrenal nodular hyperplasia
What is the most common cause of Cushing’s Syndrome?
Use of Oral Corticosteroids (prednisolone)
Give 6 clinical features of Cushing’s Syndrome
Swollen/Moon Face/
Weight gain (central obesity)/Purple striae/Buffalo Hump (far build up on back of neck)
Mood change (depression, lethargy, irritability)
Gonadal dysfunction (irregular menses, hirsutism, erectile dysfunction)
Infections
Increased BP
Premature osteoporosis or unexplained fractures
What electrolyte disturbance can be seen in Cushing’s?
Hypokalaemia (leading to metabolic alkalosis)
What is the 1st line screening test for Cushing’s? What are the findings?
Overnight (low-dose) dexamethasone suppression test.
Patients with Cushing’s do NOT have their morning cortisol spike suppressed.
Results = Elevated cortisol
What other tests can be used to screen for Cushings? (2)
24hr urinary free cortisol (2 measurements required)
Bedtime salivary cortisol (2 measurements required)
What is dexamethasone? What impact does dexamethasone have on the HPA axis?
A corticosteroid with high glucocorticoid activity, meaning it acts similarly to cortisol.
Dexamethasone negatively feeds back to the pituitary gland, decreasing ACTH release, resulting in a decrease in cortisol secretion from the Zona Fasciculata.
What is the importance of the dexamethasone suppression test? (2)
In pathological hypercortisolism, the HPA axis is partially or entirely resistant to feedback inhibition by dexamethasone, so cortisol levels will be elevated.
The test allows us to confirm diagnosis of Cushing’s Syndrome AND understand whether the cause is primary or secondary
What test allows us to diagnose Cushing’s Syndrome? What will the results show?
Low Dose (1mg) Dexamethasone Suppression Test.
Cortisol levels will remain high (as Cushing’s patients already have high circulating cortisol levels)
What test identifies the cause of Cushings?
High dose (8mg) dexamethasone suppression test
High dose dexamethasone suppression test results = Low Cortisol + Low ACTH.
What does this suggest?
AVTH secreting pituitary adenoma
High dose dexamethasone suppression test results = High Cortisol + Low ACTH
What does this suggest?
Adrenal Cushing’s (Adrenal tumour producing excess cortisol)
High dose dexamethasone suppression test results = High Cortisol + High ACTH
What does this suggest?
Paraneoplastic Cushing’s (ectopic source of ACTH - Small cell lung cancer/carcinoid tumour)
What results would you get from a high dose dexamethasone suppression test for a patient with an ACTH Secreting Pituitary adenoma?
Low Cortisol + Low ACTH
If a ACTH secreting tumour is present, the high dose dexamethasone should be enough to inhibit it’s ACTH release.
What results would you get from a high dose dexamethasone suppression test for a patient with a cortisol secreting adrenal gland tumour?
High cortisol + Low ACTH
The dexamethasone will have no impact on cortisol levels because the cortisol is being secreted from the adrenal glands irrespective of ACTH.
What results would you get from a high dose dexamethasone suppression test for a patient with a paraneoplastic ACTH secreting tumour?
High Cortisol and High ACTH
Dexamethasone inhibits ACTH secretion from the pituitary but ACTH is being produced ectopically, so it’s level will remain high.
How is Cushing’s syndrome treated?
Treat the cause;
Iatrogenic (corticosteroid use) - Stop medications
Cushing’s Disease;
- Trans-sphenoidal resection of causative pituitary tumour
- Bilateral adrenalectomy (removal of adrenal glands)
Adrenal adenoma/carcinoma;
- Adrenalectomy
Give one complication of Bilateral Adrenalectomy
Nelson’s syndrome;
Increased skin pigmentation (due to increased ACTH) from an enlarging pituitary tumour as adrenalectomy will remove the negative feedback.
May also have intracranial compressive symptoms due to pituitary growth.
Will respond to pituitary radiotherapy.
Where in the adrenal cortex is Aldosterone produced?
Zona Glomerulosa (outermost layer)
What is the primary function of aldosterone? (3)
Acts on principle cells in the distal convoluted tubule and collecting duct.
Stimulates sodium reabsorption and potassium secretion.
Achieves this by increasing expression of sodium channels and sodium/potassium ATPase in the cell membrane.
What system controls the production of aldosterone? Where is this located?
Renin-angiotensin system.
Responding to renin release by the juxtaglomerular cells of the afferent arterioles of the kidney.
Describe the Renin-Angiotensin-Aldosterone System in relation to low blood pressure.
Low blood pressure is detected by juxtaglomerular cells in the afferent arteriole of the kidney, stimulating the release of renin.
Renin converts angiotensin (produced by the liver) to angiotensin I.
Angiotensin I is converted to Angiotensin II in the lungs by Angiotensin Converting Enzyme (ACE)
Angiotensin II stimulates release of aldosterone from zona glomerulosa.
Aldosterone stimulates expression of sodium channels and Na/K+ ATPases in the membranes of principle cells in the distal convoluted tubule and collecting duct.
This increases sodium reabsorption and potassium excretion.
Also works in conjunction with ADH to increase water reabsorption in the proximal convoluted tubule.
This eventually increases plasma volume, increasing blood pressure.
Where is renin produced?
Kidney
Where is angiotensin produced?
Liver
Where is angiotensin I converted to angiotensin II? What enzyme catalyses this reaction?
In the Lungs
Catalysed by Angiotensin Converting Enzyme (ACE)
Define Conn Syndrome (Primary Hyperaldosteronism)
Describes condition characterised by excess production of aldosterone independent of the renin-aldosterone system.
What is Conn Syndrome (primary hyperaldosteronism) the most common cause of? Why?
Secondary Hypertension
Aldosterone promotes sodium reabsorption (and thus water reabsorption), thus increasing plasma volume and increasing blood pressure.
What are the main physiological effects of Conn Syndrome (Primary Hyperaldosteronism)? (5)
Increased Sodium Reabsorption (DCT)
Increased Water Reabsorption (PCT)
Increased Potassium Secretion (DCT)
Increased Hydrogen Ion Secretion (CD)
Decreased Renin Release (due to negative feedback)
When should Conn Syndrome be suspected?
Hypertension in patients;
- Under 30 with no family history
- Accelerated (malignant) hypertension
- Hypokalaemia before diuretic surgery
- Resistant to antihypertensive therapy (e.g >3 drugs)
Hypokalaemia
Alkalosis
Hypernatremia
Give 2 causes of Primary Hyperaldosteronism
Adrenal adenoma (of zona glomerulosa) - Secreting excess aldosterone (Conn Syndrome) (2/3 of cases).
Bilateral adrenocortical hyperplasia (1/3 of cases).
Give 4 features of primary hyperaldosteronism
Treatment resistant hypertension
Symptoms of hypokalaemia (muscle weakness, hypertonis, cramps, palpitations, constipation, light-headedness)
Nocturia/polyuria
Metabolic alkalosis
What must primary hyperaldosteronism be differentiated from before initiating treatement?
Secondary hyperaldosteronism which arises when there is excess renin (and hence angiotensin II) which stimulates aldosterone release.
How does secondary hyperaldosteronism occur? What can cause it?
Occurs when blood pressure in the Kidneys is disproportionally lower than the rest of the body, usually doe to reduced renal perfusion.
Causes include;
- Renal artery stenosis/Obstruction
-Accelerated hypertension
-Diuretics
-Heart Failure
What is the most important diagnostic test for Primary Hyperaldosteronism?
Aldosterone:Renin Ratio
What Aldosterone to Renin Ratio would you expect to see in a patient with Primary Hyperaldosteronism?
Increased Aldosterone and Decreased Renin
What Aldosterone to Renin ratio would you expect to see in a patient with Secondary Hyperaldosteronism?
Increased Aldosterone and Increased Renin
What may an ECG show in a patient with Primary Hyperaldosteronism? And Why?
May show features of hypokalaemia;
Small or inverted T waves
Prominent U waves
A long PR interval
Depressed ST segment
What is the treatment for Conn’s Syndrome?
Laparoscopic Adrenalectomy
Spironolactone or eplerenone post-op to control blood pressure (aldosterone antagonists)
What is the treatment for bilateral adrenal hyperplasia?
Oral spironolactone or amiloride
Describe Addison’s Disease
Aka Primary Adrenal Insufficiency
Characterised by bilateral destruction of the entire adrenal cortex.
Results in Mineralocorticoid (aldosterone), Glucocorticoid (cortisol) and androgen (sex hormone) deficiency.
Eventually leads to an elevation of ACTH and CRH due to loss of negative feedback
When is Addison’s disease usually first recognised?
Has an insidious nature so usually not recognised until an acute adrenal crisis develops.
What is the most common cause of Addison’s disease in the UK?
Autoimmune adrenalitis (80% of cases)
Give 5 other causes of Addison’s disease
TB (most common worldwide)
Adrenal metastases
CMV (in HIV patients)
Long term steroid use
Adrenal haemorrhage/infarction (meningococcal septicaemia)
Give 6 symptoms of Addison’s disease
This Addison’s in all with unexplained abdominal pain or vomiting.
Lethargy/Depression
Anorexia/Weight loss
Posutral Hypotension (due to loss of aldosterone leading to hypovolemia)
Nausea/vomiting
Hyperpigmentation of the skin (due to increased ACTH > melanin)
What test is used to diagnose Addison’s disease? What does it involve?
Synacthen test
Involves giving synthetic ACTH IM to stimulate the adrenal glands to produce cotrisol.
In healthy individuals, cortisol levels will rise in response to synacthen.
In Addison’s patients, there will be no increase in cortisol
What will serum ACTH levels be like in a patient with primary adrenal insufficiency?
High
Define secondary adrenal insufficiency.
Most commonly caused by long term steroid use.
This leads to suppression of the pituitary-adrenal axis.
Characterised by a reduction in ACTH production.
Only becomes apparent on the withdrawal of steroids
What will ACTH levels be like in a patient with secondary adrenal insufficiency?
Low
What will serum electrolytes look like in a patient with primary adrenal insufficiency? (2)
Hyponatremia
Hyperkalaemia
How is Addison’s Disease Managed?
Glucocorticoid and Mineralocorticoid replacement.
Combination of;
Hydrocortisone 20-30mg OD (given in 2/3 divided doses)
Fludrocortisone
How should an Addison’s patient manage an intercurrent illness?
Double dose of glucocorticoid (hydrocortisone)
Continue with same dose of fludrocortisone
What hormones are secreted by the hypothalamus to act on the anterior pituitary? (5)
Corticotrophin Releasing Hormone (CRH)
Thyrotropin Releasing Hormone (TRH)
Growth Hormone Releasing Hormone (GHRH)
Gonadotrophin Releasing Hormone (GnRH)
Dopamine
How is an acute Addisonian crisis managed?
Resuscitation - IV saline + Hydrocortisone
What triad is seen in Addisonian crisis? (Na, K, Glucose)
Hyponatraemia
Hyperkalaemia
Hypoglycaemia
What hormones are secreted by the anterior pituitary? (6)
Follicle Stimulating Hormone (FH)
Leutinising Hormone (LH)
Adrenocorticotropic Hormone (ACTH)
Thyroid Stimulating Hormone (TSH)
Prolactin
Growth Hormone (GH)
Describe physiological effect of Thyrotropin Releasing Hormone on the body.
Thyrotropin-releasing hormone (TRH) → thyroid-stimulating hormone (TSH) → increases the release of T3 & T4 from thyroid → increased metabolism.
Describe the physiological effect of Gonadotropin Releasing Hormone (GnRH) on the body.
-Gonadotropin-releasing hormone (GnRh) → lutenizing hormone (LH) & follicle stimulating hormone (FSH) → target gonads to increase oestrogen, progesterone & testosterone
Describe the physiological effect of Growth Hormone Releasing Hormone (GHRH) on the body.
Growth-hormone releasing hormone (GHRH) → growth hormone (GH) → stimulates growth & protein synthesis
Describe the physiological effect of Somatostatin (SST) on the body
Somatostatin (SST) → inhibits growth hormone (GH) → inhibits growth & protein synthesis
Describe the physiological effect of Corticotropin Releasing Hormone (CRH) on the body.
Corticotropin-releasing hormone (CRH) -> adrenocorticotrophic hormone (ACTH) → increases cortisol production in the adrenal cortex from zona fasiculata
Describe the physiological effect of Dopamine on the body.
Dopamine (DA) → inhibits prolactin → inhibits breast growth/development & milk production
What is the difference between the anterior and posterior pituitary glands?
Anterior Pituitary Gland - Comprised of Glandular Tissue so is the hormone secreting part of the pituitary
Posterior pituitary - Contains axons that originate in the hypothalamus (an extension of the hypothalamus)
Name 2 hormones produced by the posterior pituitary and state their function.
Vasopressin (ADH) - Promotes water reabsorption by stimulating expression of Aquaporin 2 channels in cells of the proximal tubule.
Oxytocin;
- Released upon stimulation of mammary glands, stimulating release of milk.
- Stimulates contraction of uterine smooth muscle during child birth (important for contractions)
Name and describe 3 histological types of pituitary tumours
Chromophobe (70%) - Non secretory but 50% produce prolactin.
Acidophil - Secrete Growth Hormone or Prolactin. Responsible for majority of Acromegaly cases.
Basophil - Secrete ACTH
Give 5 clinical features of pituitary tumours
Headaches
Visual field defects - Bitemporal hemianopia
Palsy of cranial nerves 3,4,5 and 6 (pressure on cavernous sinus)
Diabetes insipidus (cranial)
CSF Rhinorrhoea (CSF leaking into nose and sinuses)
A pituitary tumour secreting prolactin can cause what? (3)
Galactorrhoea
Decreased Libido
Amenorrhoea
A pituitary tumour secreting Growth Hormone can cause what? (1)
Acromegaly
A pituitary Tumour secreting ACTH can cause what? (1)
Cushing’s Disease
What investigations are required for ? pituitary adenoma? (3)
Pituitary blood profile (inc GH, prolactin, ACTH, FSH, LSH and TFTs)
Visual Field Testing
MRI brain with Contract
What suppression tests may be useful in distinguishing pituitary adenomas? (3)
Water deprivation test = Diabetes Insipidus
Dexamethasone Suppression Test = Cushing’s Disease
Glucose tolerance test = Acromegaly
What is pituitary apoplexy?
Describes haemorrhage into the pituitary, resulting in pituitary enlargement.
How may pituitary apoplexy present? (4)
Headache
Meningism (triad = headache, neck stiffness and photophobia)
Low GCS
Bitemporal hemianopia
How is pituitary apoplexy treated? (2)
Urgent IV hydrocortisone and meticulous fluid balance.
Define a craniopharyngioma and describe where it originates.
Describes a benign pituitary tumour located at the top of the pituitary gland (suprasellar)
50% present in children (5-14yrs) with growth failure.
Originates from squamous epithelial remnants of Rathke’s pouch (originates between pituitary and 3rd ventricle floor)
What is the most common hormonal disturbance of the pituitary?
Hyperprolactinaemia (overproduction of prolactin)
Give 3 causes of hyperprolactinaemia
Drugs (most common) - Dopamine antagonists (metoclopromide, anti-psychotics, MDMA/Ectasy)
Physiological changes (pregnancy, breastfeeding, stress)
Disease (prolactinoma, pituitary stalk damage, hypothyroidism)
Give 3 drugs that can cause hyperprolactinaemia
Dopamine antagonists;
Metoclopromide (anti-emetic)
Risperidone (anti-psychotic)
MDMA/Ectasy
Give 5 symptoms of hyperprolacinaemia
Lactation (galactorrhoea)
Amenorrhoea (absent periods)
Decreased libido
Erectile dysfunction (men)
Increased weight
What physiologically causes the symptoms of hyperprolactinaemia?
Prolactin suppresses GnRH from the hypothalamus > Decreases FSH + LH secretion from the anterior pituitary > reduced levels of testosterone and oestrogen.
How is hyperprolactinaemia treated?
1st line - Dopamine agonists - Capergoline or Bromocroptine
2nd line - Trans-sphenoidal resection (surgery)
Describe the function of side effects of dopamine agonists. What are they used to treat? (3)
Used to treat Hyperprolactinaemia (capergoline and bromocroptine)
Function to inhibit prolactin secretion
Side effects; nausea, postural hypotension, fibrosis (lung/heart)
Define acromegaly
Acromegaly is characterised by excessive production of growth hormone from the anterior pituitary.
This results in excessive growth of body tissues.
What is the main cause of acromegaly?
Pituitary acidophil adenomas
What hormone stimulates growth hormone secretion?
Growth Hormone Releasing Hormone (GHRH)
What hormone inhibits growth hormone secretion?
Somatostatin
What hormone produced by the stomach stimulates growth hormone secretion?
Ghrelin
Describe the Growth Hormone/IGF-1 axis
Growth hormone stimulates IGF-1 production from the Liver > This exerts growth effects on the body > IGF-1 feeds back negatively to suppress GH and GHRH release
Give 6 symptoms of acromegaly
Acroparasthesia (numbness/tingling in extremities (hands and feet))
Amenorrhoea and decreased libido
Headache
Bitemporal Hemianopia
Snoring
Sweating
What hand pathology is linked to acromegaly?
Carpal Tunnel Syndrome
Give 4 clinical signs of acromegaly
Acral enlargement (enlargement of hands and feet)
Coarsening (harsh/rough) face (wide nose, big ears, prominent supraorbital ridges - frontal bossing)
Prognathism (protruding mandible)
Macroglossia (large tongue)
Give 3 complications of acromegaly
Glucose intolerance (IGF-1 competes with insulin for it’s binding site)
Diabetes mellitus
CVS ossies (Hypertension, Left ventricular Hypertrophy, Stroke)
What investigations are used to diagnose acromegaly?
1st - Serum IGF-1 (screening)
2nd - Oral Glucose Tolerance Test (confirms diagnosis)
Additional - Blood tests (Elevated glucose, calcium and phosphate - indicates skeletal growth)
What are the expected results of an oral glucose tolerance test for a patient with acromegaly?
No suppression of Growth Hormone
How is acromegaly managed? (4)
1st - Trans-sphenoidal resection of pituitary adenoma
2nd - Somatostatin Analogies - Octerotide or Lanreotide
3rd - GH antagonist - Pregvisomat
4th - Radiotherapy
Name 2 somatostatin analogues used in the treatment of acromegaly
Octerotide and Lanreotide
Name one Growth Hormone antagonist used in the treatment of acromegaly
Pregvisomat
Describe SIADH
Syndrome of Inappropriate Anti-Diuretic Hormone Secretion (SIADH)
Characterised by a euvolemic state, concentrated urine, hypotonic hyponatraemia secondary to impaired free water excretion, arising from excessive vasopressin release (ADH)
What does diagnosis of SIADH require?
Concentrated urine (osmolality >100mOsmol/Kg or Na >20mmol/L)
Hyponatraemia
Low plasma osmolality
Give 5 causes of SIADH
Malignancy (lung small cell, pancreatic, prostate, thymus)
CNS disorders (meningoencephalitis, SAH, trauma)
Respiratory disease (Carcinoma, TB, pneumonia)
Endocrine (hypothyroidism)
Drugs (Cyclophosphamide, SSRIs, Opiates, Psychotropics)
Give 4 drug classes that can cause SIADH
Cyclophosphamide
SSRIs
Opiates
Psychotropics (carbamazepine)
What investigations are performed to diagnose SIADH? (2)
Urine osmolality (High - >100mOsm/kg)
Urine sodium concentration (High - >40mmol/L)
How is SIADH managed? (3)
Fluid restriction
Demeclocycline (reduces responsiveness of collecting tubule cells to ADH)
Vaptans (ADH receptor antagonists)
Why is it important to that fluid correction is done slowly in SIADH?
To avoid precipitating central pontine myelinolysis.
Give 3 features of Growth Hormone deficiency and what is the Rx
Short stature
Abnormal body composition
Reduced muscle mass
Rx - Growth Hormone
What is the function of the parathyroid glands?
Regulate calcium levels in the body by producing parathyroid hormone
What stimulates secretion of parathyroid hormone?
Low ionized calcium levels.
As Extracellular calcium levels decrease, PTH levels increase (and vice versa)
Give 4 actions of Parathyroid Hormone
Increases osteoclast activity (releasing calcium and phosphate from bone)
Enhances the distal tubular resorption of calcium
Decreases renal tubular resorption of phosphate
Increases production of 1,25 dihydroxy-vitamin D3
What is the net effect of PTH on calcium and phosphate?
Increase in calcium and a decrease in phosphate
Describe primary hyperparathyroidism
Characterised by overstimulation of the parathyroid glands, resulting in excessive release of parathyroid hormone.
Leading to symptoms of hypercalcaemia
In relation to calcium and PTH levels, how is hyperparathyroidism characterised?
Characterised by hypercalcaemia in the presence of elevated PTH levels.
(Usually this relationship is the inverse)
Give 3 causes of hyperparathyroidism
80% - Solitary Adenoma
20% - Hyperplasia
<5% - Parathyroid cancer
Give 6 clinical features of hyperparathyroidism
Associated with symptoms of hypercalcaemia;
Weak/tired
Depressed
Polydipsia/Polyuria
Bone pain
Abdomoinal pain
Pancreatitis
(Bones, Moans and Abdominal Groans)
What may blood tests show in a patient with primary hyperparathyroidism?
PTH - High
Ca - High
Alkaline Phosphatase - High
Phosphate - Low
How is primary hyperparathyroidism treated?
General;
- Increased fluid intake to prevent stones
-Avoid thiazides and high calcium intake
Surgical
- Excision of adenoma
What should be avoided in patients with primary hyperparathyroidism? (2)
Thiazides
High calcium intake
Give 2 surgical complications in the management of primary hyperparathyroidism
Hypoparathyroidism
Damage to recurrent laryngeal nerve
Describe secondary hyperparathyroidism. Give 2 common causes.
Any disorder that results in hypocalcaemia will elevate parathyroid hormone levels, resulting in secondary hyperparathyroidism.
Chronic Kidney Disease
Vitamin D deficiency
What will blood tests show in a patient with secondary hyperparathyroidism? (5)
PTH - High
Calcium - Low
Alkaline phosphatase - High
Phosphate - Low
Vitamin D - Low
Define hypoparathyroidism
Characterised by a relative or absolute deficiency of plasma PH synthesis and secretion. Usually occurs due to gland failure.
Give 9 symptoms of hypoparathyroidism (SPASMODIC)
S - Spasms
P - Perioral paraesthesia
A - Anxious
S - Seizures
M - Muscle tone increase
O - Orientation impaired (confusion)
D - Dermatitis
I - Impetigo
C - Chovsteks, cardiomyopathy
Define pseudohypoparathyroidism
Characterised by a failure of the target organ to respond to PTH
Describe pseudopseudohypoparathyroidism
Patient expresses normal (maternal) receptors in the kidney but also has abnormal (paternal) receptors in the body.
Describe blood test results for primary hyperparathyroidism (PTH, Ca, Phosphate)
PTH - High
Ca - High
Phosphate - Low
Describe blood test results for secondary hyperparathyroidism (PTH, Ca, Phosphate, Vitamin D)
PTH - High
Calcium - Low
Phosphate - High
Vitamin D - Low
Describe blood test results for tertiary hyperparathyroidism (PTH, Ca, Phosphate, Vitamin D, Alkaline Phosphatase)
PTH - High
Ca - Normal/High
Phosphate - Low/Normal
Vitamin D - Low/Normal
Alkaline Phosphatase - High
What is the most common cause of primary hyperparathyroidism?
Solitary adenoma
What is the most common cause of secondary hyperparathyroidism
Vitamin D deficiency
Chronic kidney disease
(Lead to parathyroid gland hyperplasia)
What is the most common cause of tertiary hyperparathyroidism
Occurs due to ongoing hyperplasia of the parathyroid gland AFTER correction of underlying renal disorder.
Hyperplasia of all 4 glands is usually the cause.
What drug is known to cause gynecomasita? And how?
Spironolactone (potassium-sparing diuretic and aldosterone antagonist)
Competitively inhibits binding of dihydrotestosterone (DHT) to androgen receptors, leading to decrease in testosterone levels and an increase in oestrogen levels.
Hormonal imbalance leads to development of breast tissue in men.
Describe the water deprivation test and describe when it is used.
Used to help evaluate patients who have polydipsia
Method;
Prevent patient from drinking water.
Ask the patient to empty their bladder.
Measure hourly urine and plasma osmolalities.
Describe the results of a water deprivation test in a patient with cranial Diabetes Insipidus
Starting Plasma Osmolality - High
Final Urine Osmolality - Low
Urine Osmolality after Desmopressin - High
(Occurs due to insufficient ADH secretion, but kidneys still respond to ADH, hence osmolality increase after Desmopressin is given)
Describe the results of a water deprivation test in a patient with nephrogenic Diabetes Insipidus
Starting Plasma Osmolality - High
Final Urine Osmolality - Low
Urine Osmolality after Desmopressin - Low
(Kidneys are unable to respond to ADH, hence why urine osmolality remains low after Desmopressin is given)
What are the 2 predominant causes of hypercalcaemia?
Malignancy (PTHrP secreting tumour)
Primary hyperparathyroidism
What part of the adrenal gland secretes aldosterone?
Zona Glomerulosa
