Endocrinology Flashcards
What are the properties of peptide hormones? How do they work?
Made from short-chain amino acids (size is anything from few AAs to small protein) - Pre-Made and stored in cell, released and dissolved into blood when needed - Large, hydrophilic, charged molecules - cannot diffuse through a plasma membrane - Bind to receptors on cell membranes, triggering a second messenger to be released within cell - very quick - Examples: Insulin, growth hormone, TSH, ADH
What are the properties of steroid hormones? How do they work?
Synthesised from cholesterol - Not stored in cell, released as soon as they are Made - Not water soluble - must be bound to transport proteins to travel in blood - Lipid soluble - can cross plasma membrane and Bind to receptor inside cell - slow response - Examples: Testosterone, oestrogen, cortisol
Tell me about catecholamine hormones (amino acid derived)
Synthesised from the amino acid tyrosine - Acts same way as peptide hormone - Large, hydrophilic, charged molecules - cannot diffuse through a plasma membrane, so released via exocytosis - Examples: Adrenaline, thyroxine
What are the cell types and their functions within the islets of langerhans in the pancreas?
Alpha cells - produce glucagon Beta cells - produce insulin and amylin Delta/D cells - produce somatostatin PP cells - produce pancreatic polypeptide
What are the classes of hormones?
Steroids - Peptides - Thyroid hormones - Catecholamines
Tell me about thyroid hormones 😎
released via proteolysis - T3 = triiodothyronine, T4 = thyroxine - Take a day to act - in blood bound to thyroglobulin binding protein (produced by liver)
What is the blood supply to the thyroid gland?
Superior Thyroid artery - off thyrocervical trunk (subclavian) - Inferior Thyroid artery - off external carotid artery
Where are the thyroid and parathyroid glands located?
- Thyroid gland sits at C5-T1 - Two lobes connected by an isthmus - Parathyroid is 4 glands on the posterior surface of thyroid glands
What effect does parathyroid hormone have on the kidneys?
- Increased conversion of 25-hydroxyvitamin D (inactive) to 1,25-dihydroxyvitamin D(active) - At the DCT: Increased Ca2+ reuptake and PO43- excretion
What effect does parathyroid hormone have on the gut?
Increased Ca2+ and PO43- absoroption
What hormones does the adrenal gland produce?
Adrenal cortex: - Zona glomerulosa - mineralocorticoids (eg: aldosterone) - Zona fasciculata - glucocorticoids (eg: cortisol) - Zona reticularis - adrenal androgens Adrenal medulla: - Catecholamines (eg: adrenaline)
Pathophysiology of T2DM
Peripheral Insulin resistance with partial Insulin deficiency - Decreased GLUT4 expression - impaired Insulin secretion - Lipid and beta amyloid deposits in pancreas, progressive b cell damage
Epidemiology of T2DM
Presents later on in life (usually 30+ years) - Males > females - People of Asian, African and Afro-Carribean ethnicity are 2-4x more likely to develop T2DM than white people
Clinical presentation of T2DM
Obese hypertensive older patient - Polydipsia - Nocturia - Polyuria - Glycosuria - Recurrent thrush
Diagnosis of T2DM
same as T1DM - Prediabetes exists this time
Risk factors for T2DM
Genetic link (stronger than T1DM) - Obesity - Alcohol excess - Hypertension - Gestational diabetes - PCOS - Drugs: corticosteroids, thiazides
Last line of treatment for T2DM if all else fails
Insulin treatment
Treatment for T2DM
Initial: Biguanide (metformin) Second line: Carry on Metformin and add either: - DPP-4 inhibitor - Pioglitazone - Sulfonylurea - SGLT-2 inhibitor
Epidemiology of Diabetic Ketoacidosis
4% of T1DM patients develop each year
Risk factors for DKA
- Poorly managed/undiagnosed T1DM - Infection/illness - Characteristic in patients around 20 years old
Pathophysiology of DKA
Absolute immune deficiency = unrestrained lipolysis and gluconeogenesis and Decreased Peripheral glucose uptake - Not all glucose from gluconeogenesis is usable so converted to ketone bodies, which is acidic
Describe Kussmaul’s breathing
Deep and rapid breathing in acidosis to expel acidic carbon dioxide
Signs of DKA
- Kussmaul’s breathing - Pear drop breath - Reduced tissue turgar (hypotension + tachycardia)
How to investigate DKA
- Ketones > 3mmol/L - RPG > 11.1mmol/L (hyperglycemic) - pH < 7.3 or HCO3- < 15mmol - Urine dipstick glyosuria/ketonuria
What are common differentials of DKA?
HHS - Lactic acidosis - identical presentation, normal serum glucose and Ketones - Starvation ketosis - physiologically appropriate lipolysis
Treatment for DKA (in order)
- ABCDE - IV fluids FIRST 0.9% saline - IV insulin 0.1units/kg/hour - once glucose level <14mmol add 10% glucose - Restore electrolytes, eg: K+
Symptoms of HHS
Generalised weakness and leg cramps - Confusion, lethargy, hallucinations, headaches - Visual disturbance - Polyuria and Polydipsia - Nausea, vomiting and abdo pain (more common in DKA)
Epidemiology of HHS
- Less than 1% of diabetes admissions - 5-15% mortality Risk factors: - Infection - MI - Poor medication compliance
Pathophysiology of HHS
- Rise in counter-regulatory hormones (glucagon, Ad, cortisol, GH) - Causes hyperglycaemia ans hyperosmolality - Electrolytes in blood overflow into urine -> excessive loss of water and electrolytes
Characteristics of HHS
Marked hyperglycaemia - hyperosmolality - Profound dehydration - Electrolyte abnormalities
Diagnosis of HHS
Diagnostic: - Hyperglycaemia ≥30mmol/L without a metabolic acidosis or significant ketonaemia - Hyperosmolality ≥320mOsmol/kg - Hypovolaemia Other tests: - Urine dipstick: heavy glycosuria - U+E: low total body K+, high serum K+
How can HHS be differentiated from Diabetic ketoacidosis?
DKA - T1DM - Patients younger and leaner - Ketoacidosis - Develops over hours to a day HHS - T2DM - No ketoacidosis - Significantly higher mortality rate - Develops over a longer time - days to a week
Treatment of HHS
- IV fluid 0.9% saline - IV insulin only if there is ketonaemia or IV fluids aren’t working - LMWH to anticoagulate patient as they have thicker blood - Electrolyte loss (K+)
What are complications of HHS treatment with insulin?
Insulin-related hypoglycaemia - Hypokalaemia
Draw out the process of phosphate regulation physiology
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What can pituitary tumours do?
- Press local structures - eg: optic chiasm -> bitemporal hemianopia - Hypopituitism - Hyperpituitarism - acromegaly, Cushing’s disease, prolactinoma
Hormones secreted by the hypothalamus and what they stimulate from the anterior pituitary
- GnRH -> FSH and LH - CRH -> ACTH - GHRH -> GH - TRH -> TSH - DA -> Prolactin
What is always given to unresponsive hypoglcyemic patients?
IM glucagon
Role of insulin
- Increase peripheral glucose uptake - Glucose -> glycogen
Biphasic release of insulin
- Glucose binds to GLUT2 receptors of pancreas on b cells, stimulating insulin release 2. Insulin binds to peripheral insulin receptors: - Activates intracellular tyrosine kinases + cascane - Increase of Glut-4 channel expression on CSM
Posterior pituitary hormones
Oxytocin (paracentricular nucleus) - milk ejection + labour induction - Vasopressin (supraorbital nucleus)
What does vasopressin do?
Vasoconstricts blood vessels - Increased APO II expression in collecting duct - Increased aldosterone
Functions of cortisol
- Increases protein and carb breakdown - Upregulates alpha 1 receptors on arterioles -> increased BP - Suppresses immune response - Increased osteoclast activity (osteoporotic) - Increased insulin resistance
Prediabetic states
FBG: 6.1-6.9 2nd post prandial: 7.8-11.0 HbA1c: 42-47 (6.0-6.4%)
First treatment for Type 2 diabetes and prediabetes before drugs
Lifestyle change - diet, exercise, modify RFs
Main complication of T2DM
Hyperosmolar hyperglycaemic state
Define T1DM
- Absolute insulin deficiency, usually resulting from autoimmune destruction of the insulin-producing beta islet cells in the pancreas - Type 4 hypersensitivity
Which genes are linked with increased risk of developing T1DM?
HLA-DR2 and HLA-DQ3 or HLA-DR4 and HLA-DQ8
Environmental factors that can increase the risk of developing T1DM
Diet - Vitamin D deficiency - Early-life exposure to viruses associated with islet inflammation (eg: enteroviruses) - Decreased gut-microbiome diversity
Epidemiology of T1DM
- Young (usually between 5-15 years) - Lean - North European descent - 10% of diabetes is type 1
Macrovascular complications of T1DM
Atherosclerosis, which leads to: - CVD - Stroke - Peripheral arterial disease
Microvascular complications of T1DM
- Nephropathy - Retinopathy -> glaucoma, cataracts - Neuropathy -> diabetic foot disease
Other autoimmune conditions that can result from T1DM (most to least common)
- Thyroid disease - Autoimmune gastritis - Pernicious anemia - Coeliac diease - Vitiligo - Addison’s disease
Psychological complications of T1DM
- Anxiety - Depression - Eating disorders Also in children: - Behavioural and conduct disorders - Family/relationship difficulties - Risk-taking behaviour
Signs of T1DM
- BMI < 25kg/m2 - Failure to thrive in children - Glove and stocking sensory loss - Reduced visual acuity - Diabetic retinopathy - Diabetic foot disease
Symptoms of T1DM
Polyuria - Polydipsia - Weigt loss - lethargy - Recurrent infections - Evidence of complications - eg: blurred vision or parasthesia
At what level of blood glucose can it no longer be absorbed?
10mmol/L Thirsty and develop polyuria - body attempts to remove excess glucose
At what level of Beta cell destruction does hyperglycaemia develop?
80-90%
Diagnosis of T1DM
Random blood glucose ≥11mmol/L Fasting blood glucose ≥7mmol/L - One abnormal value diagnostic in symptomatic patients - Two abnormal values diagnostic in asymptomatic patients
What is the most accurate test for T1DM?
HbA1C - measures glycated haemoglobin >48 mmol/mol or >6.5% suggest hyperglycaemia over 3 months
Optimal targets for glucose self monitoring
- FBG: 5-7mmol/L on waking - Plasma glucose 4-7mmol/L before meals at other times of the day - If testing after meals: 5-9mmol/L at least 90 minutes after
How can T1DM be differentiated from Latent Autoimmine Diabetes in Adults (LADA)?
- In LADA age of onset is >30 yrs - Low to normal C-peptide
How can T1DM be differentiated from Neonatal diabetes?
In neonatal diabetes: Genetic testing shows mutation in genes coding ATP K+ channel and insulin gene
How can T1DM be differentiated from Monogenic diabetes?
In monogenic diabetes: - C-peptide present - Autoantibodies absent
First line treatment for T1DM
Basal-Bollus regimen Basal - Long acting (either given twice or once daily) Bollus - Short before meals
Types of Insulin
Rapid: aspart, lisporo, novorapid, glulisine - short: regular Insulin - Intermediate: NPH (half a day) - Long: detemir, lantus, glargine
Pathophysiology of T1DM
- Beta islet cell destruction - Hyperglycemia - Low cellular glucose (increased lypolysis and gluconeogenesis) - Hyperkalemia even though there is a low body K+ (enters cells via Na+/K+ ATPases)
Complications of DKA
Coma - Cerebral oedema - Thromboembolism - Aspiration pneumonia - Death - dehydration - MI
Presentation of hypokalaemia
Hypotonia - Hyporeflexia - Arrhythmias (especially AF) - Muscle paralysis and rhabdomyolysis
Aetiology of hypokalaemia
Decreased intake of potassium Increased excretion of potassium - Thiazides + loop diuretics - Renal disease - GI loss - Increased aldosterone (Conn’s syndrome) Potassium shifted to intracellular - Insulin - Salbutamol - (other drugs)
Treatment for hypokalaemia
K+ replacement - aldosterone antagonist (spironolactone) - Treat underlying cause - Other Electrolyte defficiencies
Diagnosis of hypokalaemia
- Low K+ in U+E ECG: - Small inverted T waves - Prominent U waves - ST depression - PR prolongation
Definition of hyperkalaemia and hypokalaemia
Hyper ≥ 5mmol/L Emergency hyper = ≥ 6.5mmol/L Hypo < 3.5mmol/L
Presentation of hyperkalaemia
Muscle weakness and cramps - parasthesia - Palpitations - Tachycardia (Arrhythmias)
Aetiology of hyperkalaemia
Increased intake of potassium - IV therapy - Increased dietary intake Decreased excretion of potassium - AKI and CKD - Drugs (NSAIDs, spironolactone, ACE inhibitors) - Renal tubular acidosis (T4) - Addison’s disease Potassium shifted to extracellular - Metabolic acidosis/DKA - Rhabdomyolysis Other: trauma and burns
Effect of hyperkalaemia on types of muscle
Smooth Muscle cramping - Skeletal mucle weakness due to overcontraction - Cardiac arrythmias and arrest
Effect of hypokalaemia on types of muscle
Smooth Muscle constipation - Skeletal Muscle weakness and cramps - Cardiac arrythmias and Palpitations
Effect of hyperkalaemia on Insulin, pH and Beta 2 receptors
- Insulin deficiency as not enough K+ flows into the cell - Acidosis (H+ in and K+ out) - Beta blocker - inhibits pumping of K+ into cell
Effect of hypokalaemia on insulin, pH and beta 2 receptors
- Excess insulin as too much K+ flows into cell - Alkalosis (H+ out and K+ in) - B2 agonist - Increase B2 pumping of K+ into cell
Complications of hyperkalaemia
Cardiac arrhythmias and arrest - Hyperkalaemia is associated with broadening QRS complex
Aetiology of hypercalcaemia (90% of cases)
90%: - Hyperparathyroidism - Malignancy: bone mets, myeloma, PTHrP, lymphoma
ECG in hypercalcaemia
Short QTc
Symptoms of hypercalcaemia and hyperparathyroidism
Bones - excess resorption, ostopoenia - Stones - kidney - Groans - abdominal pain, constipation - Psychedelic moans - Confusion, Depression, Anxiety - Thrones - Polyuria and Polydipsia
How does hypercalcaemia affect muscles
Low muscle tone and contractions as Ca2+ inhibits fast Na+ influx
What happens to PTH in hypercalcaemia
It will decrease due to negative feedback (except in hyperparathyroidism)
Aetiology of hypocalcaemia
CKD (due to Decreased Vit D activation) - Severe Vit D deficiency - Primary hypoparathyroidism - Acute pancreatitis
Symptoms of hypocalcaemia and hypoparathyroidism
parasthesia - Tetany (involuntary Muscle contractions) - Chvostek sign - Trousseau sign
How does hypocalcaemia affect muscle?
Muscle spasms: hands, feet, larynx, premature labour
How does hypocalcaemia affect PTH?
Always Increases - Except in hypoparathyroidism
Difference between primary and secondary hyperthyroidism?
Primary: Pathology is in the Thyroid - Secondary: Pathology is in the hypothalamus/pituitary
TFTs for hyperthyroidism
- Low TSH, high T4 = primary hyperthyroidism (Graves’) - High TSH, high T4 = secondary hyperthyroidism OR thyroid hormone resistance
Graves’ specific hyperthyroid signs
Exophithalmos or ephthalmoplegia - Pretibial myxedema due to deposits of mucin under the skin (may Also be seen in Hashimoto’s) - Thyroid acropachy
Epidemiology and risk factors of hyperthyroidism
Middle aged women - Family history - autoimmune diseases
De Quervain’s thyroiditis
Follows a viral prodrome and can Also present with a transient thyrotoxic state - Painful goitre with raised inflammatory markers. usually self limiting
Pathophysiology of Graves’ disease
immune system produces TSH receptor antibodies that mimic TSH and stimulate the TSH receptors on the Thyroid - Increased T3 Increases metabolic rate, CO, bone resorption and activates the sympathetic nervous system
Symptoms of hyperthyroidism
Heat intolerance and sweating - Weight loss - Palpitations - Oligomenorrhoea
What is toxic multinodular goitre? (also known as Plummer’s disease)
Nodules develop on the thyroid gland and produce excessive thyroid hormone
Symptoms of thyroid storm
NDV - abdo pain - Jaundice - Confusion, delirium or Coma
Diagnosis of hyperthyroidism
First line: TFT (thyroid function test) - Anti-TSH receptor antibodies positive in Graves’ - Anti TPO antibodies in 80% of cases (but much more in hypo) - Thyroid ultrasound
First line treatment for hyperthyroidism
- Carbimazole - Blocks synthesis of T4 - Normal thyroid function after 4-8 weeks (euthyroidism) - SE: agranulocytosis, presents as sore throat/mouth ulcers - + beta blocker (eg: propanolol) alongside for rapid symptom relief
Second line treatment for hyperthyroidism
- Propylthiouracil - Prevents T4->T3 conversion - Small risk of severe hepatic reaction, including death
Radioactive iodine treatment for hyperthyroidism
- First line definitive treatment for Grave’s disease and toxic multinodulae goitre - Destroys excess thyroid tissue - Remission can take 6 months - Patient must not be pregnant or planning to get pregnant within 6 months, must also avoid close contact with children and pregnant women for 3 weeks - Also limit contact with anyone for several days after receiving the dose
Last resort treatment for hyperthyroidism
Surgery or radioactive iodine
How to stop patients from becoming hypothyroid after hyperthyroidism treatment
Give them levothyroxine
Most common cause of hypothyroidism in the developed world
- Hashimoto’s thyroiditis - Autoimmune inflammation of the thyroid gland - initially cause a goitre - Associated with anti-TPO antibodies and antithyroglobulin antibodies
Most common cause of hypothyroidism in the developing world
Iodine deficiency
What is postpartum thyroiditis
- Same mechanism as Hashimoto’s - Acute: presents during pregnancy - Resolves by itself within 1 year of symptoms
Other causes of hypothyroidism
- DeQuervain’s thyroiditis - Post-thyroidectomy or post-radioiodine - Drugs; amiodarone, lithium, carbimazole
Causes of secondary hypothyroidism (pathology at pituitary gland)
Compression from a pituitary tumour - Sheehan syndrome - Drug: cocaine, Steroids, dopamime (all inhibit TSH secretion)
Symptoms of hypothyroidism
Cold intolerance - constipation - Weight gain - lethargy - Menorrhagia
Signs of hypothyroidism
Hair loss, dry and Cold skin- Bradycardia - goitre - Decreased deep tendon reflexes - Carpal tunnel syndrome
Diagnosis of hypothyroidism
TFT (Thyroid function test) - Anti-TPO antibodies high - Tyically anaemic (any Type)
TFTs for hypothyroidism
high TSH, Low T4 = Primary hypothyroid - Low TSH, Low T4 = Secondary hypothyroid - normal/Low TSH, Low T4 = hypopituitarism
Treatment for hypothyroidism
Levothyroxine (T4) - Titrate dose so you don’t induce iatrogenic hyperthyroidism
Complication of hypothyroidism
Myxedema coma - Often infection precipitated - Rapidly drops T4 - Loss of consciousness, heart failure
Treatment for myxedema coma
Levothyroxine - antibodies - Hydrocortisone
Types of thyroid carcinoma
Papillary - 70% - Follicular - 25% - Anaplastic (worst prognosisas as it metastasises the most) - Lymphoma - Medullary cell
Most common metastasis sites for thyroid carcinoma
Lung - 50% - bone - 30% - liver - 10% - Brain - 5%
How does thyroid carcinoma usually present?
as hard and irregular Thyroid nodules - may have local Compression (eg: hoarse voice)
Diagnosis of thyroid carcinoma
Fine needle Aspiration biopsy - TFTs - Thyroid ultrasound
Treatment for thyroid carcinoma
- Papillary and follicular = thyroidectomy or radioactive iodine - Anaplastic = mostly palliative :(
Pathophysiology of Cushing’s syndrome
Chronic excess of cortisol released by the adrenal glands
Aetiology of Cushing’s syndrome
ACTH dependent causes - Cushing’s disease - Ectopic ACTH production - ACTH treatment ACTH independent causes - Iatrogenic (steroid use) - mc - Adrenal adenoma
What is Cushing’s disease?
Pituitary adenoma secreting excess ACTH
Signs of Cushing’s syndrome
Hypertension - Moon face - Central Obesity - abdominal striae - Buffalo hump (fat pad on upper back) - Proximal limb Muscle wasting - Ecchymoses and fragile skin
Symptoms of Cushing’s syndrome
Bloating and Weight gain - Mood change - Increased susceptibility to Infection - Menstrual irregularity - Reduced libido - hyperglycaemia
Pseudo-Cushing’s
Cushingoid features and abnormal cortisol levels, but not associated with HPA pathology - Common causes: alcohol excess, severe depression, obesity, pregnancy - Results in a false positive dexamethasone suppression test and 24hr free cortisol - Differentiated using an insulin stress test
Diagnosis of Cushing’s syndrome
Dexamethasone suppression test or midnight salivary cortisol - If positive, test plasma ACTH to see If ACTH dependent - If independent, see If it is pituitary or ectopic GH release
How to do dexamethasone suppression test
- Measure cortisol at 12am, before giving dexamethasone - Measure cortisol 8 hours later, at 8am - Non-Cushing’s -> suppression >50nmol/L - Cushing’s -> little/no suppression
Plasma ACTH test
- Test at 9am - High = ACTH dependent cause -> Do high dose dexamethasone suppression test - Low = ACTH independent cause -> CT adrenals to look for pathology
Treatment for Cushing’s syndrome caused by Cushing’s disease
Transsphenoidal resection or bilateral adrenalectomy
Complication of bilateral adrenalectomy
Nelson’s syndrome - Pituitary tumour will continue to enlarge with no negative feedback from adrenals - High ACTH and skin hyperpigmentation
Treatment for Cushing’s syndrome caused by adrenal adenoma
Tumour resection or unilateral adrenalectomy
Treatment for Cushing’s syndrome caused by ectopic ACTH
Treatment of underlying cancer, such as surgical removal of SCLC
Complications of Cushing’s syndrome
Osteoporosis - T2DM - Hypertension and ischaemic heart disease
Primary adrenal insufficiency
- Addison’s disease - Pathology is at the adrenal glands - Decreased producion of adrenocortical hormones (cortisol and aldosterone) - High ACTH, low adrenocortical hormones
Secondary adrenal insufficiency
Pathology is in the pituitary - Inadequate ACTH released from pituitary - Leading to Low release of adrenocortical hormones from the adrenal gland - Low ACTH, Low adrenocortical hormones
Why do patients with primary adrenal sufficiency present with bronzed skin?
High ACTH stimulates melanocytes, resulting in hyperpigmentation
Aetiology of primary adrenal insufficiency
- Developed world: Autoimmune adrenal destruction (21-hydroxylase present in 60-90% of people) - Developing world: TB (+ sarcoidosis)
Risk factors for adrenal insufficiency
Female - adrenocortical antibodies - Other autoimmune disease
Other causes of adrenal insufficiency
adrenal metastasis (Lung, liver, breast) - adrenal haemorrhage (eg: meningococcal septicaemia)
Symptoms of adrenal insufficiency
Weight loss - Nausea and vomiting - lethargy and Generalised weakeness - Salt cravings
Signs of adrenal insufficiency
- Bronze hyperpigmented skin, particularly in palms (only in Addison’s) - Postural hypotension - Hypoglycaemia - Change in body hair distribution - Loss of pubic hair in women - Associated autoimmune condition
Signs of adrenal crisis
Hyponatraemia - Hyperkalaemia - Profound fatigue - dehydration - Vascular collapse (Low BP)
Treatment of Addisonian/adrenal crisis
- Immediate 100mg hydrocortisone - IV solve + dextrose (if hypoglycaemia) - Without cortisol, you will die from adrenal crisis if you have an infection
Diagnosis of adrenal insufficiency
- First line: 8-9am cortisol - Gold standard: ACTH stimulation test (short Synacthen test) RESULTS - Low cortisol, high ACTH, poor response to synacthen = Primary adrenal insufficiency - Low cortisol, low/normal ACTH, poor response to synacthen = Secondary adrenal insufficiency OR hypopituitarism
Other investigations for adrenal insufficiency
- U+E to test for hyponatraemia and hyperkalaemia - Aldosterone:renin ratio - Adrenal CT or MRI - Test bloods for 21-hydrolase adrenal antibodies
Treatment for Adrenal insufficiency
Hydrocortisone - glucocorticoid to replace cortisol - Fludrocortisone - mineralocorticioid to replace aldosterone If necessary - Double the dose of Hydrocortisone in trauma/Infection
Tertiary adrenal insuffiiency
Caused by Inadequate CRH released by the hypothalamus - usually a result of Long term oral Steroids
Acromegaly in children
Called gigantism - Occurs before epiphyseal fusion - hypopituitarism Causes inhibition of puberty as gonadotrophs cannot be released
Aetiology of acromegaly
Functional pituitary adenoma
Pathophysiology of acromegaly
- Excess GHRH - GHRH -> GH -> High IGF-1 (produced by liver)
Signs of acromegaly caused by space occupying lesion
Bitemporal hemianopia - headaches
Signs of acromegaly to do with overgrowth of tissues
Prominent forhead and brow - Large nose, tongue, hands and feet - Large, protruding jaw - Arthritis
Signs of acromegaly to do with GH causing organ dysfunction
Hypertrophic heart - Hypertension - impaired glucose tolerance - Colorectal cancer
Other symptoms suggesting active raised growth hormone
Development of new skin tags - Profuse sweating
Diagnosis of acromegaly
- 1st line: IGF-1 serum levels (high) - Gold standard: OGTT: Oral glucose tolerance test (failure of GH suppression 2 hours post 75g glucose load)
First line treatment for acromegaly
Transsphenoidal resection of pituitary adenoma
Other treatments for acromegaly
Somatostatin analogue to block GH (eg: ocreotide) - Dopamine agonist (eg: bromocriptine) - GH antagonist (eg: pegvisomant) - Radiotherapy
Complications of acromegaly
T2DM Caused by impaired glucose tolerance - Obstructive sleep apnoea - Cardiomyopathy - Hypertension - Arthropathy - Carpal tunnel syndrome
Risk factors for hyperprolactinaemia
Females - high serum prolactin (released from lactotrophs in the ant. pituitary)
Aetiology of hyperprolactinemia
Prolactinoma - Drugs (ecstacy)
Symptoms of hyperprolactinoma
Secondary amenorrhoea - Galactorrhoea 🪐🌌 - Sexual dysfunction (M+F) - Gynecomastia, low testosterone
Diagnosis of hyperprolactinemia
- High serum prolactin - >1000mIU/L - or 500-1000mIU/L on two occasions
Best treatment for hyperprolactinemia
Dopamine agonists - eg: cabergoline or bromocriptine - Massively shrinks Prolactinoma (tumour) as Dopamine is an inhibitor of prolactin
Primary hyperparathyroidism
usually Caused by a Parathyroid adenoma - Causes hypercalcaemia
Secondary hyperparathyroidism
Caused by Parathyroid hyperplasia - Secondary to CKD + Vit D deficiency
Tertiary hyperparathyroidism
after many years of Secondary - most common cause is CKD - Glands act autonomously and release PTH regardless of Ca conc.
Malignant causes of hyperparathyroidism
Neoplasms - (Squamous cell Lung cancer, breast, renal) - Secrete PTHrP, ectopically mimics PTH
Diagnosis of primary hyperparathyroidism
high PTH - very high calcium - Low phosphate - high ALP
Diagnosis of secondary hyperparathyroidism
high PTH - Low calcium - high phosphate - high ALP
Diagnosis of tertiary hyperparathyroidism
high PTH - high calcium - high phosphate - high ALP
Other tests for hyperparathyroidism
Xr KUB for kidney Stones - DEXA scan for bone density - U+E to assess renal function - short QT on ECG
Treatment for hyperparathyroidism
- Primary: Removal of PTH adenoma/parathyroidectomy of all 4 glands :( (most definitive) - Secondary and tertiary: Treat cause - Tertiary: Removal of parathyroid glands - Malignant: Remove tumour!
Complication of hyperparathyroidism
Acute Severe hypercalcaemia - Give IV fluids + bisphosphonates
Primary vs secondary hypoparathyroidism
Primary: PTH gland failure, a number of causes Secondary: After surgery (parathyroid/thyroid ectomy)
Causes of primary hypoparathyroidism
Di George syndrome - Genetic - Radiation - autoimmune - Infiltration - Magnesium deficiency
Pseudohypoparathyroidism
- Very rare - End-organ PTH resistance due to defect in G protein signalling Associated with: - Low IQ - Short stature - Small 4th/5th metacarpals - Obesity
What is the Chvostek sign?
Twitching of facial muscles when facial nerve is trapped over parotid
What is the Trousseau sign?
Carpopedal spasm when tourniquet is applied to forearm
Diagnosis of hypoparathyroidism
Low PTH - Low calcium - high phosphate - ECG = longer QTc
Treatment for hypoparathyroidism
Calcium and Vitamin D suppements (AdCalD3)
GH/IGF-I axis
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Insulin secretion by the beta cell
glucose enters via GLUT2 transporter - K+ channels close and depolarise cell membrane - calcium channels open and CA2+ enters cell and stimulates Insulin secretory granules - Insulin secreted
Insulin action in muscle and fat cells
Insulin enters via Insulin receptors - Intracellular signalling cascades cause GLUT4 vesicles to integrate into plasma membrane - glucose enters cell via GLUT4 transporter
Alpha vs beta islet of Langerhans cells
Alpha cells: glucagon - Increases hepatic glucose by increasing glycogenolysis and gluconeogenesis - Stimulates lipolysis and muscle breakdown - Reduces peripheral glucose output Beta cells: insulin - Suppresses hepatic glucose by decreasing glycogenolysis and gluconeogenesis - Suppresses lipolysis and breakdown of muscle - Increases glucose uptake into insulin sensitive tissues
How can you get ketoacidosis in T2DM?
Happens later on in the disease - Because initially, micro secretions of Insulin are sometimes still present, inhibiting glucagon
Symptoms of DKA
Nausea and vomiting - Weight loss - Drowsy/confused - abdominal pain
Why are thiazolidinediones (pioglitazone) not commonly given as a diabetic drug?
Increase Weight - Increase risk of heart failure - Increase risk of fractures
Advantages of basal insulin in T2DM
patient adjusts Insulin themselves, based on fasting glucose measurements - Carries on with oral therapy, combination therapy is common - Less risk of hypoglycaemia at night
Advantages of premixed insulin in diabetes
Both basal and prandial together - can cover Insulin requirements though most of the day
Disadvantages of pre-mixed insulin
Requires consistent meal and exercise pattern - cannot seperately Titrate individual Insulin components - Increased risk of nocturnal and fasting hypoglycaemia
Causes of hypoglycaemia
Diabetic drugs: sulfonylureas or insulin - Non diabetic: oral, liver failure, Addison’s, increasing age
Symptoms of hypoglycaemia on the brain
Cognitive dysfunction - Blackouts - Seizures - Comas - Psychological effects
Treatment for hypoglycaemia
If not serious, food to release blood sugars - IV glucose or oral glucose gel - If no access, IM glucagon (only if alpha cells are working) - Check BM after 5 mins and if it’s increased give food
Symptoms of hypoglycaemia on the heart
Increased risk of MI - Cardiac Arrhythmias
Symptoms of hypoglycaemia on the musculoskeletal system
Falls - Accidents (inc. driving) - fractures - Dislocations
Symptoms of hypoglycaemia on circulation
inflammation - blood coagulation abnormalities - Haemodynamic changes - Endothelial dysfunction
Blood glucose of patient with hypoglycaemia
<3.5mmol/L
Thyroid axis
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Diagnosis of pseudohyperparathyroidism
high PTH - Low calcium - high phosphate
What does hypercalcaemia of malignancy do to PTH and phosphate levels?
PTH levels decrease - phosphate levels stay the same
Other causes of hypercalcaemia (other than top 90%)
Multiple myeloma - Granulomatous diseases (eg: TB and sarcoidosis) - dehydration - Drugs
How to calculate corrected calcium levels
total serum calcium + (0.02* (40-serum albumin))
Why may serum calcium levels be inaccurate?
Low serum albumin Causes a Low total serum calcium - but this is Not a Low ionised calcium - Need to do corrected calcium equation
Physiology of thyroid hormone production
iodine diffuses from Follicular Thyroid cells into the colloid (fatty empty space inbetween Follicular cells) - iodine binds to tyrosine residues on molecule thyroglobulin - Cleaved from Long chains to form T3 or T4(active)
Physiology of thyroid hormone release
Supraventricular nucleus of hypothalamus releases TRH - TSH released from thyrotrophs in anterior pituitary - binds to TSH-receptors on Thyroid - Causes T3/T4 to diffuse from colloid to Follicular cells then to the bloodstream
PTH regulation
- Tightly regulated by body Ca2+ to prevent hyper/hypocalcaemia - Directly inhibited by calcitonin - from parafollicular C cells fo the thyroid
Who would you not want to give carbimazole to?
Women wanting to get pregnant as it’s teratogenic (causes fetal abnormalities)
Pathophysiology of hyperkalaemia
high K+ decreases action potential - Easier depolarisation - abnormal heart rhythms
Diagnosis of hyperkalaemia
- High K+ on U+Es ECG: - Absent P waves - Prolonged PR - Tall tented T waves - Wide QRS - Bradycardia
Treatment for hyperkalaemia
If urgent: Calcium gluconate to stabilise cardiac membrane if there are heart problems, then insulin dextrose Non-urgent: Insulin (+dextrose)
Aetiology of hyperaldosteronism
2/3 - Adrenal adenoma (Conn’s) 1/3 - Bilateral adrenal hyperplasia Also (rare): - Familial hyperaldosteronism type 1 and 2 - Adrenal carcinoma
Secondary hyperaldosteronism
Excessive renin stimulates the adrenal glands to produce more aldosterone Causes: - Renovascular disease - Renin-secreting tumour
Pathophysiology of hyperaldosteronism
excess aldosterone(😱) - Increased sodium and water reabsorption and potassium excretion in kidneys - Hypertension and Hypokalaemia
Symptoms of hyperaldosteronism
Resistant Hypertension (unfixable with ACE inhibitors or beta blockers) - Hypokalaemia (lethargy Mood disturbance, parasthesia, Muscle cramps) - Polydipsia + Polyuria
Diagnosis of hyperaldosteronism
1st line: Aldosterone:renin ratio High ratio = Primary (do CT) Low rato = Secondary Diagnostic: High serum aldosterone not suppressed with 0.9% IV saline or fludrocortisone Also: Hypokalaemic on U+E and ECG
Treatment of hyperaldosteronism
- Single benign adrenal tumour -> unilateral adrenalectomy - Bilateral adrenal hyperplasia -> Aldosterone antagonist (spironolactone)
Two types of diabetes insipidus
Cranial - Low ADH secretion - Nephrogenic - Low response to ADH
Aetiology of cranial diabetes insipidus
ADH gene mutation - pituitary adenomas - Brain infections - Idiopathic
Aetiology of nephrogenic diabetes insipidus
- Renal tubular acidosis - ADH-R mutation - Drugs (lithium) - Electrolyte disturbance
Presentation of diabetes insipidus
Polyuria - Polydipsia - Hypernatremia - lethargy Confusion Coma - Severe dehydration
How much urine a day will make you suspect diabetes insipidus?
Over 3L
Water deprivation test for diabetes insipidus
- No fluid for 8 hours - Normally serum osmolality stays normal, urine osmolality increase - DI = serum osmolality rises while urine osmolality unchanged
Desmopressin test for diabetes insipidus
Cranial urine osmolality: After deprivation: Low After desmopressin: High Nephrogenic urine osmolality: After deprivation: Low After desmopressin: Low Primary polydipsia After deprivation: High After ADH: High
Treatment for diabetes insipidus
Cranial - Desmopressin Nephrogenic - Thiazides (+ treat underlying cause)
What are carcinoid tumours?
- Poorly malignant tumours of enterochromaffin cells which produce 5-HT/serotonin - Mostly in the GI tract at the appendix and terminal ileum - Can also be in the lungs
Carcinoid tumours vs syndrome
tumours - only the neoplastic cell, No/v little symptoms - syndrome - when tumour metastasises to the liver
Presentation of carcinoid syndrome
Diarrhoea - Flushing - Tricuspid incompetence (valve lesion) - Right upper quadrant pain - Bronchospasm
What does carcinoid syndrome tend to express?
Somatostatin receptors
Diagnosis of carcinoid syndrome
- High volume of 5-hydroxyindoleacetic acid (breakdown of serotonin) in urine - Metabolic panel and LFTs - Liver ultrasound to confirm metastases - CT/MRI to locate primary tumour
Treatment for carcinoid syndrome
Surgically excise Primary tumour - Peri-operative ocreotide (SST analogue) infusion to block tumour hormones - for metastases: above + radiofrequency ablation
Carcinoid crisis
Lif threatening - Treated with high dose SST analogue (octeotride)
What is a phaeochromocytoma?
An adrenal medullar tumour of chromaffin cells that secrete catecholamines (NAd, Ad)
Aetiology of phaeochromocytomas
- 25% familial and associated with MEN 2a+2b - Neurofibromatosis 1 (tumours deposited along myelin sheath) - Von-Hippel Lindau disease
Tumour patterns in phaeochromocytomas
- 10% bilateral - 10% cancerous - 10% familial - 10% extra-adrenal (mc location: organ of Zuckerkandl at aortic bifurcation)
Signs of phaeochromocytomas
- Hypertension (90%) - Hypertensive retinopathy - Tachycardia
Symptoms of phaeochromocytomas
Episodic headache - Profuse sweating - Palpitations - Anxiety
Diagnosis of phaeochromocytoma
- 24 hour urine metanephrine collection - Plasma free metanephrines - CT abdomen and pelvis
Why are metanephrines measured to diagnose pheochromocytoma?
Adrenaline has a very short half life in blood (only a few minutes) - Metanephrines are a breakdown product of Adrenaline and have a longer half life
Treatment of phaeochromocytoma
Peri-operative - Alpha blocker first (eg: phenoxybenzamine) - Then beta blocker (eg: atenolol, propanolol) - This prevents reactive vascoconstriction Surgical - Laproscopic adrenalectomy
Pheochromocytoma hypertensive crisis
- BP higher than 180/120 - Causes: XR contrast, TCA, opiates - First line treatment: phentolamine (alpha blocker)
What is SIAD?
Overdiagnosed cause of hyponatremia - Inappropriately released ADH, dilute euvolemia - excess ADH = more water retention = compensatory Na+ excretion to maintain euvolemia
Normal water sodium distribution vs SIADH
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Aetiology of SIAD
Cancers - SCLC and others - Infection/immunosuppression, eg: TB, pneumonia, meningitis - Abscesses - Drugs: SSRIs, carbamazepine, sulfonylureas - Head trauma
Pathophysiology of SIAD
high ADH independent of RAAS - Increased vasoconstriction - APO-II expression of collecting duct - Lead to high BP - excess H2O retained means more dilute blood and more Na+ loss
Symptoms of hyponatremia
vomiting - headache - Decreased GCS - Muscle weakness
Symptoms of extreme hyponatremia
Seizures - Neurological complications - Brainstem herniation
How can hyponatremia cause brain stem herniation?
Low Na+ means high compensatory H2O - enters skull, high ICP - Causes hyponatremic encephalopathy - risk of Brainstem herniating through foramen magnum (tentorial herniation)
Diagnosis of SIAD
decrease in serum Na+ and normal serum K+ - high urine osmolality - skin turgor and jugular venous pressure test
Differential diagnosis of SIAD
Na+ depletion - Give 0.9% saline - Na+ depletion -> serum will normalise - SIAD -> serum fails to normalise
Treatment for hyponatraemia secondary to SIAD
- Asymptomatic/mild symptoms: Fluid restrict; vaptans (vasopressin antagonist) - Severe symptoms: 3% hypertonic saline to concentrate blood
Pathophysiology of craniopharyngioma
- Squamous epithelial remnants of Rathke’s pouch - Benign, slow growing tumour infiltrates to surrounding structures - Mixed solid and cystic parts - Doesn’t spread to other parts of the body but puts pressure on suprasellar region of skull
Adamantinous vs squamous papillary craniopharyngioma
Adamantinous: Cyst formation and calcification Squamous papillary: Well circumscribed
Peak ages craniopharyngiomas occur
- 5 to 14 years - 50 to 74 years
Presentation of craniopharyngioma
raised ICP - Visual disturbances (Bitemporal hemianopia) - growth failure - Pit. hormone deficiency - Weight Increase
How common are meningiomas?
Most common tumour of region after pituitary adenoma
Cause of meningiomas
Complication of radiotherapy
Complications of meningioma
loss of Visual acuity - Visual field defects - Endocrine dysfunction
Testing gonadal axis: men
- Low testosterone, high LH/FSH: Primary hypogonadism - Low testosterone, normal/low LH/FSH: Hypopituitarism - Low testosterone and low LH: Anabolic use Measure 9hr fasted testosterone (morning) and LH/FSH in pituitary disease
Testing gonadal axis: women
Low oestradiol, high LH and FSH (FSH greater) = Pimary ovarian failure - Low oestradiol, normal/Low LH and FSH, oligo/amenorrhoea = hypopituitarism
Normal gonadal levels in women
Before puberty: - Low oestradiol - Low LH/FSH Puberty: - Increased oestradiol - Increased pulsatile LH Post menarche: - Monthly menstrual cycle with LH/FSH - Mid-cycle surge in LH and FSH - Levels of oestradiol increases through cycle
What to do after euthyroidism is achieved in hyperthyroid treatment
Maintenance carbimazole using either: - Titration block regimen - Block and replace regimen Complete remission achieved after 18 months of treatment (remission rate 50%)
What does the pituitary gland control?
Thyroid - adrenal cortex - Testis - Ovary Not the adrenal medulla
What hormones have a circadian rhythm
- Cortisol - Testosterone - DHEA - 17OH Progesterone Not T4
Which conditions do you need to rule out before confirming SIAD?
Hypothyroidism - Hypervolaemia - adrenal insufficiency - Diuretic use
Which hormones suppress appetite?
- Peptide YY - CCK - GLP 1 - Glucose
What is the main adipose signal to the brain?
Leptin
Treatment of chronic cases of SIAD
Furosemide - Vasopressin antagonist (tolvaptan) - Demeclocycline (inhibits ADH)
Typical features of hypogonadism in males
Joint and muscular aches - Decreased sexual appetite - Decreased Hair growth - Asymptomatic
What is satiety?
The physiological feeling of no hunger
What does ghrelin do?
Stimulates hunger
Risk factors of hyperthyroidism
- Smoking - Stress - HLA-DR3 - Female 20-40 years - Other autoimmune diseases
Epidemiology of hypothyroidism
- Mainly >40 years - F>M 6:1
High and low values for urine osmolality
< 300 = low >800 = high
Cancers that can cause SIAD
SCLC (small cell carcinoma) - Prostate cancer - Pancreatic cancer - Lymphomas - cancer of the thymus
What do long term corticosteroid medications lead to?
- Suppression of the adrenal glands - Long term atrophy of the adrenal glands - can’t produce enough corticosteroids - Adrenal insufficiency if medication is stopped
Differential diagnoses for presentation of polyuria and polydipsia
diabetes mellitus - diabetes insipidus - SIAD - Primary Polydipsia - hypercalcaemia
Complications of adrenal insufficiency
- Addisonian crisis (experiences by 40% of patients) - Cushing’s syndrome
Signs of HHS
Reduced GCS - dehydration - Hemiparesis (can be confused for a stroke) - Seizures
Why is there no acidosis in HHS?
- Small amounts of circulating insulin in T2DM - So lipolysis doesn’t occur
Complications of HHS
Cardiovascular - venous Thromboembolism, Arrhythmias, MI - Neuro - stroke and Seizures - AKI
NICE diagnostic criteria for T1DM
- Clinical features and evidence of hyperglycaemia - Ketosis - Rapid weight loss - < 50 years - BMI < 25 kg/m2 - Personal and/or family history of autoimmune disease
Other treatments for T1DM after basal-bollus
Mixed Insulin regimen - Continuous Insulin infusion
Mixed insulin regimen
- A mixture of short or rapid acting and intermediate-acting insulin - Twice daily - For those who can’t tolerate multiple injections for basal bollus
Continuous insulin infusion
- If patient has disabling hypoglycaemia - or persistently hyperglycaemic (HbA1c > 69mmol/mol) on multiple injection insulin therapy
Disadvantages of basal insulin in T2DM
- Doesn’t cover meals - Best used with long-acting insulin analogues (expensive)
Signs of T2DM
Acanthosis nigricans (fig.1) - Glove and stocking sensory loss - Diabetic Retinopathy - Diabetic foot disease
Drugs that can cause hypercalcaemia
Thazides - Diuretics - Lithium - Excessive Vit D or a intake
Treatment of hypercalcaemia
Aggressive IV fluids - Consider IV bisphosphonates If No response - Treat underlying cause
Drugs that can cause hypocalcaemia
bisphosphonates - Phenytoin - Loop Diuretics - Cinacalcet
Treatment of hypocalcaemia
oral calcium replacement or IV calcium gluconate - Treat the cause
How to determine if hyperaldosteronism is unilateral or bilateral
Adrenal venous sampling - Measures the amount of corticosteroid secreted from each adrenal gland
Epidemiology and risk factors of hyperparathyroidism
- Female - Radiation therapy to neck - Severe Vit D or Calcium deficiences - Familial rare conditions: MEN1 and 2A
Diagnosis of pseudohypoparathyroidism
high PTH - Low calcium - high phosphate Pseudopseudohypoparathyroidism Also exists, but levels for everything are normal
General signs of hyperthyroidism
Postural tremor - Palmar erythema - Hyperreflexia - goitre - Lid lag and retraction
Signs of thyroid storm
- Hyperpyrexia, often >40°C - Tachycardia, often >140bpm, with or without atrial fib - Reduced GCS
Diagnosis of thyroid storm
TFTs: high T3 and T4, suppressed TSH - ECG - blood glucose (perform in all patients with Reduced consciousness)
Treatment of thyroid storm
High dose propylthiouracil and KI
What is thyroid storm/thyrotoxic crisis?
- Endocrine emergency often seen in patients with Graves’ disease or toxic multinodular goitre - Secondary to precipitating factor such as infection or trauma - 10-20% mortality
Treatment for DeQuervain’s thyroiditis
NSAIDs for pain and inflammation - beta blockers for symptomatic relief
Side effects of dopamine agonists such as bromocriptine
Impulsiveness, so can lead to addictions
Link between acromegaly and prolactinoma
50% of acromegaly tumours are associated with prolactinoma
ECG in hypocalcaemia
Longer QTc and ST segment
Why can acromegaly cause sleep apnoea?
Pressure around the neck due to enlargement
Side effects of other diabetic medication
- SGLT-2 inhibitor - genitourinary infections - GLP-1 analogue - weight loss - Thiazide diuretics - weight gain
