Endocrine System Flashcards
Types of hormones
Steroids (from cholesterol)
Peptides
Altered amino acids (e.g. thyroid hormones made up of 2 tyrosine residues)
3 main types of receptors that hormones bind to
Receptors on cell surface: usually protein/peptide hormones –> conformational change –> second messengers –> modify cell response
Cytoplasmic receptors: steroid hormones –> receptor-hormone complex enters nucleus and binds to specific area of DNA to stimulate translation of protein
Nuclear receptors: thyroid hormone receptors found in cell nucleus; thyroid hormone enters cell with receptor and then enters nucleus to exert its effects
Where does the hypothalamus lie?
In the forebrain in the floor of the third ventricle
How is the hypothalamus linked to the pituitary?
Via a hypophyseal stalk
Where is the anterior pituitary (adenohypophysis) derived from?
Derived from the ectoderm, an outpouching of tissue from the oral cavity
Linked to hypothalamus via hypophyseal portal system
Where is the posterior pituitary (neurohypophysis) derived from?
Derived from a downgrowth of neural tissue
Continuous with hypothalamus
What are the nuclei in the posterior pituitary?
Paraventricular (produce oxytocin)
Supraoptic (produce ADH)
Causes of SIADH
Cancer (esp. SCLC, also pancreas, prostate)
Neuro: stroke, SAH, subdural haemorrhage, meningitis/encephalitis/abscess
Infections: TB, pneumonia
Drugs: Analgesics (opioids, NSAIDs), Barbiturates, Cyclophosphamide/Chlorpromazine/CBZ, Diuretics (thiazides), sulfonylurea, SSRI, TCA, vincristine
Others: PEEP, porphyria, alcohol withdrawal
Causes of pituitary deficiency
Infection: meningitis, encephalitis
Cerebral tumours
Radiation
Trauma i.e. frontal skull
Pituitary apoplexy: bleeding into pituitary tumour
Sheehan’s syndrome: infarction after PPH
Sarcoidosis
Rare congenital deficiencye.g. Kallman syndrome (FSH and LH deficiency)
What type of epithelium is the outer layer of the thyroid?
Cuboidal epithelium
surrounding colloid which is where the thyroid hormones are stored
What lie between the follices of the thyroid gland and what do they produce?
Parafollicular C-cells which secrete calcitonin
Hormones of the thyroid gland and their functions
T3 triiodothyronine = major hormone ACTIVE in target cells
T4 thyroxine = most prevalent form in PLASMA, less biologically active than T3
Calcitonin = lowers plasma Ca
Synthesis of thyroid hormones
Active pumping of iodide ions from extracellular space into follicular epithelium (thyroid actively concentrates iodide to 25x plasma conc)
Iodide ions enter colloid and oxidised to IODINE by PEROXIDASE
Iodine combine with tyrosine contained in thyroglobulin to form either 1 MT (monoiodotyrosine) or 2 DT (diiodotyrosine)
1 MT and 2 DT in thyroglobulin undergo coupling to either T3 or T4
How many months of reserves of hormones does a normal thyroid gland have?
3 months
Mechanism of action of thionamides (carbimazole, propylthiouracil)
Competitive inhibitor of peroxidase, blocking oxidisation of iodide to iodine
Block coupling of iodotyrosine
PTU = also inhibits peripheral deiodination of T4
Mechanism of action of anion inhibitors (e.g. perchlorate)
Competitive inhibition of iodine uptake
discontinued as can cause aplastic anaemia
Mechanism of action of iodide (e.g. Lugol’s solution)
Block binding of iodine with tyrosine residues, inhibiting hormone release
Decrease size and vascularity of thyroid gland
What is sick euthyroid syndrome?
Acute illness resulting in abnormal thyroid function markers without actually affecting thyroid function
LOW TSH, LOW T3/4
Changes in sick euthyroid syndrome
Decreased amount of binding proteins and their affinity
Decreased peripheral conversion of T4 to T3
Decreased TSH
Where is calcium stored?
99% in bone
Intracellular
Extracellular = normal levels between 2.2-2.6mmol/L, ~50% is protein-bound
Role of calcitonin
Inhibit intestinal Ca absorption
Inhibit osteoclast activity + stimulate osteoblast
Inhibit renal tubular absorption of Ca and phosphate
Why is Mg important in Ca metabolism?
Mg is required both for PTH secretion and its action on target tissues
HypoMg may both cause hypoCa and render pts unresponsive to Tx with Ca and vit D supplementation
How much Mg does the body contain and where is it stored?
1,000mmol
50% in bone
50% in muscle, soft tissues, ECF
What is the commonest cause of hyperCa in hospitalised pts?
Malignancy
What is the commonest cause of hyperCa in the community?
Primary hyperPTH (parathyroid adenoma ~80%)
Causes of hyperCa
Main = malignancy, primary hyperPTH
Less common = sarcoidosis, drugs (thiazides, lithium), Paget’s, vit A/D toxicity, thyrotoxicosis, MEN syndrome, milk alkali syndrome, immobilisation
What is free Ca level affected by?
pH (increased in acidosis)
Plasma albumin concentration
ECG changes in hyperCa
Shortening of QTc interval
When is urgent Mx of hyperCa indicated?
Ca >3.5mmol/L
Reduced consciousness
Severe abdo pain
Pre-renal failure
Mx of hyperCa
IV fluid resus with 3-6L of 0.9% NaCl in 24 hours
+/- calcitonin (quickest onset of action but short duration - tachyphylaxis - hence only given with 2nd agent)
+/- medical therapy (usually if corrected Ca >3.0)
Prednisolone if sarcoidosis, myeloma or vit D intoxication`
Examples of IV bisphosphonates
IV pamidronate = most potent, SE fever, leucopenia
IV zoledronate = response lasts 30 days, used for cancer-associated hyperCa
(bisphosphonates are analogues of pyrophosphate)
Effects of hypophosphataemia
Confusion
Convulsions
Muscle weakness (acute hypophosphataemia can lead to significant diaphragmatic weakness and delay weaning from a ventilator in ITU pt)
LEFT SHIFT of oxyHb curve = decreased O2 delivery to tissues (due to reduction in 2,3-DPG)
Causes of hypophosphataemia
HyperPTH Vit D deficiency TPN (refeeding syndrome) DKA Alcohol withdrawal Acute liver failure Paracetamol OD (phosphaturia)
Causes of hyperphosphataemia
Chronic renal failure (causing itching)
Tumour lysis syndrome
Myeloma
What type of cells does the adrenal medulla contain?
Chromaffin cells (specialised sympathetic post-ganglionic neurons)
What stimulates hormone release from the adrenal medulla?
ACh release from splanchnic nerves innervating the medulla
What does the adrenal medulla produce?
Main:
Epinephrine (adrenaline) = bind to beta-receptors
Norepinephrine (NA) = bind to alpha-receptors
Dopamine
Beta-hydroxylase (enzyme involved in catecholamine synthesis)
ATP
Opioid peptides (metenkephalin, leuenkephalin)
Which enzymes inactivate the adrenal hormones once they are released?
Catechol-O-methyl transferase
Monoamine oxidase
present in liver and kidney
Which part of the kidney tubule does aldosterone act on?
Distal convoluted tubule
What is cortisol bound to?
90% of cortisol protein-bound, 10% active
75% transcortin
15% albumin
What stimulates cortisol release?
ACTH Circadian rhythm: high in morning Stress Trauma, burns Infection Exercise Hypoglycaemia
Actions of cortisol
Metabolic (opposite to insulin): glycogenolysis, gluconeogenesis, lipolysis, breakdown of proteins
CV effects: necessary for vasopressors to increase vascular tone
CNS: euphoria
Anti-inflammatory: decrease immunocompetent cells and macrophages, stimulate lipocortin synthesis in WBCs
Immunosuppressive: decrease T cell no. and function, decrease B cell clonal expansion, decrease basophils and eosinophils
Decrease protein in bones
Increase gastric acid
Increase neutrophils/plt/RBCs
Inhibit fibroblast activity
Action of lipocortin
Inhibit phospholipase A2 and hence prevent formation of inflammatory mediators e.g. prostaglandins, leukotrienes, plt-activating factor (PAF)
Commonest enzyme defect in congenital adrenal hyperplasia (CAH)
21-hydroxylase
Rule of 10 of phaeochromocytoma
10% malignant
10% bilateral
10% arise from outside adrenal medulla
10% part of MEN syndrome
Actions of norepinephrine > epinephrine
Alpha 1 = increased gluconeogenesis, increased BP, increased tone in GI sphincters, bronchoconstriction
Alpha 2 = decreased insulin secretion
Actions of epinephrine > norepinephrine
Beta 1 = increased HR and cardiac contractility
Beta 2 = increased glycogenolysis, increased insulin and glucagon secretion, increased K+ uptake by muscle, bronchodilatation
Beta 3 = increased lipolysis
What stimulates GH release?
Hypoglycaemia = potent (+ inhibit somatostatin) Anxiety, pain Hypothermia Haemorrhage Trauma Fever Exercise
Actions of GH
Increased glycogenolysis, protein synthesis, amino acid uptake into cells
Increased lipolysis and release of FFAs
Decreased glucose uptake by cells
Decreased LDL cholesterol
Where are exocrine secretions produced in the pancreas?
The pancreatic acini
Where are endocrine secretions produced in the pancreas?
The islets of Langerhans
3 main hormones produced by islets of Langerhans
Insulin (beta cells) - 70% total secretions
Glucagon (alpha cells)
Somatostatin (delta cells)
Pancreatic polypeptide (F cells)
What is the half-life of insulin in the circulation?
Very short, 5-10min
What is insulin broken down by?
Liver
Kidneys
What is insulin stored as?
Glycogen = liver, skeletal muscles Triglycerides = adipocytes
Structure of insulin
Human insulin protein has 91 amino acids
Molecular weight 5,808 Da
Dimer of A-chain and B-chain linked by disulfide bonds
Synthesis of insulin
Proinsulin (precursor) formed by RER
Proinsulin cleaved to form insulin and C-peptide
Insulin stored in secretory granules and released in response to Ca
Factors INCREASING insulin release
Hyperglycaemia Raised fatty acids and ketone bodies PARASYMPATHETIC stimulation Amino acids (arginine, leucine) Gastrin, CCK, secretin, GIP Prostaglandins Drugs e.g. sulphonylureas
Factors DECREASING insulin release
SYMPATHETIC stimulation Alpha-adrenergic drugs Dopamine Serotonin Somatostatin
Actions of insulin
Promote glucose and aa uptake into cells Glycogenesis Glycolysis Protein synthesis Lipogenesis
Inhibit lipolysis
What stimulates somatostatin release?
Increased plasma glucose and amino acids
Increased plasma glycerol
Effects of somatostatin
Inhibit release of insulin and glucagon
Decrease GI motility, secretion and absorption
4 systems involved in body’s response to injury
Sympathetic NS
Acute phase system
Endocrine response
Vascular endothelium
Types of pancreatic endocrine tumours
Insulinoma (75%) Gastrinoma (Zollinger-Ellison) Vipoma Glucagonoma Somatostatinoma
Classic presentation of insulinoma
Whipple’s triad =
Hypoglycaemic symptoms
Reduced blood sugar levels during these periods
Relief with IV glucose
~10% malignant
Features of gastrinoma
Gastric hypersecretion
Diarrhoea
Widespread peptic ulceration
> 50% malignant
Features of Vipoma
Severe watery diarrhoea
HypoK
Achlorhydria (absent HCl)
Features of glucagonoma
Secondary DM
Anaemia
Weight loss
Characteristic rash = necrolytic migratory erythema
75% malignant
Features of somatostatinoma
DM
Cholelithiasis
Steatorrhoea
What are the SYSTEMIC effects of the acute phase response to injury?
Fever Increased HR and RR Increased vascular permeability and vasodilatation (hence decreased BP) Immune cell activation Increased leukocyte adhesion
Vascular endothelial response to trauma
Increased adhesion molecule expression to attract neutrophils
Nitric oxide production causing vasodilatation
Endothelins oppose action of NO
Platelet-activating factor (PAF) released in response to cytokines (e.g. IL-1, TNF-alpha), stimulating plt aggregation and vasoconstriction
Clinical changes in response to trauma and surgery
Hypovolaemia (third space losses)
Decreased water and Na excretion (due to aldosterone and ADH release)
Fever
Leukocytosis
Decreased albumin
Increased K (from cell death)
Metabolic changes in response to trauma and surgery
Ebb phase = initial response, phase of reduced energy expenditure, lasts ~24hrs
Flow phase = CATABOLIC phase, hyperglycaemia, negative nitrogen balance, increased O2 consumption, lipolysis
Metabolic changes in response to trauma and surgery
Ebb phase = initial response, phase of reduced energy expenditure, lasts ~24hrs
Flow phase = CATABOLIC phase, hyperglycaemia, negative nitrogen balance, muscle protein loss, increased O2 consumption, lipolysis
Respiratory changes in response to trauma and surgery
Increased RR –> resp alkalosis
Affects O2 dissociation curve –> harder for O2 to dissociate into tissues
Hormones that are INCREASED in stress response
GH ACTH, cortisol Renin, aldosterone ADH Prolactin Glucagon
Hormones that are DECREASED in stress response
Insulin
Testosterone
Oestrogen
Hormones that have NO CHANGE in stress response
TSH
LH, FSH
Medical Mx of thyroid storm
ABC: high-flow O2, IV access and fluids
If suspect infection = treat with empirical Abx
High-dose PTU (prevent peripheral conversion of T4 to T3)
Lugol’s iodine 1hr after PTU given (block release of stored T3 and T4)
Hydrocortisone (as per PTU action)
Beta blocker (for symptomatic relief)
How is diagnosis of phaeochromocytoma confirmed?
Biochem = 24h acidified urine sample for VMA (vanillylmandelic acid - breakdown product of catecholamines)
Imaging = CT and MRI (latter preferred), or radio-isotope MIBG scans
List of acute phase proteins
CRP Procalcitonin Ferritin Fibrinogen Alpha-1 antitrypsin Caeruloplasmin Serum amyloid A Haptoglobin Complement
List of NEGATIVE acute phase proteins
Albumin Transthyretin (formerly prealbumin) Transferrin Retinol binding protein Cortisol binding protein
Liver decreases the production of these proteins during the acute phase response
What level of CRP at 48hrs post-op suggest evolving complications?
CRP >150
What does CRP bind to in bacterial cells and on cells undergoing apoptosis after being synthesised in the liver?
Phosphocoline
What stimulates glucagon release?
Hypoglycaemia Increased catecholamines and plasma amino acids Sympathetic NS ACh CCK
What inhibits glucagon release?
Somatostatin
Insulin
Increased FFAs and ketones
Increased urea
Causes of hypoMg
Diuretics TPN Diarrhoea Alcohol HypoK, hypoCa
Where are PTH receptors found?
Kidneys
Bone
Half-life of PTH in plasma
4 minutes
Effects of PTH
Bone = Binds to OSTEOBLASTS which signal to osteoclasts to resorb bone and release Ca
Kidney = active reabsorption of Ca and Mg from DCT, decrease reabsorption of phosphate
GI via kidney = increase intestinal Ca absorption by increasing activated vit D
