Endocrinology Flashcards
qualities of
(a) endocrine hormones
(b) paracrine hormones
(c) autocrine hormones
(a) endocrine- glands release hormone secretion into blood stream, hormones are blood-borne and act at distant sites
(b) paracrine hormones act on adacent cels
(c) autocrine hormones feedback to the same cell that secreted the hormone
water-soluble hormones;
(a) transport
(b) cell interactions
(c) half-life
(d) clearance
(e) examples
Water soluble hormones are;
(a) unbound
(b) bind to surface receptor
(c) short half-life
(d) fast clearance
(e) e.g. peptides, monoamines
fat-soluble hormones;
(a) transport
(b) cell interactions
(c) half-life
(d) clearance
(e) examples
Fat-soluble hormones are;
(a) protein-bound
(b) diffuse into cell
(c) long half-life
(d) slow clearance
(e) e.g. thyroid hormone, steroids
peptide hormones
(a) structure and 2 examples
(b) storage
(c) solubility
(d) clearance
(a) structure- made of amino acids, between 3 (TRH) and 180 (Gonadotrophins)
(b) stored in secretory granules, often released in pulses or bursts
(c) water-soluble
(d) cleared by the target tissue or by circulating enzymes in the bloodstream
Amine hormones
(a) derivatives/formatoin
(b) action
(c) solubility
(a) amine hormones are derivatives of either phenylanine (NA and adrenaline) or tryptophan (5HT and melatonin)
NA is converted to normetanephrine by COMT enzyme and adrenaline is converted to metanephrine.
(b) Noradrenaline/Adrenaline act at adrenoreceptors (cell surface receptors, binding leads to G protein activation);
- alpha adrenoreceptors –> increased phospholipid C and protein Kinase C
- beta adrenoreceptors –> increased adenyl cyclase and cAMP
(c) water-soluble hormones
Iodothyronines
(a) solubility
(b) process of formation
(c) release
(d) action on cells & functions
(a) thyroid hormones are fat soluble
(b) formation:
- secretory cells in thyroid release thyroglobulin (glycoprotein)
- tyrosine side-chain of thyroglobulin incorporates iodine to form iodothyrosines
- iodothyrosine molecules are conjugated to form T3 and T4 –> these are stored bound to thyroglobulin in colloid
(c) release;
TSH stimulates the movement of colloid into the secretory cell and T3 and T4 are cleaved from thyroglobulin and released into the bloodstream. 20% of T3 in circulation is secreted from thyroid, rest is converted from T4
(d) thyroid hormone enters the target cell and enters the nucleus to bind to their receptor
functions: acceleration of food metabolism, increase in protein synthesis, stimulation of carb metabolism, increased ventilation rate, increased heart rate and cardiac output, acceleration of growth rate
Cholesterol derivatives & steroids;
- solubility
- vit example & transport
- steroids
- inactivation
- fat soluble
- vit D, enters cells to directly stimulate a nuclear receptor to stimulate mRNA production (and thus protein synthesis). Vit D is transported in the plasma bound to vit D binding protein
- e.g. adrenocortical and gonadal steroids. Transported in the plasma mostly bound to protein. Enter the cell and bind to their receptor in the cytoplasm (except oestrogen whose receptor is in nucleus). The hormone-receptor complex then enters he nucleus to induce its response by interacting with a response element on DNA.
- Cholesterol-derived hormones are inactivated by the liver by redox reaction, or conjugation to glucuronide and sulphate groups
- circadian rhythms; how to look for deficiency and excess
- circadian rhythm of cortisol
hormones with circadian rhythms are secreted at varying levels throughout the day- e.g. cortisol.
Cortisol is secreted at its peak first thing in the morning (6.30-9am) and levels are lowest overnight. Cortisol levels reflect energy levels.
Pituitary gland- role
(a) examples of damage to nearby structures caused by pituitary damage
(b) posterior pituitary- role
- hormones associated with posterior pituitary
(c) anterior pituitary- role
- hormones associated with anterior pituitary (5)
(a) optic chiasm sits above pituitary gland- damage can result in bitemporal hemianopia; some cranial nerves pass to the side of the pituitary fossa in the cavernous sinus- sideway growth of tumour can lead to cranial nerve palsies
(b) posterior pituitary= downgrowth of hypothalamus (i.e. Oxytocin and ADH synthesised in the hypothalamus are transported along axons to the posterior pituitary where they are stored until hypothalmic stimulation leads to their release)
(c) Anterior pituitary cells secrete loads of different hormones;
- thyrotrophs secrete TSH which acts on thyroid gland
- corticotrophs secrete ACTH which acts on the adrenal cortex
- gonadotrophs secrete FSH and LH which act on ovaries and testes
- Somatotrophs secrete GH which acts on all body cells
- Lactotrophs secrete PRL which acts on mammary glands
ADH secretion
(a) ADH synthesis/storage & effects
(b) stimulants for secretion
(c) 2 inhibitors of ADH release
(a) ADH is synthesised in the hypothalamus and stored in the posterior pituitary. It causes water retention at the kidney; stimulates the relocation of aquaporin V2 channels to the cell membrane in the collecting duct of the kidney & also acts on smooth muscle in blood vessels to stimulate vasoconstriction
(b) ADH release is stimulated by decreased blood volume (detected by kidney), increased osmolality due to increased sodium levels (detected by the brain), nausea, vomiting, stress and exercise.
(c) Caffience and alcohol inhibit ADH release
Stimulant for anterior pituitary hormone release
Hypothalmic neurosecretory cells secrete hormone releasing hormones (HRH) which travel to anterior pituitary via portal system to stimulate release of hormones. (exception is prolactin which is continuously released unless inhibited by dopamine- which it usually is)
direct and indirect effects of growth hormone
direct; increased fat and carbohydrate metabolism in target cells
indirect; act on liver; liver releases insulin-like growth factors which then act on different tissues (growth- skeletal and extra-skeletal)
Effects of pituitary dysfunction
first step of investigating pituitary dysfunction
Pituitary dysfunction can cause (1) tumour mass effects- e.g. compression of nerves; (2) hormone excess; (3) hormone deficiency
to investigate, perform hormonal tests; if these are abnormal then a pituitary MRI should be carried out
hypothalmo-pituitary-adrenal (HPA) axis function
effects of overexpression?
HPA axis leads to release of cortisol from the zona fasciculata (middle layer) of adrenal glands. Cortisol - major metabolic (breakdown of protein and storage of visceral fat) and stress hormone.
If cortisol is overproduced it can lead to excessive breakdown of protein and increased storage of visceral fat.
adrenal cortex secretions from
(a) zona glomerulosa
(b) zona fasciculata
(c) zona reticularis
(a) glomerulosa secretes aldosterone
(b) fasciculata secretes cortisol
(c) reticularis secretes sex hormones
RAAS System
- decreased sympathetic activity or low sodium levels trigger release of renin from kidney
- Renin converts Angiotensinogen to Angiotensin I
- Angiotensin I is converted by ACE to Angiotensin II (particularly in lungs)
- Angiotensin II (a vasoconstrictor which increases BP) acts on the zona glomerulosa, causing it to release aldosterone
- Aldosterone targets the kidney tubules and leads to increased reabsorption of sodium and water and increases potassium secretion –> increases blood volume and pressure
Effect on aldosterone release of
(a) stress
(b) ANP
(a) stress -> increased ACTH release –> increased aldosterone release
(b) ANP released in the atria of heart has inhibitory effect on zona glomerulosa
Effect on aldosterone release of
(a) stress
(b) ANP
(a) stress -> increased ACTH release –> increased aldosterone release
(b) ANP released in the atria of heart has inhibitory effect on zona glomerulosa
location of pituitary gland in the skull
pituitary gland sits in the sella turcica inside the skull. The sphenoid sinus is just below where the pituitary gland is located
blood supply of anterior pituitary- any arterial supply?
no arterial blood supply. Anterior pituitary receives blood through a portal venous circulation from the hypothalamus,
hypothalalamo-pituitary thyroid axis
- hypothalamus releases TRH which acts on the pituitary gland
- pituitary fland releases TSH in response to act on the thyroid gland
- Thyroid releases T4 and T3
- T4 and T3 both provide negative feedbac to the hypothalamus and pituitary
What does it mean if someone has high TSH levels? What diagnostic steps would you take?
If TSH is high, this indicates the person most likely has hypothyroidism (with increased negative feedback). If someone’s thyroid is not producing enough TH, their pituitary detects the reduced levels of thyroid hormone and produces more TSH, which then triggers your thyroid to make more thyroid hormone. This is the pituitary’s effort to raise the levels of thyroid hormone and return the system to normal.
to make sure it is not a hypothalmic or pituitary issue, you would check T4 and T3 levels along with the TSH.
hypothalmo-pituitary gonadal axis
- hypothalamus produces GnRH which acts on the pituitary
- pituitary secretes LH and FSH
- in males, LH acs on Leydig cells in testesm resulting in production of testosterone. FSH results in sperm generation through an action on sertoli cells
- In females, LH acts on thecal cells in the ovaries, resulting in the production of oestrogen. FSH results in generation of ova
- There is a negative feedback from testosterone and oestrogen to the pituitary and hypothalamus
(a) steroid effects on LH and FSH
(b) mumps effect on LH, FSH, GnRH, testosterone
(c) menopause effects on LH, FSH, GnRH, oestrogen
(a) steroid use lowers levels of LH and FSH
(b) mumps makes someone hypogonadal, which leads to an increase in FSH, LH and GnRH and decrease in testosterone
(c) menopause is due to primary ovarian failure, so LH, FSH and GnRH will all increase and oestrogen will decrease.
how is adrenal gland secretion controlled?
Through the HPA Axis;
- hypothalamus secretes CRH
- Pituitary responds to this by secreting ACTH
- ACTH acts on the adrenal gland, which produces cortisol
- Cortisol provides negative feedback to the pituitary and hypothalamus
Control of growth hormone release
Hypothalamus secretes GHRH, and this is opposed by the secretion of somatostatn (SMS). When GHRH levels are high, SMS levels are low (and vice versa)
How do growth hormone indirect actions occur?
Through the GH-IGF1 axis;
- hypothalamus releases GHRH
- pituitary gland releases GH
- Liver releases insulin-like growth factor (IGF-1)
- IGF-1 acts on a number of different tissues and provides negative feedback to the thalamus
Prolactin- significance and control of release
Prolactin is important in breastfeeding
Release is under negative control from dopamine- released by hypothalamus
When dopamine levels fall, PRL is secreted by the pituitary gland
- Prolactin levels increase if dopamine levels fall for pathological reason e.g. if patient takes a dopaminergic antagonist (e,g antipsychotic or ant-emetic drug)
Pituitary tumours can increase secretion of PRL also.
5 examples of pituitary gland disease
(1) Benign pituitary adenoma
(2) Craniopharyngioma (cystic tumours)
(3) Trauma
(4) Apoplexy/Sheehans syndrome- during pregnancy, pituitary becomes vascular and can be at risk of bleeding during delivery
(5) Sarcoid/TB
BMI classes
<18.5= underweight 18.5-24.9= normal 25-29.9= overweight 30-39.9= obese >40= morbidly obese
7 risks of obesity
- type II diabetes
- Hypertension
- Coronary artery disease
- Stroke
- Osteoarthritis
- Obstructive sleep apnoea
- Carcinoma
hypothalamus- connection to appetite
- Lateral hypothalamus= hunger center
- venteromedial hypothalmic nucleus= satiety center
leptin
(i) origin
(ii) action
(iii) effect
(i) expressed in white fat
(ii) binds to leptin receptor (cytokine receptor in hypothalamus)
(iii) switches off appetite and is immunostimulatory.
Peptide YY
- 36 amino acid peptide released from cells in the ileum and colon in response to feeding
- Binds NPY receptors
- inhibits gastric motility and reduces appetite
CCK
(i) production
(ii) action
(iii) effect
(i) CCK= peptide hormone synthesised and secreted by enteroendocrine cells in the duodenum
(ii) binds to receptors in the pyloric sphincter
(iii) delays gastric emptying, leads to gall bladder contraction and insulin release
Ghrelin
(i) origin/production
(ii) effect
(i) circulating hormone produced by enteroendocrine cells in the stomach
(ii) stimulates growth hormone release and increases appetite
POMC
(i) what is it?
(ii) clinical phenotype of POMC deficiency?
(i) precursor polypeptide produced in anterior pituitary, gives rise to hormones such as MSH (melanocyte stimulating hormone) which is important for appetite regulation and ACTH
(ii) POMC deficiency –> severe obesity at early age, and resultant lack of ACTH means they usually have red hair and pale skin
5 cell types in the anterior pituitary & hormone produced?
- Thyrotrophs secrete TSH which acts on the Thyroid Gland
- Corticotrophs secrete ACTH which acts on the adrenal cortex
- Gonadotrophs secrete FSH and LH which act on the ovaries and testes
- Somatrophs secrete GH which acts on all body cells
- Lactotrophs secrete PRL which acts on mammary glands
Thyroid hormone effects;
- acceleration of food metabolism
- increased protein synthesis
- stimulation of carbohydrate metabolism
- enhanced fat metabolism
- increased ventilation rate
- increased heart rate and cardiac output
- acceleration of growth rate
- brain development during foetal life and postnatal development
Thyroid hormone release- how much is T3 and how much is T4?
Only 20% is released in active form T3, 80% released as T4 which is a peripheral storage form of thyroid hormone, which is then converted to T3.
3 potential effects of pituitary tumours
(1) pressure on local structures
(2) hypopituitarism
(3) Functioning tumours
Presentations of pituitary tumours depend on
which way the tumour expands;
- upward growth tends to lead to headaches, visual field defects and occasionally hydrocephalus
- downward growth can result in CSF rhinorrhea (CSF from nose) due to tumour perforating the bone, but this is more common after pituitary surgery than as a presenting sign
first vision affected in bitemporal hemianopia
loss of colour vision
most common functioning pituitary tumour
- most common in
- effects
- treatment & possible side effect
prolactin microadenoma
- most common in females
- symptoms include loss of periods (due to PRL switching off production of gonadotriopin –> possible infertility and loss of libido), production of milk, visual field defect
- treat with a dopamine agonist e.g. cabergoline or bromocriptine. Increases fertility- patient may get pregnant
Gigantism
-cause
Gigantism is caused by pituitary tumour producing GH in childhood & tumour compressing on normal pituitary, preventing person from completing puberty. Gigantism occurs due to excess GH and failure of growth plates fusing
Acromegaly
- cause
- clinical presentation
- GH-producing tumour causes acromegaly
- Presentations include thickened skin (esp back of neck), greasy skin and hair, increased sweating, prognathism (protrustion of mandible), frontal bossing (prominent forehead and heavy brow ridge) and large tongue and hands.
Cushing’s disease
- Cause- most common cause
- clinical presentation
- Cushing’s caused by excess steroid hormones, main one being cortisol. Most commonly iatrogenic- due to use of steroids for another condition (can also be due to pituitary tumour)
- Presentations include moon face, hump back, central obesity, proximal myopathy, thin skin which bruises easily, poor healking and abdominal striae. Children can present with short stature.
Why is a lack of cortisol very dangerous?
Without cortisol, you could die of adrenal crisis
what exactly is the body clock? what is the primary zeitgeber?
The body clock is the suprachiasmatic nucleus in the hypothalamus- light is the primary zeitgeber.
damage to the hypothalamus can result in a loss of temperature control and loss of control of the sleep/wake cycle
Why can Addison’s disease cause vitiligo as well as adrenal insufficiency?
ACTH acts on a melanocortin receptor, which is found in the adrenal gland and also in the skin.
What causes primary Addison’s disease?
Primary addisons is due to an issue with the adrenal gland itself, most commonly autoimmune adrenalitis but could also be other things e.g. congenital adrenal hyperplasia (CAH)- other causes involve metastatc cancer, haemorrhage and infection e.g. TB
What causes secondary Addison’s disease?
Secondary Addison’s is caused by a problem with the pituitary gland. Causes include pituitary macroadenoma, stroke, infection, metastatic infiltration, radiotherapy and congenital hypopituitarism
what causes tertiary Addison’s disease?
Tertiary Addison’s disease affects the hypothalamus and suppresses the HPA axis, The main cause of this is use of steroids.
Signs and symptoms of Addison’s disease?
Fatigue, weight loss, poor recovery from illness, adrenal crisis, headache, pigmentation, pallor, hypotension
Other features which might indicate adrenal insufficiency?
past medical history (TB, post-partum bleed, cancer) & family history (autoimmunity, congenital disease)
Biochemical signs of someone who has adrenal insufficiency?
- Low sodium and high potassium (the HPA axis influences Na/K exchange in the kidney)
- Eosinophilia
- Borderline elevated TSH
Investigation for Adrenal insufficiency
- Main investigation is a hormone test to measure levels of cortisol- look when cortisol levels are expected to be at the highest levels- at 9am. (this is similar for ACTH levels).
- elevated renin can also be seen in primary adrenal insuficiency because renin attempts to compensate for the lack of HPA axons input into aldosterone secretion
- If suspecting hormone deficiency, carry out stimulation test; give patient 250mg ACTH and see if adrenal gland response increases levels of cortisol 30 mins post injection. If looking for hormone excess, carry out a suppression test.
Treatment for adrenal insufficiency
Hydrocortisone is taken two or three times daily, at a dose to replace natural cortisol levels in the day, normally 15-25 mg.
If cause is primary adrenal insufficiency, you would also need to replace aldosterone with fludrocortisone.
Symptoms of adrenal crisis
- hypotension
- cardiovascular collapse
- fatigue
- fever
- hypocalcaemia
- hyponatraemia
- hyperkalaemia
management of adrenal crisis
1 - take bloods if possible for measurement of cortisol and ACTH
2 - immediate hydrocortisone 100mg intravenous/intramuscular injection (subcutaneous if absolutely necessary) –> this should be done immediately, if they don’t have adrenal crisis, the hydrocortisone will do them no harm
3 - fluid resuscitation with 1L of normal saline per hour
4- Hydrocortisone 50-100mg iv or im every 6 hours
5- in patients with primary adrenal insufficiency, start fludrocortisone 100-200mg (when hydrocortisone done is <50mg)
6- when patient is stable, wean to normal replacement over 24-72 hours (10mg orally on final day)
limit of hydrocortisone treatment- and potential solution
Hydrocortisone doesnt mimic the natural circadian rhythm of cortisol. A new treatment is being developed called Chronocort- delayed release product that works due to a specific polymer coating that only dissolves at pH 6.8 i.e. when it reaches the ileum. it is taken before bed and can mimic the gradual rise in cortisol that occurs overnight. A second dose is taken in the morning.
What is the difference between Acromegaly and Gigantism?
Both are caused by a growth-hormone producing pituitary adenoma, but acromegaly presents with increase in size of extremities and occurs after puberty. Elongation of bones can only occur during or before puberty, therefore gigantism can only occur before/during puberty.
How does growth hormone affect tissues?
Growth hormone binds to GH receptors in the liver, which then in turn secrete hormone IGF-1. IGF-1 acts on many tissues to cause growth and increase blood pressure.
Why does acromegaly usually have a delayed diagnosis?
Acromegaly has a slow progression which causes it to have a delayed diagnosis- average 8 year delay.
Comorbidities which can be caused by acromegaly include
cerebrovascular events, headache, arthritis, type 2 diabetes m, sleep apnoea, hypertension, heart disease and increased risk of colon and breast cancer
3 principles of diagnosing acromegaly
1- recognition of clinical features
2- GH levels
3- IGF-1 levels
relationship between acromegaly and IGF-1/GH Levels
GH secretion is usually pulsatile with highest levels occuring overnight- in between pulses, GH levels are normally low. In someone with Acromegaly, there are no pulses and GH levels are high all the time- this is because the GH is released autonomously from a pituitary tumour and does not respond to negative feedback from IGF-1.
Testing for acromegaly
(1) Measure serum GH and IGF-1 levels
(2) If either of these are abnormal, perform the glucose tolerance test (give patient 75g oral glucose- this should suppress GH levels if acromegaly not present. If GH levels are less than 1mcg/L 60 mins post glucose, then acromegaly is excluded
Options for treatment of acromegaly
(1) Surgery
(2) Medical treatment
(3) Radiotherapy
Surgical treatment of acromegaly;
- advantages
- determinants of success
Surgical treatment of acromegaly is often the first choice because there is prospect of cure, rapid fall in GH (relieving symptoms), surgeon can decompress surrounding structures being compressed by tumour and it is cost effective as patient will not need ongoing treatment.
Surgery success is determined by
(1) size of tumour- microadenoma has a much higher surgical cure rate
(2) Surgeon– more skilled surgeons can remove most of tumour
Radiotherapy for acromegaly
- determinants of efficacy
- disadvantages
efficacy of radiotherapy is determined by:
- GH levels- really high levels, less likely to reach safe levels with conventional therapy
- how much the tumour has extended- massive tumour makes it less likely that safe levels of GH will be achieved after conventional therapy
Disadvantages:
- can take up to 10 years for mean serum GH levels to fall post radiotherapy
- The delayed response means patients require medical management in the meantime
- Can damage the surrounding normal pituitary structures, resulting in hypopituitarism; fall in gonadotropins, then ACTH then TSH . Around 50% if patients will have a gonadotropin deficiency post radiotherapy
- conventional radiotherapy increases risk of stroke and reduces cognitive function
Medical therapy options for acromegaly & cons
(1) dopamine agonists e.g. cabergoline- taken twice weekly to control GH and IGF-1 levels
- Cons; responses can vary widely from patient to patient- patients with lower levels of IGF-1 at beginning less likely to respond
(2) Somatostatin analogues- eg. Octrocide and lancreotide- injection. Somatostatin inhibits many hormones (binds to all 5 receptor subtypes including receptor subtype 2 which is particularly related to GH)
- cons; must be injected & many side effects (e.g GI symptoms, gallstones, glycaemic control may worsen due to effects on GH and insulin)
(3) GH Receptor antagonists e.g. pegvisomant- makes the GH site that interacts with the receptor more strongly binding and the dimerising site less strongly binding- thus acts as a competitive antagonist of GH at the receptor. Administered subcutaneously once a day
- cons of pegvisomant; very expensive- prescription tightly regulated by the NHS. Also, will not affect tumour size so tumour may continue to grow and compress other structures
Acromegaly signs
- Growth of hands, coarsening face/wide nose, big supraorbital ridges
- Macroglossia and widely spaced teeth
- Puffy lids/eyelids/skin, skin darkening, sleep apnoea
- Carpal tunnel
Acromegaly symptoms
- Acroparesthesia (burning/tingling/prickling/numbness sensations in the extremities) - Headache
- Decreased libido, increased sweating
- Snoring
- Backache
what is prolactinoma?
Risk factor for prolactinoma
Prolactinoma- pituitary adenoma resulting in overproduction of prolactin
Females are much more likely to get prolactinomas than men (reason not yet clear)
clinical features of prolactinoma
- local effects if tumour is a macroadenoma= headache, visual field defects, CSF leak in rare cases
- effects of prolactin include menstrual irregularity or amenorrhoea, infertility, galactorrhea, low libido, low testosterone in men
why is it important to conduct a thorough drug history on a patient with suspected hyperprolactinaemia?
Patients on anti-dopamine medications will have high prolactin levels- e.g. patients who are on anti-psychotics will usually always have high dopamine levels and therefore cannot be treated with a dopamine agonist (as the antagonist they are taking is usually important for treatment of other condition)
management of prolactinoma
Prolactinomas are managed medically rather than surgically using a dopamine agonist e.g. cabergoline, bromocriptine or quiagolide. Cabergoline given in small doses e.g. 025-0.5mg once per week.
Main role and 3 actions of PTH
Parathyroid hormone maintains serum calcium levels by;
1) increased calcium reabsorption at the kidney
2) increased calcium absorption in the intestine
3) increased calcium resorption from bones
PTH action in kidney
- increases calc reabsoprtion
- decreases phosphate absorption
- increases 1alpha hydroxylation of 25-OH vit D, so increass active form of vit D (1,25-OH vit D)
PTH action in intestine
Indirectly causes increased Calc absorption because of increased 1,2-OH vit D levels
PTH action in bone
PTH favours bone resorption by osteoclasts more than bone formation by osteoblasts, by increasing bone remodelling.
How are calcium levels maintained?
a negative feedback system; small changes in serum calcium result in large changes in PTH.
If calcium levels decrease by 10%, PTH levels double.
If calcium levels increase by 10%, PTH decreases by 70%.
When might a patient appear to have hypocalcaemia without actually having it?
A low serum albumin can result in low total serum calcium because calcium ions normally bind to albumin - but it will not result in a low ionised calcium.
How do you calculate corrected calcium using serum calcium?
Corrected calcium= total serum calcium + 0.02(40-serum albumin)
Consequences of hypocalcaemia
- paraesthesia (pins and needles of extremities/peri-oral area)
- Muscle spasms of hands and feet, larynx and can cause premature labour
- seizures
- basal ganglia calcification if chronic
- cataracts if chronic
- ECG abnormalities- long QT interval
clinical signs of hypocalcaemia
- Chvostek’s sign- tap over facial nerve as it exits parotid, if patient is hypocalcaemic, there will be spasm of facial muscles
- Trossaeu’s sign- inflate BP cuff 20mmHg above patient’s systolic BP for 5 mins on arm. Hand will take characteristic shape due to muscle spasm.
Causes of hypocalcaemia
osteomalacia (due to vit D deficiency), hypoparathyoidism, surgical hypoparathyroidism, autoimmune conditions, magnesium deficiency, acute rhabdomylosis, respiratory alkalosis, pseudohypoparathyroidism (tissue resistance to PTH), acute pancreatitis
Management of hypocalcaemia
- mild symptoms; give calcium 5mmol/6h
- severe symptoms; give 10ml of 10% caclium gluconate (2.25mmol) IV over 30 min, repeat as necessary. If due to alkalosis, correct alkalosis.
what is psuedohypoparathyroidism?
Pseudohypoparathyroidism occurs when the parathyroid glands detect and secrete PTH normally, but target tissues don’t respond to PTH for some reason. Can be genetic e.g. type I Albright Hereditary osteodystrophy, where mutation results in a deficiency in the G protein of the receptor. Type Ia patients miss ring finger knuckle (+ short stature, obesity, round facies)
Hypercalcaemia- clinical presentations
Bones, Stones, Moans, Groans, Thrones & Psychic Groans
- Bone conditions- e.g. osteitis fibrosa cystica (due to PTH overproduction which leads to overstimulation of osteoclasts)
- Stones- kidney stones, diabetes insipidus
- Abdominal pain and vomiting
- Polyuria & constipation
- Thirst
- Confusion possibly leading to delirium
Causes of hypercalcaemia
- primary hyperparathyroidism
- tertiary hyperparathyroidism-in renal failure, kidneys cannot activate vit D so patients get functional vit D deficiency -> leads to decreased calc absorption from gut and subsequent decrease in serum calcium. PTH levels increase as they should and this results in nodular hyperplasia and autonomy. As a result, bone resorption increases and the person becomes chronically hypercalcaemic and develops osteoporosis.
- Malignancy
- Thiazides
- Thyrotoxicosis
- Sarcoidosis
- Familial hypocalciuric/ benign hypercalcaemia
- Milk-Alkali syndrome
- Adrenal insufficiency
- Phaeochromocytoma
Consequences of primary hyperparathyroidism
bones, stones, groans and psychic moans
what can happen to the Parathyroid glands following tertiary hyperparathyroidism?
If tertiary hyperparathyroidism occcurs, PTH levels will rise. if this becomes chronic, then the glands undergo changes because the cells of the gland are in overdrive, causing nodular hyperplasia (glands become abnormally enlarged) and autonomy (paathyroid glands stop responding to external calcium signals and are switched on all the time)
what changes to calcium absorption occur during tertiary hyperparathyroidism and what is the risk? What will happen to phosphate levels?
The renal failure in tertiary hyperparathyroidism means that calcium cannot be absorbed effectively from the gut or reabsorbed from the kidney, but bone resorption still allows for increased serum calcium. The resultant increase in resorption means the person can become hypercalcaemic and develop osteoporosis.
Patient will have chronic hyperphosphataemia. normally when PTH is high, phosphate is excreted by the kidneys but it cant in patients with renal failure- so serum levels of phosphate increase.
VIt D Deficiency (secondary hyperparathyroidism)
- PTH level
- Calcium level
- Phosphate level
- PTH action appropriate or inappropriate?
- PTH level increases
- Calcium level decreases
- Phosphate level increases
- PTH action appropriate
Hypoparathyroidism
- PTH level
- Calcium level
- Phosphate level
- PTH action appropriate or inappropriate?
- PTH level decreases
- Calcium level increases
- Phosphate level decreases
- PTH action inappropriate
Pseudohypoparathyroidism
- PTH level
- Calcium level
- Phosphate level
- PTH appropriate or inappropriate?
- PTH level increases
- Calcium level decreases
- Phosphate level increases
- PTH action appropriate
Pseudopseudohypoparathyroidism
- PTH level
- Calcium level
- Phosphate level
- PTH appropriate or inappropriate?
- PTH level normal
- Calcium level normal
- Phosphate level normal
- PTH action appropriate
Hypercalcaemia of malignancy
- PTH level
- Calcium level
- Phosphate level
- PTH appropriate or inappropriate?
- PTH level decreases
- Calcium level increases
- Phosphate level decreases or could be normal (depends on cancer mechanism)
- PTH action appropriate
Primary hyperparathyroidism
- PTH level
- Calcium level
- Phosphate level
- PTH appropriate or inappropriate?
- PTH level increases
- Calcium level increases
- Phosphate level decreases
- PTH action inappropriate
Tertiary hyperparathyroidism
- PTH level
- Calcium level
- Phosphate level
- PTH appropriate or inappropriate?
- PTH level increases
- Calcium level increaeses
- Phosphate level increases
- PTH action inappropriate?
What is the most common endocrine disorder?
Thyroid disease- presents as hyperthyroidism, hypothyroidism, goitre-enlarged thyroid gland
Why is thyroid autoimmunity important? What are the 4 types of autoimmunity?
Thyroid autoimmunity is a major cause of thyroid disease.
4 types;
1- Focal thyroiditis and/or positive thyroid perioxidase (PTO) and thyroglobulin antibodies
2- Postpartum thyroiditis- usually occurs within six months of delivery, usually causing temporary hyperthyroidism
3- Autoimmune hypothyroidism; e.g. Hashimoto’s and atrophic thyroiditis
4- Grave’s disease- hyperthyroidism where thyroid-associated ophthalmopathy is a common extrathyroidal manifestation
Typical features of Hashimoto’s
- Goitre
- Thinning eyebrows
- Coarse hair
- Puffy skin
Typical features of Grave’s disease
- enlargement of the thyroid
- peri-orbital oedema
- Thin and gaunt features
- Exophthalmos (bulging eyes)
What is the causative factor for Grave’s disease?
TSH Receptor (TSH-R) antibodies- stimulate TSH receptor on thyroid cells, causing hyperthyroidism.
What is thyroid-associated ophthalmopathy?
Present in most patients with Graves’ disease and autoimmune hypothyroidism. It is due to swelling of the extraocular muscles. It is most likely caused by autoantigen in the extraocular muscle that cross reacts with a thyroid autoantigen.
Three main mechanisms which cause hyperthyroidism (excess of thyroid hormones in blood)
1- overproduction of thyroid hormone
2- leakage of preformed hormone from thyroid (as occurs in inflammatory processes i.e. thyroiditis)
3- ingestion of excess thyroid hormone
common causes of hyperthyroidism
- graves disease
- toxic multinodular goitre (palpable thyroid enlargement)
- toxic adenoma
clinical features of hyperthyroidism
- weight loss
- tachycardia
- hyperphagia
- anxiety
- heat intolerance
- sweating
- diarrhoea
- lid lag and staring
- menstrual disturbance- amenorrhea, oligomenorrhea, decreased fertility
investigations for hyperthyroidism
- clinical history along with physical signs are usually sufficient to make a diagnosis
- thyroid function tests to confirm biochemical hyperthyroidism; in primary, free T4 is increased & free T3 will be increased but TSH will be suppressed, in secondary hyperthyroidism free T4 and T3 will be increased and TSH will be inappropriately increased
- diagnosis of underlying cause is important because treatment varies, so supporting investigations will be required to see what underlying cause is; including thyroid antibodies and iodine uptake scan
treatment of hyperthyroidism
- anti-thyroid drugs- These cannot be used in thyroiditis
- Radio-iodine
- Surgery- partial (e.g. if toxic adenoma) or subtotal thyroidectomy (in multinodular or diffuse Graves’ disease)
Hyperthyroidism- anti-thyroid drugs
- examples
- mechanisms
- thinamides, carbimazole, propylthiouracil, methimazole
- Drugs decrease the synthesis of new thyroid hormone.
- Propylthiouracil inhibits the conversion of T3 to T4
Graves’ disease treatment
Either;
- titration regimen of antithyroid drugs for 12-18 months
- block and replace regiment with T4 for 6-12 months
Types of hypothyroidism
- Primary hypothyroidism- accounts for more than 99% of cases and is due to an absence of dysfunction of the thyroid gland. Most cases are due to Hashimoto’s thyroiditis
- Secondary hypothyroidism- due to pituitary dysfunction
- Tertiary hypothyroidism- due to hypothalmic dysfunction
Main causes of hypothyroidism in adults
- Hashimoto’s (autoimmune disease)
- iodine therapy for hyperthyroidism
- thyroidectomy
- postpartum thyroiditis
- drugs
- thyroiditides
- iodine deficiency
- thyroid hormone resistance
clinical features of hypothyroidism
- fatigue
- weight gain
- cold intolerance
- constipation
- menstrual disturbance
- muscle cramps
- slow cerebration
- dry, rough skin
- peri-orbital oedema
- delayed muscle reflexes
- carotenaemia
- oedema
- hair loss- eyebrows, thinning of hair
investigation of hypothyroidism
1- primary hypothyroidism
2- secondary and tertiary hypothyroidism
1- in primary hypothyroidism; increased TSH is the most sensitive marker, with a decrease in free T3 and T4. Positive titre of TPO antibodies is usually seen in Hashimoto’s
2- in secondary/tertiary hypothyroidism, TSH will be inappropriately low for reduced T4/T3 levels. May appear normal but should be high given the lack of negative feedback
Treatment for hypothyroidism
- contraindication
- treatment of choice; synthetic levothyroxine (T4 analogue).
- if symptoms mild, start with fairly low dose of 7mcg, in young adults with symptomatic hypothyroidism, give full replacement of 100mcg.
- In primary, doses of L-thyroxine are titrated until TSH levels normalise
- L-Thyroxine should be used in caution in patients with ischaemic heart disease- can trigger angina or MI in patients who have been hypothroid for a while, so should start on lower doses
Drugs that can affect the function of the thyroid gland
- amiodarone - inhibits conversion of inactive T4 to T3. Can lead to hypothyroidism or hyperthyroidism
- lithium
- interferon (used in hepatitis C and MS therapies)
- immune therapies (used in oncology or rheumatology)
how much fluid is in each compartment of the body?
- Extracellular fluid (14L) –> 3.5L intravascular fluid, 10.5L interstitial fluid
- Intracellular fluid (28L)
Water excess effects on;
- plasma osmolality
- cellular hydration
- thirst
- vasopressin secretion –> overall total body water
- plasma osmolality decreases
- cellular hydration increases
- increased cellular hydration -> decreased thirst, resulting in reduced water intake
- reduced vasopressin secetion, leading to an increase in water excretion by the kidney –> overall result will be decrease in total body water
Water loss e.g. diarrhoea/vomiting effects on;
- plasma osmolality
- cellular hydration
- thirst
- vasopressin secretion –> overall total body water
- plasma osmolality increases
- cellular hydration increases
- decreased cellular hydration -> increased thirst leading to increased water intake
- increased vasopressin secretion leading to decrease in water excretion by the kidney -> overall result is increase in total body water
vasopressin
- where is it produced & secreted
- what is its effect
- what controls release of vasopressin
- vasopressin (ADH) is a peptide hormone produced by the hypothalamus and secreted by the posterior pituitary gland
- vasopressin (1) binds to V1 receptors on vascular smooth muscle to cause vasoconstriction, and (2) acts on renal collecting ducts via V2 receptors to increase water permeability, decreasing water excretion by kidney
What controls vasopressin release?
Vasopressin release is controlled by
- osmoreceptors in the hypothalamus for day-day control
- baroreceptors in the brainstem and great vessels which work in emergency situations such as hypovolaemic shock
baroreceptor effect in shock
baroreceptors can override signals from osmoreceptors so that there will be vasopressin release no matter what plasma osmolality is
nuclei in hypothalamus that produce vasopressin
the supraoptic nucleus and the paraventricular nucleus
role of osmoreceptors
osmoreceptor centre lies near the thirst centre in the hypothalamus. Projects to the supraoptic and paraventricular nucleus
total insensible loss- water excretion
stool- 0.1L/day
sweat- 0.1L/day
pulmonary surfaces- 0.3L/day
Total urine filtered by kidneys
Total urine output per day
Total filtered by kidneys per day- 180L/day
1-1.5L/day excreted per day
What is the main determinant of plasma osmolality?
Sodium is the major extracellular cation and thus the main determinant of plasma osmolality -> serum sodium levels are determined by total body water
relationship between plasma vasopressin and urine concentration?
- as vasopressin increases, there is initially no change in urine osmolality -> then there is a linear increase in urine osmolality as vasopressin continues to rise
- Urine osmolality plateaus at its maximum of 1200 mOsmol/kg -> urine cannot get more concentrated than this
Diabetes insipidus- symptoms
- polyuria (excessive production of urine)
- polydipsia (excessive thirst/drinking)
- symptoms of hypernatraemia (lethargy/weakness/thirst)
What is diabetes insipidus?
What are the two categories of causes?
Diabetes insipidus is where the kidneys are unable to retain water due to a problem with either the production or action of vasopressin (ADH) -> could be because of reduced ADH secretion from posterior pituitary or impaired response of the kidney to ADH
The two categories of causes are cranial and nephrogenic.
causes of cranial Diabetes Insipidus?
- congenital (defects in ADH gene)
- tumour (may also present with hypopituitarism) -> craniopharyngioma, metastases, pituitary tumour
- trauma (temporary if distal to pituitary stalk as proximal nerve endings grow out)
- vascular- haemorrhage, aneurysm, Sheehans’
- infection; meningoencephalitis
- inflammatory- granuloma, Guillain Barre syndrome
causes of nephrogenic Diabetes Insipidus?
- Inheritied
- Metabolic; low potassium, high calcium
- drugs; lithium, demeclocyline
- chronic renal disease
- diabetes mellitus
- post-obstructive uropathy
- infiltrative disease- e.g. amyloid
what is cranial diabetes insipidus?
As plasma osmolality increases, vasopressin does not increase in response
What is nephrogenic diabetes insipidus?
Nephrogenic diabetes insipidus is caused by resistance to vasopressin action, even though it is released normally from the posterior pituitary
What will happen to a patient with cranial diabetes insipidus who is water deprived?
- plasma osmolality will rise rapidly and then fall when desmopressin is administered
- urine osmolality will not change until desmopressin is administered, then it rises
What will happen to a patient with nephrogenic diabetes insipidus who is water deprived?
- plasma osmolality rises and does not respond to desmopressin
- urine osmolality does not change and does not respond to desmopressin
test for diagnosing diabetes insipidus
water deprivation test
management of cranial diabetes insipidus
- treat any underlying condition
- administer desmopressin (vasopressin analogue) -> tablets, nasal spray, subcutaneous
management of nephrogenic diabetes insipidus
- treat the cause
- if it persists, 5mg bendroflumethazide orally
Hyponatraemia definition
serum sodium of less than 135/mmol/L, severe= less than 125mmol/L
Signs and symptoms of hyponatraemia
in order of increasing severity;
- initially anorexia, nausea and malaise
- headache, irritability, confusion, weakness, reduced GCS
- seizures
- cardiac failure or oedema
causes of hyponatraemia
- syndrome of inappropriate ADH secretion
- blood sample taken from drip arm
- sodium deficiency e.g. from a low sodium intake or increased loss due to diarrhoea and vomiting
- renal failure
- malignancy
- liver failure
- Addison’s
Describe the brain’s volume adaption response to gradual onset hyponatraemia
- when hyponatraemia occus, the CSF will immediately change to a hypotonic state
- cells will take on water
- rapid adaptation occurs through loss of sodium, potassium and chloride ions into CSF
- slow adaptation occurs through a loss of organic osmalites from cells to the CSF -> water will follow these solutes out of cells
risk of carrying out therapy for hyponatraemia too quickly
rapid increase in sodium leads to more water leaving neurons -> can result in osmotic demyelination and this will lead to coma, confusion, fits and possibly death
proper therapy for someone who is hyponatraemic
(a) chronic
(b) acute
- slowly correct hypotonic state with Na and water
(a) chronic; correction must be very slow at <8mmol/L increase in 24hrs
(b) acute; they can have their sodium corrected more rapidly
tests for hyponatraemia
- plasma osmolality
- urine osmolality
- plasma glucose
- urine sodium
- urine dipstick for protein
- TSH
- cortisol
What is SIADH?
SIADH accounts for 25% of all hyponatraemia
- patient secretes too much ADH when it should not be secreted
- urine is therefore appropriately concentrated
- Patient has water retention so ECF volume is mildly increased
Causes of SIADH
- central nervous system disorders (head injury, meningitis, encephalitis, brain tumour/abscess, haemorrhage/thrombosis, GB syndrome
- Tumours; carcinoma, lymphoma, leukemia, thymoma, sarcoma, mesothelioma
- Respiratory causes; pneumonia, TB, severe asthma, pneumothorax, emphysema
- drugs; carbabmazipine, thiazides, cytotoxics, desmopressin, vasopressin, SSRIs, PPIs
management of SIADH
- diagnose/treat underlying conditions
- fluid restriction of less than 1L/day
- vasopressin receptor agonists
- if patient has severe hyponatraemia, patient needs to be treated with hypertonic normal saline
Development of the anterior and posterior pituitary
- anterior pituitary develops from Rathke’s pouch in the roof of the mouth
- posterior pituitary develops as a downgrowth of the hypothalamus, which also forms the infindibulum (pituitary stalk) composed of axons
two main types of craniopharyngioma
(1) adamantinous- cystic with calcification
(2) squamous papillary- well-circumscribed tumour
where are cranipharyngiomas formed? are they benign or malignant?
cranipharyngiomas usually grow near the base of the brain, just above the pituitary gland.
They are benign but can invade surrounding structures
What can happen if craniopharyngiomas extend into the suprasellar region? What are some signs of this?
craniopharyngiomas can damage the rest of the pituitary gland if they extend into the suprasellar region. Signs include; - raised intracranial pressure - visual disturbances - growth failure - pituitary hormone deficiency - weight increase
Formation & tructure of Rathke’s cysts
- Rathke’s cysts are derived from remnants of Rathke’s pouch. They are composed of a single layer of epithelial cells with mucoid, cellular or serous components in the cyst fluid.
- Mainly small and asymptomatic
- if symptomatic, patients can present with headache, amenorrhoea, hypopituitarism and hydrocephalus
- what is a meningioma?
- common cause of meningiomas
- symptoms of meningiomas
- meningiomas are tumours that form in the meninges.
- meningiomas are commonly caused by previous radiotherapy in the area
- symptoms include loss of visual acuity, visual field defects and signs and symptoms of endocrine dysfunction
are pituitary adenomas symptomatic?
Most adenomas are incidentalomas, but macroadenomas may cause visual disturbances and headaches
how to test for pituitary issues?
- carry out a hromone test
- if hormone tests are abnormal or patient has suspected tumour mass effects, do an MRI scan of pituitary
main local mass effects of pituitary tumours
- visual field defects
- headaches
- cranial nerve palsy
- temporal lobe epilepsy
- CSF rhinorrhea
what is a pheochromocytoma and what can it cause?
Pheochromocytoma is a rare tumor of adrenal gland tissue. It results in the release of too much epinephrine and norepinephrine, hormones that control heart rate, metabolism, and blood pressure
During the puberty stage (12 to 18-years-old), what drives this growth?
sex steroids and growth hormone
Effects of GH dysfunction
Prescription
- short stature
- abnormal body composition
- reduced muscle mass
- poor quality of life
Prescribe GH
Effects of LH/FSH dysfunction
Prescription
- hypogonadism
- reduced sperm count males
- infertility
- menstruation probs female
Prescribe testosterone in males, Oestradiol/progesterone in females
TSH dysfunction
prescription
- hypothyroidism
Prescribe Levothyroxine
ACTH dysfunction consequences
Prescription
-adrenal failure
- decreased pigment
Prescribe hydrocortisone
ADH dysfunction
prescription
- Diabetes insipidus (AD deficiency- decreased water absorption in kidney, resulting in polyuria and polydipsia) Prescribe DDAVP (desmopressin)
growth hormone replacement- principles of prescription
- patient less than 60, start them on 0.2-0.4mg/day, daily injection
- GH replacement improves lipid profiles, body composition and bone mineral density
What are the Tanner stages?
The Tanner scale is a scale of physical development in children, adolescents and adults. The scale defines physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitals, testicular volume and development of pubic hair.
Tanner stages- Boys
-stage 1: Prepubertal- no pubic hair
testicular length less than 2.5cm
testicular volume less than 3ml
-stage 2: sparse growth of lightly curly pubic hair, mainly at base of penis
testes less than 3ml
scrotum thinning and reddening
- Stage 3: thicker, curlier hair spread to mons pubis
- Stage 4; adult-type hair, not yet spread to medial surface of thighs
penis further enlargened; testes larger, darker scrotal skin colour - Stage 5; adult-type hair spread to medial surface of thighs
genitalia adult size and shape
How is testicular volume measured? What is normal adult testicular volume?
Testicular volume is measured using orchidometers. Normal adult male volume is 15-25ml.
Tanner stages- Girls
- stage 1; prepubertal- no hair, elevation of papilla only
- stage 2; sparse growth of minimally pigmented hair, mainly on labia, breast bud noted/palpable, enlargement of areola
- stage 3; darker hair spreading over mons pubis, further enlargement of breast and areola with no separation of contours
- stage 4; thick adult-type hair not yet spread to medial surface of thighs, projection of areola and papilla to form secondary mound above level of breast
- stage 5; hair adult type and distributed in classic inverse triangle, adult contour breast with projection of papilla only
what is the first visible change in females in puberty? what is this induced by and what other hormones are involved? how long does it take?
breast development is the first visible change of puberty, induced by oestrogen. Other hormones involved are prolactin, glucocorticoids and insulin. It is completed in approx 3 years
What changes happen to the uterus during puberty?
- tubular shape -> pear shape
- single layer endometrium -> endometrium with increased thickness
maturation of external genitalia due to oestrogens includes
- labia majora and minora increase in size and thickness
- rogation and a change in colour of the labia majora
- hymen thickens
- clitoris enlarges
- vestibular glands (skenes and bartholin’s glands) begin secretion
effect of adrenal and ovarian androgens
pubic and axillary hair grows
When does the hypothalamus start to release GnRH? How is it secreted?
What happens as a result?
Hypothalamus starts secreting GnRH at puberty in a pulsatile manner.
This causes a.pituitary to secrete LH and FSH from gonadotroph cells.
Precocious puberty
- which gender more likely?
- Causes?
- 90% of cases of precocious puberty occur in females
- idiopathic in 80% of female cases and 30% of male cases, but all other cases caused by brain tumour or CNS disorders
is precocious pseudopuberty GnRH dependent?
No- caused is elsewhere, e.g. hCG-secreting tumours formed in gonads, brain, liver, retroperitoneum/mediastinum, congenital adrenal hyperplasia, etc
treatment of precocious puberty
- GnRH superagonist to suppress the pulsatility of GnRH secretion (therefore blocking the whole axis)
causes of delayed puberty
- much more common in males- usually idiopathic resulting from delayed activation of hypothalmic pulse generator
- hypogonadotrophic hypogonadism (LH and FSH levels raised, but no response from gonads)
- could be functional- e.g. may be related to another condition e.g. Type I diabetes (more common in males)
indications for investigating delayed puberty in girls?
- lack of breast development by 13 years
- more than 5 years between breast development and menarche (first occurance of menstruation)
- lack of pubic hair by 14 years
- absent menarche by 15-16 yrs
indications for investigating delayed puberty in boys?
- lack of testicular enlargement by 14 yrs
- lack of pubic hair by 15yrs
- more than 5 yrs to complete genital enlargement
What is CDGP?
CDGP= constitutional delay of growth and puberty. it is the extreme of normal physiological variation- most common cause of delayed puberty. Frequently due to family history
How is CDGP diagnosed?
Diagnosis of exclusion- eliminate other potential causes
what are the two types of hypogonadism?
- hypergonadotrophic hypogonadism- GnRH, FSH and LH levels are high but gonads are not responsive
- hypogonadotrophic hypogonadism- GnRH and/or LH/FSH levels are low but gonads would work normally
most common cause of isolated gonadotrophic deficiency
Kallman’s syndrome
features of turner’s syndrome
- webbing of neck
- low posterior hairline
- small mandible
- prominent ears
- broad chest
- epicanthal folds
- high arched palate
- cubitus vulgus
- hyperconvex fingernails
in the fasting state;
- glucose comes from
- glucose is delivered to
- insulin & glucagon levels
- glucose comes from the liver from (i) breakdown of glycogen and (ii) from gluconeogenesis which utilises 3D precursors such as lactate, alanine and glycerol to synthesis glucose
- glucose is delivered to insulin dependent tissues, predominantly the brain and RBCs
- insulin levels are low and glucagon levels are high
- muscles use free fatty acids for fuel
- some processes are sensitive to insulin and low levels of insulin prevent unrestrained breakdown of fat
in the post-prandial (after feeding) state
- glucose levels
- ingested glucose distribution
- glycogen levels
- free fatty acid levels
- rising glucose, which occurs within 5-10mins of eating, stimulates insulin secretion and suppresses glucagon
- 4-% of ingested glucose goes to the liver and 60% to the periphery, mostly muscle
- ingested glucose helps replenish glycogen stores in liver and muscle
- high insulin and glucose levels suppress lipolysis and therefore levels of free fatty acids fall
cells in the pancreas that secrete
- insulin
- glucagon
- insulin is secreted by beta cells
- glucagon is secreted by alpha cells
how is insulin secreted from the beta cell? what does this do?
- Glucose enters the beta cell via glut2 channels
- glucose is metabolised by glucokinase to glucose-6-phosphate, trapping glucose in the cell
- glucose-6-phosphate is further metabolised, increasing the ATP levels
- ATP closes the Katp channel, which results in depolarisation of the beta-cell membrane
- voltage-gated calcium channels open, allowing calcium ions to enter the cell
- calcium binds to proteins allowing the docking of insulin secretory granules to the cell membrane, and thus insulin is secreted
- insulin results in mobilisation of Glut4 channels to the cell membrane. This allows glucose to enter the cell
actions of insulin
- suppresses hepatic glucose output by decreasing glycogenolysis (breakdown of glycogen)
- increases glucose uptake in insulin-sensitive tissues, such as muscles and adipose
- suppresses lipolysis and breakdown of muscle
actions of glucagon
- increases hepatic glucose output by increasing glycogenolysis and gluconeogenesis
- reduces peripheral glucose uptake
- stimulates peripheral release of gluconeogenic precursors
- stimulates lipolysis to produce glycerol
- stimulates muscle glycogenolysis to produce glucose
- stimulates muscle breakdown to produce amino acids
what is diabetes mellitus?
a disorder of carbohydrate metabolism where the body does not produce enough insulin, resulting in high levels of sugar in the bloodstream.
how does diabetes mellitus cause morbidity and mortality?
- acute hyperglycaemia, which can result in diabetic ketoacidosis (DKA) which is common, and
serious conditions associated with diabetes
- stroke
- cardiovascular disease
- diabetic retinopathy
- diabetic neuropathy
- diabetic nephropathy
What is type 1 diabetes mellitus?
What other risk is there with type 1 dm?
insulin deficiency characterised by a loss of beta-cells due to autoimmune destruction.
- Beta cells express antigens of the HLA histocompatibility system, perhaps in response to an envionrmental event such as a viral infection. This activates a chronic cell-mediated immune process, leading to chronic insulitis.
- Patients who have type 1 dm are at risk of having a family history of other autoimmune conditions, or themselves having another one of these conditions- the main one is thyroid disease.
In type 1 diabetes mellitus, failure of insulin secretion leads to…
- continued breakdown of glycogen (increased levels of glucose)
- unrestrained lipolysis and skeletal muscle breakdown, providing gluconeogenic precursors
- inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
- -> Rising glucose conc results in increased urinary glucose losses as the renal threshold of 10mM is exceeded, resulting in polyuria
- -> Osmolality of blood changes and this activates the thirst centre of the hypothalamus and this leads to polydipsia.
Failure to treat type 1 dm leads to
- increased circulating glucagon due to the loss of local inhibition by insulin in the islets, further increasing glucose levels in the blood
- perceived stress leads to increased cortisol and adrenaline
- progressive catabolic state and increasing levels of ketones
What is type 2 diabetes mellitus?
insulin resistance, and impaired insulin secretion in response to glucose
Weight loss is associated with which type of diabetes?
Type 1 diabetes mellitus- loss of adipose and muscle tissue
What is hyperglycemia?
Hyperglycemia= high blood sugar (glucose) levels.
- Can affect people with type 1 or type 2 diabetes mellitus (or women with gestational diabetes).
impaired insulin action in diabetes leads to
- reduced muscle and fat uptake after eating
- failure to suppress lipolysis and therefore this results in high circulating free fatty acids
- abnormally high glucose output after a meal
Do type 2 diabetes mellitus patients have glucosuria or ketonuria?
glucosuria
Presenting features of diabetes
- polydipsia
- polyuria
- weight loss and fatigue
- hunger
- infections
- blurred vision
if unsure of whether t1 or t2 dm, you should….
do a blood test to check of islet autoantibodies, and in the meantime treat it as though it is type 1 dm, as consequences would be potentially more severe if this diagnosis is missed
autoantibodies which are tested for in T1DM are
- Anti-GAD
- Pancreatic islet cell antibody
- Islet antigen-2 antibody
- ZnT8
T1DM is associated with other autoimmune diseases, including
- hypothyroidism
- Addison’s
- Coeliac disease
Do type 1 diabetes mellitus patients have glucosuria or ketonuria?
glucosuria and ketonuria
What happens during diabetic ketoacidosis?
- hyperglycaemia- plasma glucose <50mmol/L
- raised plasma ketones- urinary ketones >2+
- metabolic acidosis- plasma bicaronate of <15mmol/L
symptoms of DKA over days
- polyuria
- polydipsia
- nausea and vomiting
- weight loss
- weakness
- abdominal pain
- drowsiness and confusion
signs of DKA
- kussumaul breathing (hyperventilation) - respiratory compensation of metabolic acidosis
- dehydration- average fluid loss 5-6L
- hypotension
- tachycardia
- coma
Management of DKA
(1) Rehydration; 3L of saline in first 3 hours- dilutes glucose and ketones
(2) Insulin; inhibits lipolysis, ketogenesis and acidosis, reduce glucose production by liver and increased glucose uptake by the tissues
(3) replacement of electrolytes is likely within an hour or two of starting insulin, specifically potassium replacement
(4) think about precipitating factor that resulted in the DKA and treat this- e.g. infection
possible implications of DKA
- cerebral oedema
- adult respiratory distress syndrome
- thromboembolism
- aspiration pneumonia
- death
Type 1 DM therapy
- aim
- treatment
- aim of t1dm treatment= restore the physiology of beta cell
- insulin treatment must be given by injection- given twice daily mixture of short and medium acting insulin
- take basal bolus once or twice daily of medium acting insulin plus pre-meal quick acting insulin
T1DM patients need to…
judge carb intake to adjust insulin dose to match it. Also need awareness of how exercise can lower blood glucose and adjust the dose to account for this.
Alcohol also influences how much insulin will be required
Badly controlled T1DM can result in
hyperglycaemia or hypoglycaemia
signs and symptoms of hypoglycaemia
- shaking
- tachycardia
- palpitations
- sweating
- dizziness
- anxiety
- hunger
- impaired vision
- slurred speech
- weakness
- fatigue
- headache
- irritability
- personality changes
- aggression
What is MODY? How is it caused?
maturity onset diabetes of the young, diagnosed under 25 years old. Caused by a single autosomal dominant gene defect that alters beta-cell function
Risk factors for MODY
- those with a parent affected by diabetes
- those with an absence of autoantibodies
- evidence of non-insulin dependence (good control of low dose insulin, no ketosis, measurable C peptide)
- sensitivity to sulphonylureas
What is the significance of C peptide?
C-peptide is secreted in proportion to insulin and is a marker of endogenous insulin production
other forms of diabetes
- maternally inherited diabetes and deafness
- lipodystrophy
- permanent neonatal diabetes
- exocrine diabetes
- drug induced diabetes
drugs which have a risk of diabetes include
- glucocorticoids
- thiazides
- protease inhibitors
- antipsychotics
macrovascular complications of diabetes are
- stroke
- cardiovascular disease
- peripheral vascular disease
microvascular complications of diabetes
- diabetic retinopathy
- diabetic nephropathy
- diabetic peripheral neuropathy
risk factors of diabetic peripheral neuropathy
- hypertension
- smoking
- high HbA1c
- long diabetes duration
- high BMI
- raised triglycerides and high total cholesterol
treatment of diabetic peripheral neuropathy
= good glycaemic control
- medications including tricyclic antidepressants, SSRIs, opioids, etc
- therapies such as transcutaneous nerve stimulation, acupuncture, spinal cord stimulation, psychological interventions (e.g. hypnosis)
symptoms of peripheral vascular disease
- intermittent claudication- pain on walking that comes on after a particular distance and can manifest as cramps in the calf or thigh for example
- rest pain- particularly occurs when the patient is lying down in bed and is a sign that the disease is severe i.e. where the patient has critical ischaemia (pain often occurs in feet)
signs of peripheral vascular disease
- diminished or absent pedal pulses
- coolness of the feet and toes
- poor skin and nails
- absence of hair on the feet and legs
treatment of peripheral vascular disease
- advise the patient to stop smoking
- advise patient to walk through the pain if they have intermittent claudication. This will encourage collateral vessels to form and will improve perfustion and thus lessen symptoms
- advise patient on how to improve other risk factors such as hyperglycaemia and dyslipidaemia
- surgical intervention will be offered to any patient that has rest pain
risk factors for diabetic retinopathy
- how it is detected
- long duration diabetes
- poor glycaemic control
- hypertensive patients
- those on insulin treatment
- during pregnancy- due to intensive insulin treatment that patients get during pregnancy to ensure good glycaemic control
Diabetic eye screening is the way to effectively detect it early
treatment for diabetic retinopathy
- laser therapy (focal or grid treatment, pe`ripheral scatter)
treatment- Type 1 Diabetes
all patients with type 1 diabetes require insulin therapy.
e. g. Basal-Bolus regimen:
- separation of basal from bolus insulin to mimic physiology
- pre-meal rapid acting boluses are adjusted according to pre-meal glucose measurements and the carbohydrate content of food
- basal insulin should control blood glucose in between meals and articularly during the night
- basal insulin is adjusted to maintain fasting blood glucose between 5-7mmol/L
standard regime does not account for snacks
significance of HbA1c for type 1 diabetes in young patients
- the lower the Hb1ac, the lower the risk of developing retinopathy
- HbA1c of 5.5%= normal, greater than 6.5%= diabetes.
When are insulin levels normally highest?
After a meal- when it is most needed for glucose metabolism
What are two examples of premixed insulins?
what are the disadvantages of using them?
When are they used?
- mixtard and humulin
Disadvantages:
- they don’t mimic normal physiology very well
- requires consistent meal and exercise pattern because there is no adjustment of doses involved
- not possible to separately titrate individual insulin components
- there is increased risk of nocturnal hypoglycaemia
- increased risk of fasting hyperglycaemia if basal component does not last long enough
they are used in patients who otherwise struggle to manage their treatment regimen of multiple injections per day (five or more) as this only requires two
Advantages & Disadvantages of once-daily basal insulin in T2DM
Advantages:
- simple for the patient
- patient can adjust insulin themselves based on fasting glucose measurements and id is good for the patient to be in charge of their own treatment
- patient can continue oral therapy
- less risk of hypoglycaemia at night compared with no insulin therapy at all
Disadvantages;
- does not cover mealtimes
- long-acting analogues are expensive so NPH is often used which is not as good
When does basal-bolus insulin therapy usually begin for patients with T2DM?
Many patients currently begin insulin therapy when HbA1c levels are more than 9% (but they really should begin much earlier)
Hypoglycaemia classifications
- Level 1; less than 3.9mmol/L (no symptoms)
- Level 2; serious biochemical- plasma glucose of less than 3mmol/L (non-severe- patient can self-treat, cognitive function is mildly impaired)
- Level 3; serious biochemical- severe: patient has impaired cognitive function sufficient to require external help to recover
common symptoms of hypoglycaemia due to adrenaline release
- trembling
- palpitations
- sweating
- anxiety
- hunger
non-stress symptoms of hypoglycaemia
- difficulty concentrating
- confusion
- weakness
- drowsiness
- dizziness
- vision changes
- difficulty speaking
why are patients with diabets susceptible to hypoglycaemia?
- they take insulin and a side effect of this treatment is hypoglycemia
- their defences against hypoglycaemia are not effective- the normal physiological response to prevent hypoglycaemia involves control of insulin output; when blood glucose reaches 4.6mmol/L, there is inhibition of endogenous insulin secretion.
In diabetes, at 3.8mmol/L blood glucose, glucagon secretion is increased- this results in glucose release from the liver
At 3.5mmol/L glood glucose, adrenaline secretion is increased
At 3.2-3mmol/L blood glucose, patient will get autonomic and neuroglycopenic symptoms
What happens to the adrenaline response to hypoglycaemia in T1DM over time?
Changes from 3.5mmol/L to 2.5mmol/L; patients now only have symptom onset at this much lower level of blood glucose. This means patients will suddenly get neurological symptoms of the hypoglycaemia before the symptoms caused by rising adrenaline.
Results of glycopenia and blood glucose level at which it occurs
occurs when blood glucose is below 1.5mmol/L
Results in reduced conscious level, convulsions and coma
risk factors for severe hypoglycaemia in T2DM patients on insulin or suphonylureas
- advancing age
- cognitive impairment
- depression
- aggressive treatment of glycaemia
- impaired awareness of hypoglycaemia
- duration of multiple daily injections of insulin therapy
- renal impairment
what is the normal HbA1c target for a patient with T2DM? When should it be relaxed
Normal target us HbA1c oof less than 53mmol/mol (7%)
appropriate to relax targets in the following circumstances;
- patients with severe complications
- patients with advanced comorbities
- patients with cognitive impairment
- those with limited life-expectancy
- if patients achieve unacceptable hypoglycaemia from stringent control
the 5 key steps of treatment of hypoglycaemia
1- recognise symptoms so they can be treated as soon as they occur
2- confirm the need for treatment if possible (blood glucose less than 3,9mmol/l is the alert value)
3- treat with 15g fast acting carbohydrate to relieve symptoms
4- retest in 15min to ensure blood glucose is more than 4mmol/l and retreat if needed
5- eat a long-acting carbohydrate to prevent recurrence of symptoms
objectives of treatment in type 2 diabetes
- good glycaemic control
- reducing the risk of cardiovascular morbidity/mortality, chronic kidney disease and microvascular complications
- weight reduction through increasing physical activity and decreasing dietary fat
In T2DM, insulin resistance and reduced insulin secretion results in
- increased lipolysis leading to increased free fatty acid levels
- increased glucose production by the liver, leading to increased blood glucose levels
- decreased glucose uptake by muscles, also increasing blood glucose levels
- first line drug in the treatment of T2DM
- second line options
- 1st line= Metformin
- 2nd line options= sulphonylureas, incretin-based agents, SGLT-2 inhibitors, insulin
incretins influence glucose homeostasis via multiple actions including
- glucose-dependent insulin secretion
- post-prandial glucagon suppression
- slowing of gastric emptying
