biochemistry Flashcards
what are the 3 main different types of secretion?
endocrines
- ie hormones
paracrine
- stuff acts locally
autocrine
- affects the cell secreting the protein
where is the pituatory gland situated?
pituatory gland aka?
what are the two parts of the pituatory gland?
- aka?
how are each controlled?
situateed in the sella turcica, a depression in the sphenoid bone
hypophysis
anterior lobe
- makes up 75% of gland
- aka adenohypophysis
- controlled by hormones released by hypothalamus (ends in RH - releasing hormone)
posterior lobe
- makes up 25% of gland
- aka neurohypophysis
- controlled by neuronal control from hypothalamus
what hormones are:
- produced in anterior pituatory lobe? 6
- stored in posterior pituatory lobe? 2
anterior pituatory
- growth hormone
- prolactin
- ACTH (adrenocorticotrophic hormone)
- TSH (thyroid stimulating hormone)
- FSH (follicle stimulating hormone)
- LH (lutenising hormone)
posterior pituatory
- ADH
- oxytocin
nb hypothalamus INHIBITS secretion of prolactin
- it stimulates everything else
what are the causes of anterior pituatory hypofunction? 5
- tumours (non-secretory adenoma or metastatic carcinoma)
- trauma
- infarction
- inflammation (granulomatous, autoimmune, other infection)
- iatrogenic
what are the two types of clinical effects caused by primary pituatory tumours?
functional clinical effect
- secondary to hormone being over-produced
local effects:
- due to pressure on optic chiasma or adjacent pituatory
what are three most common types of anterior pituatory adenomas?
- which is most common?
- what syndromes do they cause?
prolactinoma
- commonest
- galactorrhoea + menstural disturbance
growth hormone secreting
- gigantism in children
- acromegaly in adults
ACTH secreting
- cushings syndrome
thyroid:
- 3 parts?
- what is anterior to it?
- what is posterior to it?
- right lobe
- isthmus
- left lobe
- strap neck muscles are anterior to it
- it surrounds the thyroid cartilage around the trachea
- recurrent laryngeal nerve located in the tracheo-oesophageal groove close to posterior aspects of lateral lobes
why can thyroid enlargement (or botched thyroidectomy) cause horseness of voice?
due to damage to recurrent laryngeal nerve
what are the two types of cell in the thyroid gland?
what does each produce/secrete?
follicular cells
- secretes T3 + T4
parafollicular cells (aka C cells) - secretes calcitonin
what is the function of calcitonin?
lowers blood calcium (opposite of parathyroid hormone) by stimulate reabsorbtion by bone
chronic lymphocytic thyroiditis
- aka?
- what does it cause?
- pathogenesis?
- who does it normally affect?
- what does it increase your risk of?
aka hasimotos thyroiditis
hypothyroidism
the autoimmune production of anti-thyroid antibodies -> chronic inflammation (painless goitre)
- thyroid cancer
mainly older women
graves disease:
- what gender/age most at risk?
- pathogenesis?
- females
- 20s + 30s
autoimmune process leading to production of thyroid-stimulating autoantibodies
T3 + T4 elevated, TSH markedly suppressed
what is pretibial myxoedema?
what causes it?
hyperpigmentation and non-pitting oedema on the anterior lower limb (pre-tibial)
graves disease
nb only about 5% of people with graves disease have it
multinodular goitre:
- what is it?
- does it cause hyper or hypothyroidism?
- potential complications?
enlargement of thyroid with varying degrees of nodularity
- one or more palpable nodules
can be either but most patients are euthyroid (ie neither hypo or hyper)
tracheal compression or dysphagia may develop with large nodules
nb dominant nodule may be mistaken clinically for thyroid carcinoma
follicullar adenoma
- what is it?
- gender/age mainly affected?
- how differentiated from multinodular goitre?
- clinical presentation?
benign encapsulated tumour of follicular cells
- female
- middle/old aged
normally solitary nodule (as opposed to many)
often asymptomatic, painless neck mass
most don’t produce any T3 or T4 but if they do then called TOXIC follicular adenoma
what are the two types of carcinomas arising from follicular cells of the thyroid?
what % of thyroid cancers does each make up?
who does each tend to affect?
likelihood of lymph node spread at presentation?
papillary carcinoma:
- > 70% (commonest)
- females
- wide age range, mean 45years (tends to be younger women)
- 50% have lymph node involvement at presentation
follicular carcinoma:
- about 15%
- females
- middle/old aged
- only 5-10% have involvement at presentation
what histological findings may be seen in papillary carcinoma of the thyroid? 3
- can be ill defined/infiltrative or some may be encapsulated (better prognosis)
- may by cystic (better prognosis)
- psammoma bodies are common (calcifications, can be seen on USS)
what oncogene mutation is seen in many patients with follicular carcinoma of the thyroid?
Ras mutations
symptoms of thyroid cancer? 7
- lump in the thyroid
- swollen glands (lymph nodes)
- unexplained hoarse voice
- dysphagia
- sore throat
- fatigue
- weight loss
nb symptoms are often not present/very mild
what is the difference between primary, secondary and tertiary hyperparathyroidism:
- calcium levels?
- PTH?
- causes?
primary:
- calcium usually high
- PTH inappropropriately high
- cause: sporadic or familial
secondary:
- hyperplasia of glands with elevated PTH in response to prolonged hypocalcaemia
- calcium normal or low
- PTH appropriately high
- causes: mainly CKD or vit D deficiency
tertiary:
- in associated with longstanding secondary hyperparathyroidism, parathyroid glands loose ability to switch off, though calcium is within normal ranges
- calcium usually high
- PTH inappropiately high
- causes: after prolonged secondary HPT, usually in CKD
nb chemically, tertiary looks very similar to primary but different causes
causes of hyperparathyroidism:
- primary? 3
- secondary? 3
primary:
- 85% are due to single adenomas
- 10-15% diffuse chief or clear cell hyperplasia
- 1% carcinoma
secondary:
- chronic kidney disease (failure to convert vit D)
- vit D deficiency
- malabsorption
what are the risk factors fordeveloping primary hyperparathyroidism? 4
- female
- old
- ionising radiation
- MEN 2a syndrome
(MEN = multiple endocrine neoplasm)
symptoms of primary hyperparathyroidism? 15
- what are the symptoms due to?
what % are asymptomatic?
70-80% are asymptomatic
excessive calcium reabsorption from bone:
- osteopenia + osteoporosis -> BONE PAIN + PATHOLOGICAL FRACTURES
excessive renal calcium excretion:
- RENAL CALCULI (most common presentation)
hypercalcaemia:
- muscle WEAKNESS, FATIGUE
- neuropsychiatric manifestations: DEPRESSION, DEMENTIA, CONFUSION, MEMORY PROBLEMS
- POLYURIA, POLYDIPSIA, DEHYDRATION
- HYPERTENSION
- ABDO PAIN, NAUSEA, VOMITTING
- CONSTIPATION
“bones, stones, abdominal groans, and psychic moans”.
what actions does the release of parathyroid hormone trigger? 4
what stimulate the parathyroid glands?
- Increases the release of calcium from bone matrix
- Increases calcium reabsorption by the kidney
- Increases renal production of 1,25-dihydroxyvitamin D3, which increases intestinal absorption of calcium
- Increases phosphate excretion by kidney
LOW blood Ca stimulate glands
what are the three familial neoplastic syndromes which parathyroid adenomas can form part of?
what is the inheritence pattern?
- MEN 1
- MEN 2
- hyperparathyroidism + jaw tumour syndrome
autosomal dominant inheritence
nb there are quite a few overlapping MEN syndromes, with varying patterns, don’t need to know details of each just be aware they exist
what is the difference in morphology/histology of the glands in primary hyperparathyroidism when compared to secondary/tertiary?
primary:
- one enlarged gland
- others smaller than normal (due to neg feedback)
secondary/tertiary:
- all glands show hyperplasia as they are all responding to low blood calcium
histology is the same for all three!!
adrenal glands:
- what’s produced in the medulla? 3
- what’s produced in the cortex? 3
MEDULLA:
- adrenaline
- noradrenaliine
- dopamine
CORTEX:
- androgens (eg testosterone)
- glucocorticoids (eg cortisol)
- mineralcorticoids (eg aldosterone)
“basically stuff that’s also used as neurotransmitters are in the MIDdle (ie MEDulla) because brain is inside the skull, think of cortex like the skull”
what type of hormones are adrenaline, noradrenaline and dopamine?
(ie what group of hormones is produced by the adrenal medulla?)
catecholamines
which part of the adrenal gland is under the control of the hypothalamus/pituatory?
cortex
“medulla is in the middle so more hidden away from blood stream etc”
main three types of causes of cushing’s syndrome?
what hormone is it an excess of?
exogenous causes
- excessive glucocorticoid medication (ie iatrogenic)
endogenous causes
- adrenal cortical tumours
- adrenal cortical hyperplasia
- ACTH secreting pituitary adenoma
paraneoplastic syndrome
- from small cell lung cancer
- very rare though
cortisol (glucocorticoids)
symptoms of cushings syndrome? 17
hint: cortisol is stress hormone! - think about what body would do if chronically stressed!
- truncal obesity
- ‘buffalo hump’ (fat deposits on back of neck + shoulders)
- ‘moon face’ (round, red, puffy)
- weak muscles
- weak bones (osteoporosis)
- mood swings/depression
- headaches
- chronic fatigue
- increased hair growth (hisuitism)
- prominent stretch marks (abdo striae)
- excessive sweating
- acne
- erectile dysfunction
- irregular/aabsent periods
- thin skin
- cuts/bruises heal slowly
- high blood pressure
conn’s syndrome:
- aka?
- gender/age affected?
- causes? 2
- pathogenesis?
primary hyperaldosteronism
- females more
- middle aged (30-50)
- adrenal cortical hyperplasia/adenoma
- familial hyperaldosteronism
excess production of the hormone aldosterone -> salt + water retention and low potassium (due to increased kidney secretion of it)
signs/symptoms of conn’s syndrome? 5
- high BP
- headaches
- muscle weakness
- muscle spasms
- excessive urination
bottom 3 symptoms are due to low blood potassium
- however over half of people with conns will have blood potassium within normal range
nb this is almost always asymptomatic
- only sign is nor high BP which is often mistaken for essential hypertension
addisons disease:
- what is it?
- most common cause?
- treatment?
- prognosis?
primary adrenal cortical insufficiency (mainly lack of cortisol, but also low aldosterone)
- caused by adrenal dysgenesis or dysfunction
autoimmune cause is most common
- though condition is very rare!
treatment = long term steroid replacement
if undiagnosed can prove fatal!
symptoms/signs of addisons disease? 7
- hyperpigmentation
- postural hypotension
- hyponatraemia
- hypoglycaemia
- weight loss
- tiredness
- abdo pain
nb need a high index of suspision, very non-specific signs
phaeochromocytoma:
- what is it?
- cause?
- test?
- benign or malignant?
catecholamine-secreting (noradrenaline + adrenaline) tumour arising from adrenal medulla
most are sporadic
- can be part of familial cancer syndromes though (eg MEN 2a+b, von hippel-lindau etc)
- urine test for catecholamines (will be elevated)
90% benign, 10% malignant
excellent prognosis for benign when surgically removed
- malignant tumours may be aggressive
nb can get extra-adrenal ones too!!!
nb 10% are in kids, can happen at any age
signs/symptoms of phaeochromocytoma?
- hypertension
- palpitations
- excessive sweating
- headaches
- anxiety
“basically constant ‘fight or flight’ response due to too much adrenaline”
peptide hormones vs steroid hormones:
- 3 examples of each?
- where act on target cell?
- how produced/stored?
peptide hormones:
- eg PTH, ACTH, TSH
- tend to act on cell-membrane recptors -> intracellular cascade -> mRNA transcription
- stored in granules then released
steroid hormones:
- eg testosterone, oestradiol, cortisol
- tend to act on INTRA-cellular receptors -> mRNA transcription
- made when they are needed
nb steroid hormones can also act on cell-surface receptors but, as they are lipophillic, can get through cell membranes without need for receptors
how are steroid hormones transported in the blood?
circulate bound to serum proteins
what hormone is produced by the thymus gland to stimulate T-cell production?
thymosin
what hormone is produced by the heart?
what is this in response to?
what effect does it have?
BNP (brain naturitic peptide - weirdly named!)
in response to excessive myocyte stretch
trigger naturesis (sodium excretion) in the kidney to lower blood pressure + so reduce strain on heart
“the policies of the BNP parties strain my heart!”
what peptide is produced as a side effect of endogenous insulin production?
c-peptide
nb thought to just be a waste product but now thought to have endocrine actions of its own
what brain structure is responsible for circadian/diurnal rhythms?
what hormone does it secrete?
pineal gland (main mart of the epithalamus, a part of the diencephalon)
melatonin
melatonin triggers you to fall asleep (natural light inhibits melatonin production)
nb melanin is produced by melanocytes in the skin and is pigmented - don’t get them confused!!
TSH and T3/T4 levels in:
- primary hypothyroidism?
- secondary hypothyroidism?
- primary hypothyroidism, not taking thyroxine consistently?
- primary hyperthyroidism?
- secondary hyperthyroidism?
primary hypothyroidism:
- low T3/T4
- high TSH
secondary hypothyroidism:
- low T3/T4
- low TSH
primary hypothyroidism, not taking thyroxine consistently:
- high T3/T4
- high TSH
primary hyperthyroidism
- high T3/T4
- low TSH
secondary hyperthyroidism:
- high T3/T4
- high TSH
what 5 types of cancers can cause ectopic ACTH secretion -> high cortisol? (a type of paraneoplastic syndrome) 5
- benign carcinoid tumours of the lung
- small cell lung cancers
- islet cell tumours of pancreas
- medullary carcinoma of the thyroid
- tumours of the thymus gland
what is the name for primary adrenal insufficiency?
addisons disease
aka primary hypocortisolism
what principles of testing are used to test for hormone overor under production?
hormone levels vary through out the day so random tests are of little help
need to do dynamic testing
if you suspect excess production, try to suppress production
if you suspect insufficient production, try to stiumulate production
describe the normal distribution of blood cortisol levels throughout the day
there is a peak in cortisol at about 9am then steadily lowers throughout the day (but peaks after eating and exercise)
then low during the night
what is the difference between cushing’s disease and cushing’s syndrome?
cushing disease is primary adrenal overproduction of cortisol
cushing’s syndrome is another cause of excess cortisol, eg exogenous steroid use, ACTH secreting tumour etc
if you have over production of cortisol do you get amenorrhoea/oligomenorrhea (very light periods) or menorhagia (very heavy periods)?
if high cortisol (cushings):
- amenorrhoea/oligomenorrhoea
if very low cortisol (addisons):
- menorhhagia
“think of it like, if your body is under a lot of stress, cortisol is stress hormone, then body’s priority is NOT to become pregnant and thus put extra strain on body”
nb men with cushings can often be impotent
what may back pain in cushing’s syndrome be a sign of?
what psychiatric disturbances can be seen in cushings?
osteoporosis
depression, psychosis (+ others)
nb can also get high BP, muscle weakness, headaches, nausea + visual disturbances
what test is used to test for cushing’s disease? how does it work?
overnight dexamethasone suppression test
tests patient’s cortisol level during day
then patient takes a dexamethasone (steroid) pill at midnight, this should suppress endogenous steroid production
then retest blood cortisol at 9am in morning and it should be lower than the previous day, if not, then high likelihood of cushings
what is the test for addisons disease/primary adrenal failure? how does it work?
measure blood cortisol at 9am
then give SYNACTHEN (an ACTH analogue)
then measure blood cortisol 30 mins later, if not significantly increased then high likelihood of adrenal insufficiency
which thyroid hormone is the active form?
which is in higher abundance?
T4 is in higher abundance and is converted into T3 (the active form
“normally things like proteins are activated by having something removed, so going from T4->T3, you are removing one T”
what is ‘sick euthyroid syndrome’?
what is the mechanism that causes it?
what does this mean in clinical practise?
when a patient is very unwell (with whatever condition), lots of cytokines are produced as part of the inflammatory response
the cytokines act systemically and, as well as many other actions, they decrease the circulating T3 + T4
therefore if you test someones blood T3/T4 levels when they are very sick, they are likely to have low T3/T4 levels, even if there is no thyroid pathology
so you shouldn’t test people’s thyroid function when they are unwell
nb euthyroid means normal thyroid (ie not hypo or hyper)
what is the enzyme responsible for converting T4 -> T3?
when is it inhibited?
deiodinase
in sick euthyroid syndrome -> low T3 levels
nb there are also other mechanisms that lower T3/T4 in sick euthyroid syndrome
what test can you do to work out if a woman is going throught the menopause?
what is the mechanism behind this?
why should you be cautious in doing this?
test their levels of FSH
when ovaries stop producing oestrogen (menopause) then the hypothalamus/pituatory doesn’t get negative feedback and so produces a lot MORE FSH
so a women going throught the menopause will have high blood FSH
HOWEVER a women who is still ovulating (pre-menopausal) will physiologically have high FSH in the middle of her cycle
therefore this test is not very relaible and so is not done often in clinical practise
what are the three main peaks of testosterone production in a male’s life?
a peak in foetus, then drops before birth
a peak around 2-4 months of age (get spotty) then drops
low during childhood
massive peak during puberty/low 20s then slowly decreases throughout adulthood
what is the test for a phaeochromocytoma?
what two things are being tested for?
24hr urine collection
measure levels of catecholamine metabolites
nb do this because the actual catecholamines are very unstable and present at low concentrations in blood + vary wildly throughout day so hard to reliably measure however metabolites are excreted in urine
nb phaeochromocytoma is a tumour of the adrenal medulla
what is whipple’s triad?
what is it a test for?
the clinical presentation of pancreatic insulinomas, 3 criteria:
- FASTING hypoglycaemia
- symptoms of hypoglycaemia
- immediate relief of symptoms after the administration of IV glucose
insulinomas
nb this is in no way related to whipple’s disease but IS named after the same surgeon who invented the whipple’s procedure for surgical resection of cancers of the head of the pancreas
what is the current gold standard test for insulinomas?
what would indicate a positive result?
in adults who fit the whipple’s criteria (low blood glucose, symptoms of hypoglycaemia), the patient has to undertake a 72-hour fast (in hospital) - they are allowed water!
then blood glucose and insulin are tested
results in a normal person:
- low blood glucose
- LOW blood insulin
results in someone with an insulinoma:
- low blood glucose
- HIGH blood insulin
nb before doing this fast you would check other medical and drug history to see if there was any other cause for the hypoglycaemia
nb in addition c-peptide levels are measured (which should be as high as the insulin levels), if they are low then it indicates the excess insulin is exogenous (has been injected)
what are the two groups of symptoms seen in hypoglycaemia/insulinomas?
pathophysiology?
give some examples
neuroglycopenia:
- double/blurred vision
- confusion/abnormal behaviour
- amnesia
- seizures
- loss of consiousness
- coma
adrenergic
- weakness, warmth
- sweating
- hunger
- tremor
- palpitations/tachycardia
- anxiety
brain has a high demand for glucose so is the first thing to suffer is the brain -> neuroglycopenic symptoms
when the blood glucose drops it triggers a release of adrenaline by the adrenal glands (in ordewr to try to raise blood glucose) -> adrenergic symptoms
nb while adrenaline may raise the glucose levels in normal patients with moderately low glucose levels, it is insufficient to overcome the effect of the continuously secreted insulin by insulinomas
what are two other names for:
- type 1 diabetes mellitus?
- type 2 diabetes mellitus?
type 1 DM:
- insulin dependent DM (IDDM)
- ketotic DM
type 2 DM:
- non-insulin dependent DM (NIDDM)
- non-ketotic DM
insulin:
- 3 things it increases/stimulates?
- 3 things it inhibits?
stimulates:
- synthesis of glycogen
- glucose uptake from blood into tissues
- fatty acid, triglyceride + protein synthesis
inhibits:
- gluconeogenesis
- glycogenolysis
- ketogenesis, lipolysis + proteolysis
nb released when blood glucose is high so these actions reduce blood glucose and have a metabolic effect (ie opposite of catabolic) - insulin builds stuff up!!
what 4 hormones increase blood glucose (ie opposite ofm insulin)?
- glucagon
- adrenaline
- growth hormone
- cortisol
where is glucagon produced?
what are its affects? 4
ALPHA CELLS of pancreatic islets (nb insulin produced by beta cells)
increases blood glucose by stimulating:
- glycogenolysis
- glucogenogenesis
- ketogenesis
- lipolysis
what are the effects of:
- adrenaline/growth hormone? 2
- cortisol? 4
adrenaline/growth hormone:
- stimulate glycogenolysis
- stimulate lipolysis
cortisol:
- stimulates gluconeogenesis
- increases glycogen synthesis
- stimulates proteolysis
- reduces tissue glucose use
what are the definitions of:
- hyperglycaemia (diabetes)?
- hypoglycaemia
in a RANDOM blood test!
what is the definition of diabetes in a FASTING blood test?
diabetes:
- random: >11 mmol/l
- fasting: >7 mmol/l
hypoglycaemia:
- random: <4 mmol/l
- “four is the floor”
diabetes:
- symptoms? 4
- signs? 4
symptoms:
- thirst
- polyuria
- weight loss
- fatigue
signs:
- dry mouth
- weight loss
- glycosuria
- hyperglycaemia
is there a higher prevalance of diabetes in asian + afro-caribbean people or caucasain people?
asian + afro-carribean people
what are the diagnostic criteria for diagnosing diabetes (excluding gestational diabetes)
typical symptoms
AND
- random plasma glucose >11 mmol/l
OR - fasting plasma glucose >7 mmol/l
if NO typical symptoms of diabetes, repeat testing on a different day to confirm diagnosis
nb can also use oral glucose tolerance test OR HbA1c levels but these are used less! - only in specific circumstances
what are the two types of glucose tolerance tests (GTT)?
how do they work?
interpretation of them?
- oral (OGTT)
- IV (IVGTT)
take fasting blood glucose
then give 75g oral/IV glucose load
take plasma glucose at 2hrs post-glucose load
fasting:
- normal <6.1 mmol/l
- diabetic > or = 7 mmol/l
2-hour post-glucose load:
- normal <7.8 mmol/l
- diabetic > or = 11.1 mmol/l
what are the definitions of:
- impaired fasting glucose?
- impaired glucose tolerance?
impaired fasting glucose:
- fasting blood glucose >6.1 and <7 mmol/l
impaired glucose tolerance:
- 2 hours post-glucose load >7.8 and <11.1 mmol/l (on the 75g OGTT)
ie this is ‘prediabetes’ - though a controversial term
apart from tesing blood glucose levels (normal/fasting/GTT), what other investigations would you want to do in someone you suspected to have diabetes? 5
why?
HbA1c
- sees hyperglycaemia over past 3 months
renal function
- may have already developed diabetic nephropathy and some drugs given to diabetics are nephrotoxic so wouldn’t want to worsen this
liver function
- see if it’s part of metabolic syndrome
lipids
- see if it’s part of metabolic syndrome
thyroid function
- test type 1 diabetics thyroid function every year as they are at increased risk of getting autoimmune thyroid conditions
glycated haemoglobin (HbA1c):
- mainly used for?
- what is it useless for? 2
mainly used for MONITORING diabetics control over long period (up to 3 months - lifespan of RBCs)
nb sometimes used in diagnosis of type 2 DM
useless in:
- diagnosisng type 1 diabetes or fast-onset diabetes of any sort
- anyone with an increased RBC turnover (eg sickle cell)
what is the diagnostic criteria for gestational diabetes? incl values
diagnosed using 75g 2-hour oral GTT
diagnosed if:
- fasting > or = 5.76 mmol/l
- 2-hour post-glucose load plasma glucose > or = 7.8 mmol/l
these are LOWER cut offs than for ‘normal diabetes’
- as, in pregnancy, blood glucose levels are physiologically lower than normal due to increased plasma volume
type 1 diabetes:
- pathophysiology?
- usually affects?
- apart from plasma glucose testing, what other tests can be done?
- clinical presentation?
- onset of symptoms?
autoimmune destruction of the insulin-producing islet Beta cells
usually young (but can be ANY age)
autoantibody tests
- eg ICA, IA2, GAD
- polyuria
- looking dehydrated
- loosing a lot of weight
- can present with ketoacidosis
symptoms tend to come on over a period of weeks (much faster than type 2 DM)
name + briefly describe:
- 1 less common subtype of type 1 DM?
- 2 less common subtypes of type 2 DM?
- who do they affect?
- respond to what treatment?
LADA (latent autoimmune diabetes in adults)
- a subtype of type 1 DM
- older patients, often female
- medical or fam hist of autoimmune conditions
- tends to present more slowly than typical type 1 so often misdiagnosed as type 2 but don’t respond well to lifestyle changes
- responds to insulin
- autoantibodies present
ketosis-prone type 2 DM
- often obese, ethnic minority
- ketosis when physically stressed with another illness
- will temporarily require insulin when ill
- but not insulin-dependent when well
MODY (maturity onset diabetes of the young)
- aka mason-type DM
- autosomal dominant inheritence
- type 2 DM, but onset UNDER 25 years
- 6 different types, all to do with different genetic mutations but same clinically
- insulin not required initially
describe gestational diabetes
diabetes arising, or diagnosed, in pregnancy
- diabetes appears during pregnancy
- diabetes resolves after pregnancy
- at risk of gestational diabetes retiurning with future pregnancies
- at risk of ‘normal’ type 2 diabetes in future
nb tends to present in late 2nd or 3rd trimester
name 6 pancreatic conditions which can cause secondary diabetes
- chronic pancreatitis (often caused by alcohol excess)
- acute pancreatitis
- pancreatic cancer (incl glucagonoma)
- pancreatectomy
- cystic fibrosis
- haemochromatosis
basically anything which damages the pancreas can reduce production of insulin
haemochromatosis:
- what is it?
- who gets it?
- histological stain used to diagnose?
hereditary iron overload storage disorder
excess iron can build up anywhere
if builds up in pancreas -> destruction of beta cells -> diabetes
get hyperpigmentation so called ‘bronze diabetes’
genetic!
perl’s iron stain, stains iron in the pancreas blue
nb can also get transfusional iron overload, secondary to lots of blood transfusions, and this has the same clinical effects
what 3 types of drugs can lead to secondary diabetes?
- diuretics
- long-term steroids (cushings syndrome)
- anti-psychotics (eg olanzapine) - often cause you to put on weight
what 3 endocrine disorders can lead to secondary diabetes?
why?
acromegaly (GH excess)
cushings disease/syndrome (steroid excess)
- get impaired insulin tolerance
phaeochromocytoma (adrenaline etc excess)
because these affect counter-regulatory hormones (ie stuff that increase blood glucose levels) so blanace between them and insulin is mucked up!
name 2 genetic syndromes which can lead to secondary diabetes?
- Friedrich’s ataxia
- dystrophia myotonica
these are both predominantely neurological conditions
what are the main uses of calcium ions (Ca2+) in the human body? 5
- muscle contraction
- neuronal excitation
- enzyme activity (Na/K ATPase, hexokinase etc)
- blood clotting
- key structural component in bone
phosphate:
- chemical formula?
- main uses in the body? 6
- predominantly intra or extracellular
PO4-
- the P in ATP
- intracellular signalling
- cellular metabolic processes (eg glycolysis)
- backbone of DNA
- membrane phospholipids
- key structural component in bone
predominantly INTRAcellular
magnesium:
- chemical formula?
- main uses in body? 5
- predominantly intra or extracellular?
Mg2+ (a divalent cation)
- cofactor for ATP
- enzymatic function
- neuromuscular excitability
- regulates ion channels
- comprises 1% of bone matrix
predominantly INTRAcellular
what are the 4 concepts of homeostasis of inorganic ions?
- intake
- excretion/loss
- tissue redistribution
- storage (norm in bone)
what is the reference range for blood calcium?
what are the two key controlling factors of this level?
2.20-2.60 mmol/L
nb very narrow reference range
- PTH
- vit D + metabolites
what three types of calcium are in the blood (ie make up ‘total calcium’)?
describe them
total Ca = ionised Ca + bound Ca + complexed Ca
ionised Ca
- physiologically active fraction
- calcium sensing receptor
- cellular effects
- regulation of PTH
bound Ca
- physiologically inactive
- predominantely bound to albumin
complexed Ca
- salts (calcium phosphate + calcium citrate)
If someone had kidney problems what effect could this have on all the different types of blood calcium?
what would be done to remedy this?
there would be a reduction in total calcium as a lot of albumin (with Ca bound to it) would be lost)
however the ionised Ca would stay they same and, since this is the only physiologically active type of Ca, nothing would need to be done!
so, although blood tests may look like patient is hypocalcaemic their Ca levels are actually fine
what is adjusted calcium? when is it used?
level of total blood calcium but this is ADJUSTED to correct for changes in albumin
reference range is unchanged but patient samples are adjusted to take account of the fact of the patient’s albumin levels
this is mainly done when someone has low levels of albumin (eg due to kidney disease) so that the calcium state can be evaluated independent of the problem causing the low albumin
what is the routine measurement done on blood tests to assess calcium levels
what are the main drawbacks of this?
total calcium
(cost + convenience)
doesn’t necessarily reflect ionised calcium:
- total Ca affected by amount of albumin
- pH influences ionised calcium
what changes in the different types of plasma calcium are seen in:
- acidosis?
- alkalosis?
acidosis:
- ionised Ca increases
- bound Ca decreases
- – so patient effectively becomes HYPERcalcaemic
alkalosis:
- ionised Ca decreases
- bound Ca increases
- – so patient effectively becomes HYPOcalcaemic
for both of these TOTAL Ca is likely to be unchanged
nb for both of these, levels of complexed calcium stay the same
what is a clinical implication of ionised calcium levels being affects by pH
patients who are baseline HYPOcalcaemic and then develop acidosis (for whatever reason) don’t develop symptoms of acidosis
because many of the symptoms of acidosis are due to the increase in ionised calcium (effectively becoming hypercalcaemic)
- nb many are due to decrease in pH as well
however, if a patient is HYPOcalcaemic before they become acidotic then the acidosis will effectively just increase their ionised calcium levels to within normal levels
therefore the lack of very high levels of ionised calcium will mask some of the symptoms of acidosis so it may not be recognised clinically
what is the main clinical manifestation of hypocalcaemia?
can this result from alkalosis of acidosis?
tetany
intermittent muscular spasms
alkalosis (as this leads to a drop in ionised calcium)
what effect does:
- the amount of body fat have on vitamin D levels?
- age have on vit D levels?
if you have high body fat then vit D (being a fat soluable vitamin) is taken up by a lot of adipose tissue where it stay and it not physioloigcally active
- therefore it LOWERS the amount of physiologically active vit D in the body
vit D levels DECREASE with increased age
does low or high blood calcium stimulate the parathyroid glands?
LOW blood Ca stimulates release of PTH
as PTH increases blood Ca
what two effects does PTH have on the kidney?
- increases Ca retention
- increases phosphate EXCRETION
what is EDTA?
what is it used for medically?
what effect does it have on plasma levels of calcium?
a compound
- used to bind heavy metal ions (and thus inactivate them
- used for chelation therapy (iron, mercury, lead etc poisoning
it is also found in blood collection tubes as it acts as an anticoagulant
- so got to be careful to use correct draw orders so don’t contaminate different blood samples
calcium
- binds it so lowers blood calcium
nb the reason EDTA is works as an anticoagulant for blood samples is BECAUSE it binds calcium and so prevents it acting as a cofactor for clotting cascade and platelets
medical causes of hypocalcaemia?
- hypoproteinaemia
- vit D deficiency
- hypoparathyroidism
- inadequate intake of Ca
- pseudohypoparathyroidism
what can cause vit D deficiency? 5
- inadequate sunlight
- dietary/malabsorption
- hepatic disease
- renal disease
- end organ vit D resistance
what is pseudohypoparathyroidism?
end organ PTH resistance
so levels of blood PTH would be high but would be having no affect
so not subsequewnt increasein plasma Ca
what is the LIKELY cause of hypocalcaemia if:
- low Ca, low PTH?
- low Ca, high PTH?
low Ca, low PTH:
- hypoparathyroidism
low Ca, high PTH:
- vit D deficiency
what are some common causes of hypercalcaemia? 9
- hyperparathyroidism
- other endocrine disorders (hyperthyroidism, acromegaly, phaechromocytoma, addisons)
- lytic malignant lesions
- PTH release as part of a paraneoplastic syndrome
- drugs
- excess exogenous vit D supplements
- sarcoidosis
- bone disease
- immobilisation
why does sarcoidosis cause hypercalcaemia?
because the granulomas in sarcoidosis produce high levels of the enzyme which catalyses vit D into its active form (norm produced by kidneys)
-> increase in vit D -> hypercalcaemia
if you find someone with hypercalcaemia, what investigations should you do next to try to identify a cause? 5
- consider adjusted Ca (look at the albumin levels)
- check drug history
- exclude excess vit D intake
- check for renal failure
- measure Ca + PTH simultaneously
(then consider rare + more complex causes)
what memory aid is used to remember the signs/symptoms of hypercalcaemia?
what are these signs/symptoms? 14
“bones, stones, moans + groans”
bones:
- bone pain
stones:
- renal calculi
- bilary calculi
moans:
- mood disturbances/depression
- cognitive dysfunction/confusion
- fatigue
- coma
groans:
- headaches
- abdo pain
- nausea/vomitting
- reduction in appetite (anorexia)
- constipation
other:
- increased thirst (polydipsia)
- polyuria
what is a likely cause of hypercalcemia if patient has:
- high Ca, low PTH?
- high Ca, high PTH?
high Ca, low PTH:
- bone metastases
high Ca, high PTH:
- hyperparathyroidism
what are the main four groups of causes of phosphate deficiency?
hyperparathyroidism (has opp effect as on Ca)
excess losses
- renal tubular damage
- GI
- diabetes (diuresis)
poor intake
- malnutrition
- inadequate IVN
ECF/ICF redistribution
nb remember that phosphate levels that you measure are of blood phosphate but most phosphate is intracellular
signs/symptoms of phosphate deficiency?
- haemolysis
- thrombocytopenia
- poor granulocyte function
- severe muscle weakness
- respiratory muscle failure
- rhabdomyolysis
- confusion/irratibility -> coma
- renal dysfunction
nb phosphate deficiency is often overlooked! look for it!!
main two groups of causes of low blood magnesium?
renal:
- diuresis
- hypercalcaemic states
- drugs (antibiotics, chemo, diuretics)
GI tract:
- malnutrition
- intravenous nutrition
- diarrhoea
- malabsorption
what are the effects of low magnesium on the:
- CVS? 2
- CNS? 4
- muscles? 3
CVS:
- cardiac irritability
- reduced contractility
CNS:
- hyper-reflexia
- tetany
- ataxia/vertigo
- psychosis/depression
muscle:
- weakness
- muscle fibrillation
- myopathic EMG
however most patients are asymptomatic + many patients recover spontaneously
what additional inorganic ion does hartmanns solution contain (compared to ‘normal’ fluids)?
Potassium (K)
so always check potassium levels of patient before giving hartmanns
what are the 4 main functions of bone in body
- structural support for the body
- protection of vital organs
- blood cell production (in bone marrow)
- storage bank for minerals (esp calcium)
what are the two types of bone which make up most bones?
cortical bone:
- hard
- outer layer
- most of strength + mass
trabecular bone:
- spongey
- inner layer
- high surface area + is metabolically active
what is the membrane around bone called?
periosteum
what are the two main constituents of the extracellular components of bone?
organic matrix
- mainly collagen
inorganic components
- hydroxyapatite
- minerals (calcium, phosphate)
what is osteoid?
non-mieralised organic matrix, mainkly collagen
basically bone, before it is ‘mineralised’ with inorganic ions
what are the three types of bone cells?
what are their functions?
osteoblasts:
- make osteoid (non-mineralised bone)
- communicate with other bone cells
osteocytes:
- osteoblasts that are ‘trapped’ within matrix
- develop long cytoplasmic extensions
- assess + communicate state of bone
- mechanosensory properties
osteoclasts:
- break down bone
- increase blood calcium levels
is alkaline phosphatase released by osteoblasts or osteoclasts
osteoblasts
high alk phos means new bone is being made
which bone cell does PTH stimulate?
osteoclasts
PTH wants to break down bone to increase blood Ca
what is hydroxyapatite?
the inorganic thing that mineralises osteoid -> proper bone
it’s a calcium-phosphate-hydroxide salt
at what age is your peak bone mass?
how does thi vary between men + women
peak is about age 25-30
then gradually decreases
men have higher peak and decrease slower
women’s bone mass decerases significantly post-menopause
what are the main biochemical markers of:
- bone formation (osteoblast activity)? 2
- bone resorption (osteoclast activity)? 1
bone formation
- procollagen type I propeptides (P1NP)
- alkaline phosphatase
bone resorption
- crosslinked telopeptides of type I collagen (NTX, CTX)
MUST know these
what percentage (in health) of alkaline phosphatase is produced by the:
- liver?
- bones?
what can you use to differentiate between the origin of raised ALP?
liver 50%
bone 50%
specific isoenzymes can be measured when there is diagnostic doubt as to the origin
what things can cause ALP (from bone) to rise? 5
- childhood/pubertal growth spurt
- pregnancy (esp 3rd trimester)
- following fractures (healing process)
- hyperparathyroidism (primary or secondary)
- pagets disease of the bone
as well as for diagnosis, what is CTX used for medically?
used to monitor anti-resorptive therapy
ie treatment for osteoporosis
as this treatment should reduce the action of osteoclasts, and thus CTX should decrease
can also be used to measure compliance with this medication
what results does a DEXA scan give?
what are the ranges for normal, osteopenia + osteoporosis?
it gives out a T score
- mean is zero, standard deviation is 1
normal bone density
= >-1
osteopenia
= between -1 and -2.5
osteoporosis
= -2.5 and below
osteoporosis:
- what is it?
- tests done? 2
loss of bone quality AND quantity
- xray
- DEXA scan
bone markers aren’t overly useful
risk factors for osteoporosis:
- female
- old age
- early menopause
- alcohol
- smoking
- any chronic inflammatory condition (eg UC)
- long term steroid use
is HRT a risk factor or protective for osteoporosis?
protective
as it maintains oestrogen levels
nb reason why bone density decreases post-menopause is due to lack of oestrogen, so replacing this reduces the bone loss
what 3 main types of fractures do people with osteoporosis tend to get?
- neck of femur fracture
- wrist fracture (esp colles fracture, fracture of radius)
- wedge fractures in spine
what three symptoms/signs do wedge fractures of the spine tend to give?
- unexplained loss of height
- unexplained kyphosis
- back pain
what is the main treatment used for osteoporosis?
drug suffix?
how do they work?
bisphosphanates
- dronate
eg alendronate, zoledronate
stop more bone being broken down
mimic pyrophosphate structure so are taken up by skeleton then ingested by osteoclasts -> apoptosis of osteoclasts
what are the problems/side effects of bisphosphanates?
- poor mabsorption
- difficult to take
- can cause oesophageal/upper GI problems
- flu-like side effects
- osteonecrosis of the jaw
- atypical femur fractures
so tend to only use for a few years then stop
what are the two main types of bone metastases?
what’s the difference between them?
what cancers tends to produce each type?
which type will lead to hypercalcaemia?
lytic:
- destruction of normal bone
- will -> hypercalcaemia
- – breast
- – lung
- – kidney
- – thyroid
sclerotic/osteoblastic:
- deposition of new bone
- – prostate
- – lymphoma
- – (breast/lung occassionally)
which bones do cancers tend to metastasise to?
- skull
- humerus
- spine
- pelvis
- femur
what main types of presenting symptoms would you expect to see in bone metastases? 5
why?
bone pain
- often worse at night, better with movement
- usually becomes constant
broken bones
- pathological fractures
numbness, paralysis, trouble urinating
- due to spinal cord compression from spinal mets
loss of appetite, nausea, thirst, confusion, fatigue
- symptoms of hypercalcaemia
anaemia
- due to disruption of bone marrow
what two types of imaging can be used to look for bone mets?
nuclear medicine bone scan
pet scan
what three main groups of symptoms do you tend to see in primary hyperparathyroidism?
nb think about mechanism
symptoms due to hypercalcaemia
renal disease (esp renal calculi)
bone disease (osteoporosis, osteitis fibrosa cystica)
pagets disease of the bone:
- what is it?
- age/gender mainly affected?
- cause?
- main biochemical sign?
rabid bone turnover and formation -> abnormal bone remodelling
- mainly over 50 years
- higher prevelence in men
cause poorly understood
- probable genetic and environ triggers (FH in 15% of cases)
elevated ALP (indicating increased bone turnover)
nb don’t get confused with pagets of the breast/vulva, totally unrelated!!
clinical features of paget’s disease of bone? 5
- bone pain
- bone deformity
- secondary OA (dt abnormal strains)
- fractures
- cranial nerve defects if skull affected (eg hearing or vision loss)
which bones are most commonly affected in pagets disease of the bone?
- lower lumbar vertebrae
- pelvis
- femur
what can pagets disease of the bone (rarely) lead to?
what would be a red flag for this?
osteosarcoma
ongoing pain in someone with well-treated pagets
treatment for pagets?
monitoring? 2
bisphosphonates
- when you reduce osteoclast activity, you also reduce osteoblast activity, basically just stops changes occuring to bone
- ALP levels
- pain reported by patient
osteomalacia:
- what is it?
- causes?
lack of mineralisation of bone (with calcium AND/OR phosphate)
- low calcium
- low vit D
- excess excretion of phosphate (genetic)
osteomalacia means soft bones
nb if get in childhood = rickets
symptoms of osteomalacia?
- diffuse bone pains (norm symmetrical)
- muscle weakness
- bone weakness -> fractures
in someone with osteomalacia what would happen to these markers:
- ALP?
- vit D?
- calcium?
- PTH?
high ALP
low vit D
possibly low calcium
high PTH (secondary to the low calcium)
why do you get high ALP in osteomalacia?
low vit D -> low plasma calcium -> secondary hyperparathyroidism -> high bone turnover -> high ALP
what would you expect to happen to levels of ALP, Ca, phosphate + PTH in:
- primary hyperPTH?
- osteomalacia?
- osteoporosis?
- pagets?
- bone mets?
primary hyperPTH:
- high ALP
- high Ca
- low phosphate
- high PTH
osteomalacia:
- high ALP
- (low Ca)
- low phosphate
- (high PTH)
osteoporosis:
- all normal!!
pagets:
- high ALP
- normal others
bone mets:
- high ALP
- (high Ca - if lytic)
- normal phosphate
- (low PTH - if lyitc, secondary to high Ca)
what is an example of a loop diuretic?
what effects can loop diuretics have on plasma levels of:
- sodium?
- potassium?
- chloride?
- bicarbonate?
what other 2 effects can they have?
furosemide
can cause low levels of all of these, especially potassium!
- as basically peeing out electrolytes
EXCEPT bicarbonate
- this goes up, metabolic alkalosis
also can get quite dehydrated
- glucose intolerance
- elevations in serum urate -> gout
how can malignant hypertension lead to secondary hyperaldosteronism?
- what effects does this have on electrolytes?
what ethnic group is malignant hypertension most common in?
malignant hypertension causes narrowing of arterioles, particularly those supplying the juxtaglomerular apparatus
- > low perfusion to the kidney and a reflex hypersecretion of renin, which (via angiotensin) causes excessive aldosterone release
- > excess water and sodium retention (but potassium excretion)
west indians
someone suffering acutely with hypocortisolaemia would show what changes on their blood tests:
- sodium?
- potassium?
what is this called?
- low sodium
- high potassium
addisonian crisis
what blood test results would you expect to see if a blood sample was contaminated with EDTA? 2
very low adjusted calcium
high potassium
what electrolyte (2) and other blood test (2) abnormalities would be seen in someone suffering an AKI secondary to dehydration/hypovolemia?
- high potassium
- low bicarbonate (hence acidotic)
- high urea
- high createnine
nb can be hypovolemic due to vomitting
what diagnosis would you suspect in a patient with these blood results?
- low sodium
- high urea
- high creatinine
- high total protein
- normal albumin
- high globulins
why?
myeloma
low sodium is due to pseudohyponatraemia
- water is being replaced by protein giving an artefactually low sodium
- measured by direct method the sodium would be normal
renal impairment (high urea + creatinine) is due to depositions of monoclonal antibodies - also explains high globulin and total protein level
what effect does immobilisation have of blood calcium levels?
increase in calcium levels
esp when high bone turnover, eg in pagets
