Clinical biochem Flashcards
2 factors that blood sodium conc depends on?
Total body sodium
Body water volume
- Osmolality def
- Osmolality unit
- Calculation
1.
- The osmolality of a solution is a measure of the number of osmotically active particles in a solvent.
- In clinical biochem: it is the measure of the number of osmotically active particles in 1kg of solvent
2. mOsm/kg
(OSMOLARITY - this is the number of particles in 1L of solution rather than 1kg. )
- Osmolality = 2([Na+] + [K+]) + [glucose] + [urea]
Note:
Sodium and potassium are both cations in solution - i.e. they are positively charged ions. Chloride concentration may be estimated as being equal to the sodium plus the potassium concentrations. So thats why theyre doubled
Note II:
Osmolality is calculated and measured to see if there is another osmotically active substance present which does not include sodium, potassium, chloride, glucose or urea. This may include ethylene glycol or alcohol.
Vasopression
- synthesided/ released from?
- 3 triggers for secretion of vasopressin?
- effect?
- Vasopressin/ADH is synthesized in the hypothalamus and secreted by the posterior pituitary gland.
- I. Stress: e.g. pain, nausea
II. Decreased blood volume by 10%
III. Drugs: e.g. analgesics antidepressants antipsychotics - increased water permeability in distal tubule –> increased water reabsorption
RAAS?
Effects of Angiotensin II?
Effects of aldosterone?
Reduced NaCl delivery, increased SNA, increased catecholamines, drop in arterial p – > release of renin by macula densa cells
Angiotensinogen (liver) –renin –>Angiotensin I
Angiotensin I –ACE (lungs)–> angiotensin II
Angiotensin II – peptidase (plasma) –> angiotensin III (inactive)
Angiotensin II:
- vasoconstriction
- stimulates thirst
- renal blood flow redistribution
- increased Na absorption
- aldosterone release from adrenal cortex
Aldosterone water retension in : -salivary gland - GI - sweat gland - kidneys
What are the 3 important hormones secreted by kidneys?
1- active form of vit D : important for Ca and phosphate metabolism
2- renin: renin-angiotensin-aldosterone system–> BP regulation
3- erythropoietin–> synthesis of RBC
Glomerular filtration rate (GFR)
- def?
- Depends on?
- Glomerular filtrate formed each minute in all nephrons of both kidneys
- I. Pre-renal: Intracapillary pressure (eg heart failure, or hypovol shock)
II. Renal: Number of nephrons and glomerular function
III. Post-renal: Tubular luminal pressure (eg enlarged prostate)
Glomerular function tests
- Serum urea
- In malnourished patient: low urea level as proteins being preserved
- If there is bleeding, Hg is broken down producing a high serum urea: so it is easily affected - Serum creatinine
- depends on muscle mass
- produced at constant rate by muscle
- not affected by diseases
Acute kidney injury def?
Any physical, chemical, toxic, or ischaemic insult causing a rise in creatinine OR fall in urine output over a timescale of hours to days.
- Increases mortality – 2, 4, 6x @ 1 year in stage 1,2,3
Causes of acute kidney injury (AKI)?
- Pre-renal 2
- Renal 4
- Post-renal 3
- a. Hypovolaemia
- Haemorrhage
- Sepsis
b. Pump failure - a. Ischaemia (acute tubular necrosis)
b. Nephrotoxins
- Drugs, poisons, metals, myoglobin, paraproteins
c. Glomerulonephritis
d. Interstitial nephritis - a. Stones
b. Tumour
c. Prostate
Ischaemic acute kidney injury stages?
Tests to help differentiate the two?
STAGE 1: Reversible by fluid resus
- Low plasma volume
- Low renal perfusion
- Low GFR (“Pre-renal uraemia”)
if perfusion not restored–>Hypoxic damage
STAGE 2:
- made worse by fluid resus
- acute tubular necrosis (ATN)
Tests: 1. Urea:plasma osmolality Pre-renal uraemia: >2:1 ATN: 1:1 2. Urine [Na] Pre-renal uraeima : <20 ATN: >20 (impaired reabsorption)
4 clinical features of AKI?
- Failure to remove nitrogenous waste products
Nausea; malaise; confusion - Fluid overload
Cardiac failure; Oedema - Retain acidic waste products of metabolism
100 mmol/day from metabolism
Life threatening once plasma pH <7.0 - Retain Potassium
Life threatening once [K+] > ~8 mmol/L
Proximal tubule 3 main functions?
Bulk reclamation of solutes
- ~70% Na, K, Ca, Cl
- ~100% HCO3 , Glucose, Urate, Amino acids
- Isosmotic reabsorption of water (~70%)
Fanconi syndrome?
Globular tubular defect
Ion channels defective for reabsorption of solutes
Countercurrent system?
I. Countercurrent multiplication
- Active
- in Loop of Henle
- Dilutes urine (by removing solutes in thick ascending limb)
- Generates hypertonic medulla
II. Countercurrent exchange
- Passive
- in Distal tubule and collecting duct
- Concentrates urine (vasopressin opens the water channels allowing water to leave the collecting duct)
Where does aldosterone act on in kidneys?
Distal tubule, activating channels causing reabsorption of Na ions leading to absorption of water.
eGFR formula
GFR = creatinine production rate /serum [creatinine]
Creatinine production rate is related to muscle mass, which can be estimated from age and sex
(x 0.742 if female, x 1.21 if African)
Causes of chronic kidney disease (CKD)
- Diabetes mellitus
- Hypertension
- Polycystic Kidney Disease
- Glomerulonephritis, pyelonephritis, interstitial nephritis
- Multisystem disease
- Drugs
Stages of chronic kidney disease?
Stage 1. >90 GFR mL/min Stage 2. 60-90 GFR mL/min Stage 3a. 45-60 GFR mL/min = Hypertension / ↑ CVD risk Stage 3b. 30-45 GFR mL/min = Low calcium 2º ↑ PTH Stage 4. 15-30 GFR mL/min = + anaemia = + anorexia = + high phosphate Stage 5. <15 GFR mL/min = + salt & water retention = + acidosis & ↑ K+
Note: Albumin level in urine also important:
A1. normal to mildly raised
A2. Moderately raised
A3. Severely raised
Acute coronary syndrome
I. Unstable angina
- def
- ECG
- Cardiac enzymes
II. NSTEMI
- def
- ECG
- Cardiac enzymes
III. STEMI
- def
- ECG
- Cardiac enzymes
I. Unstable angina
- Non-occlusive thrombosis
- No ECG changes
- Normal cardiac enzymes
II. NSTEMI
- Non-occlusive thrombosis
- ST depression +/- T wave inversion
- Elevated cardiac enzymes
III. STEMI
- Occlusive thrombosis
- ST elevation or left bundle branch block
- Elevated cardiac enzymes
Biomarkers for acute coronary syndrome
- Troponin
- creatinine kinase myocardial
- used in coonjunction with troponin
- useful in re-infarction
- produced by brain, heart, muscle, serum - myoglobin
- rises and falls very quickly - fatty acid binding protein
- coceptin
- ischaemia modified albumin
Troponin
- 3 types
- causes for its raised level?
- High sensitivity troponin
- TN-T, TN-I, TN-C (not cardiac specific)
2.
- Congestive Cardiac Failure
- Renal failure
- AF
- myocarditis
- PE
- electric burns - can be measured straight after (as opposed to 7 hr post MI)
- requires repeated measurements to monitor troponin levels
B-type antidiuretic protein (BNP)
- released by?
- effects? 3
- used for? 2
- ventricles
- reduces TPR
- Reduces venous pressure
- Natriuresis (urination)
- i. indicator of risk of death, heart failure, and recurrence of acute MI
ii. diagnosis and grading of congestive cardiac failure
Secondary hypertension causes?
I. renal
II. endocrine
- cushing
- conn syndrome
- hyperthyroidism/parathyroidism
- acromegaly
- phaeochromocytoma
Phaeochromocytoma
- def
- Sx 4
- Ix 2
- catecholamine producing tumours of adrenal medulla
- sweating, palpitation, weight loss, high BP
I. 24 hour urine
- check either catecholamine levels or their metabolites (metanephrine)
- good sensitivity and specificity
- affected by drugs: eg. paracetamol, cough syrup, tricyclic antidepressant, beta blockers)
- sample needs to be collected in acid
II. Plasma metanephrine
- high sensitivity, low specificity
- patients must be rested for 15-30 min
- affected by caffeine, alcohol, smoking
- only used as a secondary test
Conn syndrome
- def
- causes
- Ix
- excess aldosterone production, leading to alkalosis/hypokalaemia
- primary: adrenal adenoma
seccondary: increased renin secretion - Plasma aldosterone to renin ratio:
- requires a rested patient (>30 min) and not on diuretics (ACE inhibitors, spironolactone)
- Results:
= in conn: low renin, high aldosterone (-ive feedback by inhibition of renin)
= in secondary: high renin, high aldosterone
I. Cholesterol
- in normal physiology?
- in pathology?
II. Triglyceride
- in normal physiology?
- in pathology?
I. Cholesterol
- cell membrane synthesis
- precursor for vit D/steroids
- hypercholesterolaemia (RF atheroma)
II. Triglyceride
- ienergy storage
- Hypertriglyceraemia (mild/moderate: atheroma, severe: pancreatitis)
Lipoproteins
- function
- made off 2
- 5 types
- transport of lipids in blood
- Apo-proteins: structural, cofactor, receptor ligand
- phospholipids: hydrophilic barrier, allowing lipid transport
- Chylomicron (1%chol, 99%TG)
- VLDL
- LDL
- IDL
- HDL
Lipid profile
- 3 measurements
- LDL calculation? limitation? requirement?
- Non-HDL calculation
1.
- Total Chol
- HDL
- TG
2. LDL = tot chol- HDL - TG/2.2 - an estimate only - can be calculated during fasting only as TG level is affected by it 3. Non-HDL= Tot chol- HDL - both LDL and VLDL (both atherogenic) - doesnt require fasting measurement (as fasting does not affect chol levels)
Normal and ideal values for the following:
- total cholesterol
- triglyceride
- LDL
- Non-HDL chol
- 5.9, <4
- <1.7, <1.2
- 4, <2
- 4.5, <2.5
Causes of hyperlipidaemia?
Primary: - Familial Hypercholesterolaemia - Familial combined hyperlipidaemia - Type III hyperlipidaemia - Severe Hypertriglyceridaemia Secondary: - Alcohol - HIV - Anorexia - Drugs =Anti retrovirals = Retinoids = Steroids - Diabetes - Liver disease - Renal disease = Nephrotic syndrome - Hypothyroidism
Familial hypercholesterolaemia
- genetic
- how common
- 3 possible causes
- 2 Sx
- chol/TG level?
- autosomal dominant
- 1:300
- LDL receptor, Apo B or PCSK9 defect
- tendon xanthomata, corneal arcus
- chol>7.5 , TG normal
Familial combined hyperlipidaemia
- genetic
- cause
- cholesterol & TG level?
- Mx?
- autosomal dominant
- over production of VLDL by liver
- chol & trig 5-10
- statins
Type 3 hyperrlipidaemia
- cause 3
- cholesterol and TG level?
- Sx
- Mx
- Apo E2:E2 + alcohol + diet
- 5-15
- palmar crease xanthomata
- statin/fibrates
Severe hyperglyceraemia
- cause
- TG level
- Sx? 3
- Mx
- Lipo lipase deficiency
- TG>10
- eruptive xanthomata, Lipaemia retinalis and acute pancreatitis
- Mx: fibrates
Drugs to:
I. reduce cholesterol
II. reduce triglyceride
I. reduce cholesterol
1. Statin
- HMGCoA reductase inhibitor
- both reducing liver production and upregulating LDL receptors
2. Ezetimibe
- Cholesterol absorption inhibitor in gut
3. Bile substrate
4. Evolocumab:
- PCSK9 inhibitor
(PCSK9 binds irreversibly to LDL receptor, the receptor has to be broken down, instead of being reused)
II. reduce triglyceride
- Fibrates
- upregulates lipase to breakdown more TG to free fatty acid - fish oil (omacor)
- false substrate
Secretions of anterior pituitary
- TSH: acts on thyroid
- ACTH: acts on adrenal cortex
- FSH/LH: acts on ovaries/testes
- GH: entire body
- PRL: prolactin acts on mammary gland
Investigations of anterior pituitary?
- Basal hormone level
- affected by diurnal variation
- there is pulsatile release - stimulation test
- ACTH: hypoglycaemia
- GH: hypoglycaemia - suppression test
- ACTH: dexamethasone
- GH: glucose (GTT)
Acromegaly
- def
- Sx
I. facial
II. CVS
III. GI
IV. renal
V. glucose - Ix 2
- increased growth hormone secretion
2. I. - remodelling of nasopharynx (snoring, sleep apnea) - protruding jaw (spread teeth) II. CVS - Increased Na/H2O reabsorption (aldstrn)- > increased BP III. GI - polyps IV. renal - Increased vit D->calcitriol : calciuria V. glucose glucose intolerance
- I. basal GH & IGF-1
- IGF-1 better since less affected by diurnal pattern and pulsatile release
II. Glucose tolerance test:
- 75 g of glucose giving to fasting patient
- every 30 min glucose and GH are measured
- Normal: GH level is suppressed to <1 micrpgrams
- if not suppressed acromegaly
Growth hormone deficiency
- sx?
- causes
- Ix 2
- Child: short stature
adult: less clear - tumours, surgery, irradiation, head injury, , meningitis
- I. basal GH/IGF-1
- note: IGF-1 levels vary significantly during growing age, so hard to tell what is normal
II. Stimulation
- mainly insulin used (> 5yo)
- others : glucagon (<5yo), arginine, clonidine
- if levels dont rise, GH deficient
Thyroid hormones
- T3 vs T4
- Biniding proteins? 3
- What proportion are bound in blood?
- which is active? bound or free?
- What varies more, TSH levels or free T4 level?
- thyrotoxic def
- T3 is 5 times more active
- T3 mostly produced in tissues (by conversion of T4>T3), only small amount (<20%) produced in thyroid
- T4 only secreted by thyroid
- thyroid binding protein tbg, thyroid binding pre-albumin, albumin
- > 99% bound
- free form is the active form
- TSH changes from 0.01 to 100 while T4 changes from 1-40
- high T4 levels (low TSH)
Primary hypothyroidism
- Sx?
- TSH/T4/T3 levels?
- Mx
- Lethargy, tiredness
- Weight gain
- Cold intolerance
- Coarsening of hair & skin
- Slow reflexes, hoarseness
- Constipation
- Menstrual abnormalities
- Bradycardia
- Raised TSH
- Low FT4
- FT3 – not helpful
- Thyroxin (T4)
SE: increased risk of AF
Primary hyperthyroidism
- Sx?
- TSH/T4/T3 levels?
- Weight loss
- Heat inttolerance
- Palpitations
- Agitation, tremor
- Muscle weakness
- Diarrhoea
- Thyroid eye disease
- Menstrual abnormalities
- Undetectable TSH
- Raised FT4
- Raised FT3
Effect of steroids on TSH,T4,T3?
On cortisol level?
Low TSH, T3
Normal T4
4 adrenal hormones?
I. adrenal cortex
1. aldosterone: zona glomerulosa
2. cortisol: zona fasiculatis and reticularis
3. adrenal androgens: zona fasiculatis and reticularis
II. adrenal medulla
4. catecholamines
Cortisol
- what proportion free? what proportion bound?
- which fraction (free/bound) active form?
- daily production
- 4 functions
- what triggers release?
- Released along with which products?
- 90% bound to CBG, albumin
- active form is free
- 25mg/day
- I. insulin antagonist
II. glucogenesis
III. protein catabolism
IV. immunosuppressants - cortisone releasing hormone (CRH) from hypothalamus acts on ant pituitary, causing release of ACTH which works on adrenal cortex
- β-endorphins and α-melanotropin (skin pigmentation)
Addison’s disease
- def?
- Sx 3
- Ix 3
- primary adrenal insufficiency
- reduced glucose, and BP,
- increased potassium
- pigmentation
- I. increased ACTH, low cortisol
II. dynamic synacthen stimulation test:
- 250 micrograms of synacthen (synthetic ACTH) IM
- Normal individuals: incremental increase in cortisol level > 420 nanomol/L
- Otherwise abnormal
III. Electrolytes
- low Na
- high urea (volume depletion)
- high K
Dynamic synacthen stimulation test?
- Tests for addison’s disease (adrenal insufficiency)
- 250 micrograms of synacthen (synthetic ACTH) IM given
- cortisol measured every 30 min
- Normal individuals: incremental increase in cortisol level, > 420 nanomol/L
- Otherwise abnormal
Congenital adrenal hyperplasia (CAH)
- Most common cause?
- 2 main classical types?
- Sx in newborn/adult?
- Ix?
- > 90% due to 21-hydroxylase deficiency
- simple viralising (male like Sx due to androgen affected)
- salt wasting (aldosterone affected)
- a. Newborn:
- Ambiguous external genitalia
- Pigmented scrotum
- Salt wasting
- Sudden unexplained death (males)
b. Adult:
- Hirsutism
- Menstrual cycle disorder
- Subfertility
4. I. Blood: 17α hydroxy progesterone Electrolytes Glucose II. urine - Electrolytes - Steroid profile
Cushing’s
- Sx
I. NVS, II. Fat retension III. GU IV. renal/adrenal V. CVS VI. MSK - Ix? 2
1. I. Mental disturbances II. Obesity: - Fat redistribution - Truncal Obesity - Striae III. Hyperandrogenism - Hirsutism - Acne - Amenerrhoea IV. Kidneys/adrenal gland - Insulin resistance - Glucose intolerance - Salt retention V. CVS - Hypertension VI. MSK Osteoporosis
2. I. reduced serum cortisol - false -ive, stressful II. Salivary cortisol - demonstrate loss of diurnal - stress free III. urine free cortisol - not great IV. dexamethasone suppression a. 1 mg overnight test (to exclude cushing's) - 9:00 am cortisol should be <50 mmol/L - high false positive - false -ive in cyclinal cushing's b. Low dose dexamethasone - 0.5 mg 6 hourly for 48 hours - normal suppression, cushing's no suppression
Causes of high cortisol:
- ACTH high
- ACTH low
How to differentiate between them?
- cushings
- ectopic
- adenoma or carcinoma of adrenal gland
- iatrogenic
High dose dexamethasone:
- 2mg 6 hourly dependent for 48h-72 hrs
- pituitary dependent (cushing’s): suppress
- adrenal and ectopic ACTH: no suppression
Water distriubution in a healthy adult
- 68% inracellular
- 33% extracellular
- 8% plasma
- 25% interstitial
Hyponatraemia causes
- Pseudo-hyponatraemia
- Compensatory hyponatraemia
- Normal total body volume hyponatraemia
- Depleted volume
- Volume expanded hyponatraemia
Pseudo-hyponatraemia
- due to high level of lipid/protein in blood
- means in 1L plasma, there’s less Na (but Na hasnt gone down)
- low osmolarity, low [Na]
- unchanged osmolality
Compensatory hyponatraemia
- high level of glucose (hyperglycaemia), causes water to enter vessels
- shows as a reduction in [Na], but Na level is unchanged
Volume depleted hyponatraemia?
Two types?
Causes?
Urine [Na]?
Mx?
a. renal:
- caused by diuretics, addisons( reduced aldosterone)
- Urine [Na] > 30
- Mx: normal saline
b. extra-renal
- caused by diarrhoea, vomiting
- Urine [Na] < 30
- Mx: normal saline
Euvolaemic hyponatraemia
causes?
Urine [Na]?
Mx?
eg SAID (SYNDROME OF INAPPROPRIATE ANTIDIURESIS) , or hypothyroidism
Na>30
Fluid restriction
Volume expanded hyponatraemia
causes?
Urine [Na]?
Mx?
nephrotic, cirrhosis, heart failure
Na<30
Mx:
- fluid restriction
- aldosterone antagonist: spironolactone
- loop diuretics
U&Es:
- cause of high urea?
- cause of high potassium
- water depletion
2. impaired Na/K exchange (eg low aldosterone) means K is not excreted
Syndrome of inappropriate antidiuresis (SAID)
- what type of diagnosis?
- causes?
- Mx?
- diagnosis of exclusion
2. I. Neoplasia - Bronchial carcinoma -Pancreatic carcinoma - Lymphoma II. Pulmonary disorders - Pneumonia - Tuberculosis - Bronchiectasis - Pneumothorax - Positive pressure ventilation III. Neurological disorders - Encephalitis IV. Meningitis V. Head injury VI. Porphyria
3. I. Treat the underlying cause II. Fluid restriction • 500 – 800 mL per 24h III. Demeclocycline IV. Tolvaptan (V2 antagonist) V. Hypertonic saline (☠) (needs to be very slow to avoid cerebral dehydration)
Phenylketonuria
- what general group of illnesses does it belong to?
- mutation in?
- Ix?
- pathophysiology?
- Mx?
- prognosis
- Inherited Metabolic Disorders (IMD)
- Mutations of phenylalanine hydroxylase gene
• Absent or reduced enzyme activity or impaired binding to
cofactor BH4 - Diagnosis - increased plasma phenylalanine (substrate) and
reduced tyrosine (product) - Pathophysiology - neurotoxicity of PA and impairedneurotransmitter synthesis
- Treatment with low phenylalanine diet + supplements –
- prognosis good.
3 main types of Inherited Metabolic Disorders (IMD)?
- Disorders involving complex molecules
- Symptoms permanent, progressive, independent of intercurrent illness and unrelated to food intake
- Involves cellular organelles and includes diseases that disturb the synthesis or catabolism of complex molecules
- eg Lysosomal storage disorders - Intoxication
- Symptoms due to acute or progressive intoxication from the accumulation of toxic compounds proximal to a metabolic block.
- Presentation can be acute e.g. vomiting, lethargy, coma, liver failure or chronic e.g. progressive developmental delay, cardiomyopathy
- e.g Urea cycle defects - Energy insufficiency
- Symptoms due to deficiency in energy production or utilisation
- Defects expressed in liver, myocardium, muscle & brain.
- Common symptoms include hypoglycaemia, hyperlacticacidaemia,
hypotonia, myopathy, cardiomyopathy, SIDs.
- E.g fatty acid oxidation defects
Lysosomal storage disorders
- what are lysosomes?
- consequences of defect
- age?
- clinical features?
- progression
- Treatment options in LSDs
- Lysosomes - cellular organelles where hydrolytic enzymes process
ingested materials or damaged organelles into substances that the cell
can re-utilise – ‘the cell recycling centre’ - Defects lead to accumulation of partially degraded substances within
the lysosome leading to disturbed cell homeostasis and early cell death.
- Cells with low turnover rates (e.g. neurons) or rich in lysosomes (white cells) most vulnerable to damage. - Clinical features usually develop 3-6 months of age.
- Most present with neurological symptoms, hepatosplenomegaly, respiratory, cardiac and bone problems common.
5. Conditions slowly progress to life threatening, multi-organ disease 6. • Supportive/ palliative care • Enzyme replacement therapy • Bone marrow transplantation (HSCT) • Substrate reduction therapy • Chaperone therapy • Gene therapy
Urea cycle defects
- main complication
- define hyperammonaemia
- sx
- acute management
- chronic management
- progress
- Hyperammonaemia
- Hyperammonaemia defined as
Premature neonate NH3 > 150 umol/L
Term neonate > 100 umol/L
Infant & child > 40 umol/L - Acute tachypnoea, lethargy, vomiting convulsions, encephalopathy
4. I. Stop protein intake II. High calorie infusion (glucose) to prevent catabolism III. Arginine – to ‘drive’ urea cycle IV. Promote ammonia removal • Sodium benzoate/phenylbutyrate • Haemofiltration (NH3 >300 umol/L)
- I. Referred to paediatric metabolic clinic for longterm follow up
II. Low protein diet
III. Benzoate & Phenylbutyrate
IV. Arginine & Citrulline
V. Emergency regime to avoid catabolism during intercurrent illness - Significant developmental delay – sitting with support aged 2 years
- Metabolic control brittle (NH3 60-200)
- Referred to Birmingham Liver Unit for consideration of liver transplant
Medium-chain acyl-CoA dehydrogenase
deficiency (MCAD)
- age of presentation
- what is it?
- diagnosis?
- acute mx
- chronic mx
- sx
- Usually presents 4 months - 3 years
- Metabolic crisis precipitated by fasting, illness, operations
- Diagnosis
– organic acids in urine
– blood spot acylcarnitines - increased octanoyl carnitine
– mutation analysis - common mutation K329E - – High dose glucose IV + insulin
– IV carnitine - _ Avoid fasting
– Diet low fat, high carbohydrate
– Emergency regime
– Oral carnitine - hypoglycaemia
I. Neonate/infant - irritability, somnolence, tachypnoea,
hypothermia, apnoea, hypotonia, seizures
II. Older infants/children – sweating, apathy, nausea, headaches,
unusual behaviour, seizures, coma
Response to fasting
- Endogenous glucose production (glycogenolysis and gluconeogenesis)
- Reduced peripheral glucose utilisation
(alternative energy substrates – fatty acid/ketone oxidation)
Serum protein measurements?
- quantitative
- total
- albumin
- globulin - semi-quantitative
- serum electrophoresis (separate by charge)
- paraproteins
Albumin
- synthesised where?
- half-life?
- main functions?
- normal concentration of range
- Liver synthesis
- Half life ~20 days
- Main role - Transport
- Oncotic pressure
- 35-50 g/L
Causes of low albumin?
- Reduced synthesis
I. Liver disease
Chronic liver disease - liver will continue to make Albumin until 90-95% damaged
II. Malabsorption
Reduced supply of amino acids from GIT to liver
III. Malnutrition
Reduced supply of amino acids
- Increased Breakdown (catabolism)
I. Severe illness Sepsis Inflammation Trauma II. Malignancy
- Excess loss
I. Renal
- Nephrotic syndrome : Proteinuria > 3g / day
- Low Alb plus oedema, dyslipidaemia, viscosity, +/- renal impairment
II. Gastrointestinal
Protein loosing enteropathy
III. Skin
Burns, psoriasis
- Dilution (including artefact)
I. Iatrogenic (excess protein-free fluids)
II. Oedematous states
CCF, CLD
III. Pregnancy
- Redistribution
I. Increased capillary permeability Sepsis Inflammation Response to trauma II. Recumbency small but significant changes
Consequences of low albumin?
- oedema
- Calciuria: If Less albumin available to bind calcium the excess calcium is excreted. (Total calcium will reduce although free calcium is maintained at the same concentration)
Proteinuria
- normal total protein level in urine?
- normal albumin level in urine?
- threshold of albumin detection in urine dipstick test?
- 2 tests for examining protein in urine?
- Normal urine total protein <150 mg/24h
- Normal urine albumin < 30 mg/24h
- Protein dip-stick detects albumin >300 mg/L
- dipstick and albumin creatinine ratio
5.
ACR: albumin creatinine ratio
- used for?
- when shouldnt be used?
- what is it?
- markers for?
- normal level?
- proteinuria,
- Should not be used during an acute illness
- Spot urine test
- Early morning preferred
- Marker for Renal Disease
Marker CVD morbidity & mortality - Normal ACR <3.0 g/mol
Transudate vs exudate?
Lights criteria?
Transudates =
- Fluid with low protein filtration across capillary endothelium
- (due to oncotic pressure)
Exudates =
- Fluid with high protein
- Secretion due to inflammatory process (increased permeability)
Lights criteria = Fluid Alb: Serum Alb >0.5
Then fluid is an exudate
Causes of proteinuria?
- Glomerular
- Most common pathological cause
- Increased GBM permeability
e. g. nephrotic syndrome
- > 3g/24 h protein excreted
- very low serum albumin
- most common cause - immunologically mediated glomerulonehpritis
- Transient with illness or exercise - Tubular
- impaired reabsorption of protein
- Causes of tubular damage- heavy metals, renotoxic drugs, chronic pyelonephritis and inherited syndromes e.g. Fanconi’s syndrome - Overflow
- increased plasma concentration of protein
- filtered load exceeds reabsorptive capacity - Post renal
- Urinary tract infection
- Seminal fluid, pus or blood in urine
- Post renal tumour
Hypergammaglobulinaemia
I. Polyclonal:
Inflammation, Infection, Autoimmune disease, CLD
II. Monoclonal
- Multiple Myeloma
- Waldenström’s macroglobulinaemia
- Monoclonal gammopathy of undetermined significance (MGUS)
- Other B cell malignancies
Acute phase proteins
I. INCREASED
- CRP
- Ferritin
- Alpha 1 antitrypsin
- Caeurolplasmin
- Fibrinogen
- Haptoglobulin
- Serum Amyloid A
II. DECREASED
- Albumin
- Transferrin
C-reactive protein
I. released in response to?
II. delay in response to changes?
III. level with abx?
I. Fast response to injury
- inflammation
- bacterial infection
II. Rapid increase (6hrs), Rapid fall with treatment
III. With Antibiotics - fall 50% within 24hrs
Haptoglobulin
- binds?
- taken up by?
- marker of?
- Binds free Hb released from intravascular haemolysis
- Then is taken up by reticuloendothelial system
- Low in haemolytic anaemia but also in
CLD, metastises, sepsis
Caeruloplasmin
- binds to
- decreased in
- increased in?
- Copper carrying protein
- Low in Wilsons disease
- Increased in acute phase (and in pregnancy or COP)
Alkaline phosphatase (ALP) isoenzymes sources?
Sources:
1. Liver/biliary system
(increased in Cholestasis, cirrhosis, liver cancer, IBD)
2. Bone
(Fracture, growth, paget’s, cancer, osteomyelitis, vitamin D deficiency, hyperpararthyroidism, CKD)
3. Others Placenta, GIT
α-1 antitrypsin
- normal role
- linked with?
- α-1 protease inhibitor
- Normally controls proteolytic enzymes from macrophages
- Linked with early onset Emphysema and CLD
uses of CRP (c reactive protein)?
- Detecting infection
- Bacterial
- Immunosuppression - Response to treatment
- CT Disease
- But not SLE - IBD
- Prognosis e.g Acute Pancreatitis
- Cardiovascular risk
Hypernatraemia causes
1. Not enough water I. Inadequate water intake II. Impaired water retention - Diabetes insipidus - Osmotic diuresis III. Loss of hypotonic fluids (burns, sweat)
- Too much sodium
I. Excessive sodium intake
II. Increased sodium retention
- Primary aldosteronism (Conn syndrome)
Diabetes insipidus - causes
I. Cranial 1 .Idiopathic - Familial (autosomal dominant) - Sporadic 2. Secondary - Trauma (accidents, surgery) - Tumours (craniopharyngioma, pit. adenoma) - Granuloma (sarcoid, histiocytosis X) - Infections (encephalitis, meningitis) - Vascular (aneurysm, hypoxia, vasculitis) - Autoimmune
II. Nephrogenic
- Idiopathic
- Secondary
- Drugs/toxins
- —- Demeclocycline
- —- Lithium
- Metabolic
- —- Hypercalcaemia
- —- Hypokalaemia
- —- Amyloid
- Vascular
- —- e.g.sickle cell disease
- AKI recovery phase
Why when suspecting hypernatraemia it is important to measure calcium?
calcium interfers with vasopressin action, if high can be the cause of water depletion/dehydration
Water deprivation test
I. describe the procedure
II. what is it used for?
III. follow up test after abnormal result?
I.
1. Stop drinking/ eating
2. Measure urine osmolarity hourly for 8 hours
3. Osmolarity of urine increases in normal patients
4. Monitor closely for dangerous dehydration (serum osmolarity and weight measured every 2 hours)
II. to diagnose diabetes insipidous, if osmolarity doesnt go up, means the kidneys are losing too much water
III. give them DDVAP (ie desmopressin)
- If still fail to give a concentrated urine, it is a nephrogenic problem (kidneys unresponsive)
- If concentrate urine , means there is a cranial problem (hypothalamus)
Urine potassium excretion depends on
- Availability of sodium for exchange
- Plasma aldosterone concentration
- Relative intracellular [K+] and [H+]
How loop diuretics cause hypokalaemia?
Blocks Na reabsorption
More Na gets to distal convoluted tubule
Na is reabsorbed excreting more K
Effect of acidosis on [K]?
More H for Na exchanged at the distal tubule, less available for K, less K excreted
Hyperkalaemia
Effect of insulin and catecholamine on potassium levels?
Insulin: increases K uptake by activating Na/K exchange pump, so used as a treatment (along with glucose) to acutely drop blood K level
Catecholamine: increases Na/K exchange activity, so after an MI, high catecholamine levels leads to hypokalaemia
Causes of Hypokalaemia
I. renal loss
- Alkalosis
- Drugs
- Diuretics (thiazides and loop) - Mineralocorticoid excess
- 1° hyperaldosteronism
- 2° hyperaldosteronism
- Cushing’s syndrome
- Ectopic ACTH - Kidney disease
- Renal tubular acidosis
- Interstitial nephritis
- AKI recovery phase - Miscellaneous
- Hypomagnasaemia
- Hypercalcaemia
II. extrarenal loss
- GI loss
- Diarrhoea
- Villous adenoma (sigmoid)
- Pancreatic fistula - EC to IC shift
- Insulin
- Catecholamines
- Refeeding syndrome - Inadequate intake
- Alcoholism
- Anorexia nervos
Causes of hyperkalaemia
I. Renal
- Renal failure
- Acute Kidney Injury
- End-stage chronic kidney disease - Drugs
- Potassium-sparing diuretics
- Amiloride
- Spironolactone
- ACE inhibitors and A2 blockers - Mineralocorticoid deficiency
- Addison disease
- Hyporeninaemic hypoaldosteronism
II. extrarenal
- Pseudohyperkalaemia
- Haemolysis
- Leukocytosis
- Thrombocytosis - Increased potassium input
- Exogenous
- Endogenous
- Tissue necrosis
- Haemolysis
- Malignancy
- Chemotherapy - IC to EC shift
- Acidosis
- Hypoxia
- Insulin deficiency
Actions of PTH
I. bone
II. kidney
I. Bone
Stimulates bone resorption by increasing the number and activity of osteoclasts
Requires normal levels of 1,25 (OH)2 Vit D
↑ Ca ↑ PO4 II. Kidney Increases renal tubular reabsorption of calcium Decreases renal tubular reabsorption of phosphate Promotes 1α hydroxylation of 25 OH vitamin D∴ gut absorption of Ca ↑ Ca ↓ PO4
Actions of 1,25 (OH)2Vitamin D
I. gut
II. bone
III. kidney
I. Gut
- Increased absorption of calcium (PO4) small intestine
II. Bone
- promotes growth and development by increasing the supply of Ca, PO4 for bone mineralisation.
- Synergistic action with PTH when calcium low to stimulate bone resorption.
III.Kidney
- Increased reabsorption of Ca and PO4
Net effect ↑ Ca ↑ PO4
1 α hydroxylase stimulated by:
Low plasma phosphate
Increased PTH (? due to reduced PO4)
Oestrogens, prolactin, growth hormone
Calcitonin
- actions
- uses
- Actions
- Bone: Inhibits osteoclast activity ∴ reduced bone resorption
- Kidney: Reduced tubular reabsorption of Ca & PO4
- Net effect ↓ Ca ↓ PO4 - Main use
- Tumour marker
- Therapeutic treatment of hypercalcaemia & Pagets disease
Hypercalcaemia - symptoms and signs
I. renal
II GI
III. NVS
IV. CVS
Bones stones groans and psychic moans
I. Renal - Polyuria - Renal calculi II. GI - Anorexia, nausea, vomiting - Constipation - Abdo pain - peptic ulceration III. Neurological - Depression, fatigue - Confusion IV. Cardiovascular - ECG changes (shortened QT interval) - Bradycardia
Hypercalcaemia - classification of causes
- Artifactual
- Dehydration
- Prolonged application of a tourniquet - Increased intake/absorption
- XS vitamin D
- Sarcoidosis - Increased bone resorption
- Primary Hyperparathyroidism (most common cause)
- Malignancy
- Thyrotoxicosis
- Immobilisaton - Increased renal reabsorption
- Thiazide diuretics
- Familial hypocalciuric hypercalcaemia (setpoint is set at a higher point)
3 types of Malignancy that lead to hypercalcaemia
- Humoral hypercalcaemia of malignancy
Bone resorptive factors - PTHrp, TNF, IL-1 - Metastatic hypercalcaemia
Direct effect on bone - Dis-regulated Vitamin D metabolism
Particularly haematological malignancy
Hypercalcaemia - treatment
- Rehydration
- Bisphosphonates (anti-reabsorptive)
- Steroids (used for malignant disease)
Hypocalcaemia - symptoms and signs
I. Neurological
Lethargy, depression, psychosis
Tetany, parasthaesia, cramps
II. Cardiovascular
ECG changes (prolonged QT interval)
Arrythmias
III. Soft tissue
Cataracts
Brittle nails, hair
Hypocalcaemia - classification of causes
- Artifactual
- Reduced plasma albumin
- Unsuitable sample - Decreased intake/absorption
- Vitamin D deficiency - Decreased flux of calcium from bone
- PTH deficiency/resistence
- Treatment with antiresorptive agents - Increased flux of calcium to bone
- Hungry bone syndrome (excess PTH for too long, when taking parathyroid gland out, bone absorbs all the Ca quickly) - Extraskeletal sequestration
- Acute pancreatitis
Commonest cause: iatrogenic hypoparathyroidism
Hypocalcaemia - treatment
- Diet
- Oral calcium supplements
- Oral vitamin D
- IV Calcium gluconate
Vit D deficiency causes and consequences
- Reduced intake/absorption of vitamin D
Malnutrition
Reduced sunlight
Malabsorption - Impaired Vitamin D metabolism
Renal disease
Anticonvulsant therapy - Consequences
Delay in mineralisation of newly formed bone - bone softening and skeletal abnormality.
Rickets - children
Osteomalacia - adults
Hypoparathyroidism causes
1. PTH deficiency Surgical Congenital - Di George syndrome (cant release PTH) Idiopathic Infiltrative
- PTH resistence
Magnesium deficiency
Pseudohypoparathyroidism( hypocalcaemic, PTH increased, but cant act on the receptor)
Extracellular ca distribution
50% free (ionised)
40% bound
10% complexed
Note:
Intracellular Ca 0.6%
Extracellular 0.1-0.2%
Sub-fertility
- def
- causes
- Cumulative conception rates:
- 4 Months 65%
- 9 Months 82%
- 12 Months 85% - Sperm defects 24%
- Ovulatory failure 21%
- tubal damage 14%
- endometriosis 6%
- unexplained 28%
Primary Ovarian Failure
- results in
- LH/FSH/oestrodiol levels?
- causes
- Impaired follicular development- OVARIAN PROBLEM
- High LH/FSH (mainly FSH)
Low oestradiol - Premature ovarian insufficiency
- Post menopausal
- Autoimmune damage
-Surgery
-Irradiation - Dysgenesis (Turners syndrome)
Secondary Ovarian Failure
- results in
- LH/FSH/oestrodiol levels?
- causes
- Impaired follicular development > Low oestradiol (HYPOTHALMIC-PITUITARY PROBLEM)
- Impaired LH/FSH production, low LH/FSH
- LHRH deficiency (KALLMAN SYNDROME, problem with migration in utero, through the olfactory nerve)
- Pituitary tumours (prolactinoma)
- Secondary hypopituitarism (e.g. irradiation, infiltrative & vascular disorders)
- Functional (weight loss, stress, exercise, starvation, trying to protect you against pregnancy)
- Systemic disease (e.g. thyroid, adrenal)
Hyper-Prolactinaemia
- physiologial causes
- pathological causes
1. I. Pregnancy II. Stress III. Drug induced - Dopamine receptor antagonist phenothiazines - Dopamine depleting agents, methyl dopa - Oestrogens IV. presence of macroprolactin : large MW form of prolactin: doesnt get cleared as easy as monomeric prolactin. But not physiologically active 2. I. Pituitary tumour - prolactin secreting micro / macro adenoma - acromegaly - functionless pituitary tumour II. Lesions hypothalamic / pituitary stalk III. Primary hypothyroidism (TRH) IV. Chronic renal failure
Polycystic Ovarian Syndrome (PCOS)
- what proportion of patients with oligomenorrhea/amenorrhea?
- ultrasound findings
- sx
- endocrine levels?
- 87-90% of patients with oligomenorrhea , 26-37% of patients with amenorrhoea
- > 15 cysts arranged around cortex echogenic stromal compartment
3.
- Obesity
- Insulin resistance
- Increased cardiovascular risk
- Hirsutism
- Oestrogenisation - High LH, normal FSH, high LH:FSH ratio.
Effects of Physiological Changes on Laboratory Tests during pregnancy
I. chemical
II. physiological
III. Endocrine
I. Chemical
- Increases - Alk phos (produced by placenta, rising in 3rd trimester), hormone binding proteins
- Decreases- Albumin, creatinine, urea
II. Physiological
- Increases- plasma volume, cardiac output, weight gain, GFR early pregnancy
- Decreases- Fasting BG early pregnancy, renal threshold for glucose
III. Endocrine
- Increase- Oestrogen, progesterone, prolactin, hCG
- Decrease- LH & FSH
3 complicationsof pregnancy that complicate the lab results?
I.Gestational diabetes - Diagnostic problem: ---- 15% women develop glycosuria ---- No accepted reference ranges - Diagnostic tests ---- Blood glucose, random/fasting ---- GTT II. Hypertension and pre-eclampsia
III. Obstetric cholestasis
Pregnancy Related Liver Disease “Big 5”
- Pre-eclampsia
- HELLP
- Hyperemesis Gravidarum
- Acute Fatty Liver of Pregnancy
- Obstetric Cholestasis
HELLP (ELLP) syndrome
Haemolysis, Elevated Liver Enzymes, Low Platelets
Obstetric Cholestasis
- when does it occur
- cardinal feature?
- Biochem tests?
- Usually occurs in the 3rd trimester
- Cardinal feature is generalised pruritis
- Biochemical tests
I. Serum bile acids (sensitive but not specific)
II. ALT & AST often raised
III. Alkaline phosphatase & bilirubin -
no significant contribution
Function of LH/FSH?
LH acts on theca and
mature granulosa cells
FSH acts on follicular
granulosa cells
Menstrual cycle
follicular phase: - a cohort of follicles are recruited - mostly regress - FSH makes it to enlarge - it produces oestrogen - Rise in oestrogen causes LH release - LH causes rupture of follicle Luteal phase: - corpus luteum carries on producing progesterone
Investigations to assess infertility?
LH/FSH, Prolactin, TFT, Testosterone Oestradiol/Oestrogen status
Assessment of ovulation?
Progesterone (nmol/L) level:
I. >30 ovulation–> normal ovulation
II. <30 reduced conception rate (low probably of conception)
III. Low level repeat next cycle
Timing:
Measurement needs to be done on “Day 21” progesterone, 7 days before menses
Infertility causes?
- Assess Ovulation (progesterone)
- Anovulation (Oligo/amenorrhoea)
- Exclude uterine abnormalities/pregnancy
- LH/FSH, Prolactin, TFT, Testosterone
Oestradiol/Oestrogen status - I. Primary ovarian failure
II. Secondary ovarian failure
III. PCO
Effect on prolactin
I. Dopamine
II. TRH/PRF?
I. suppresses its release
II. stimulates it (but it pathological (as opposed to physiological) )
Macroprolactinoma
large prolactin secreting tumour
FSH/LH roles in male?
FSH stimulates sertoli cells to produce spermatozoa
LH stimulates Laydig cells to produce testosterone
Sub-fertile male analysis?
Testicular problems affecting men fertility and hormonal changes?
Hypothalamic problems affecting men fertility and hormonal changes?
Semen analysis
- If abnormal, then do LH,FSH, PLT, testosterone levels:
- This tells us whether its a testicular problem, or hypothalamic problem
I. Testicular problem:
- hypergonadotrophic hypogonadism (testicular failure)
Low T, High LH & FSH - Isolated germinal compartment failure
Normal T & LH, High FSH - Non-Endocrine
(obstructive azoospermia, retrograde ejaculation)
Normal T, LH & FSH
II. Hypothalamic/Pituitary
- Hypogonadotrophic hypogonadism
Low T, LH & FSH
Early and late signs of pre-eclampsia in women
Early: - hypertension - raised urate Late: - raised urea and creatinine - low GFR - Proteinuria - oedema (not always)
