Chemical Pathology- Part 1 (p72-85- Fluid balance, electrolytes, acid-base, LFTs, porphyrias, pituitary + thyroid) Flashcards
What % of body is water?
60
What is ratio of intracellular:extracellular fluid?
2:1
What does extracellular fluid include (three different things)?
Intravascular
Interstitial (between cells- largest component)
Transcellular- epithelial lined spaces e.g. CSF, joint fluid etc
Define osmolality
Total number of particles in solution- measured with an osmometer (units- mmol/kg)
Define osmolarity
The concentration of a solution- calculated (units mmol/l)
What physiological determinants of osmolality and osmolarity are there in serum/plasma?
Na+ K+ Cl- HCO3- Urea Glucose
What pathological determinants of osmolality and osmolarity are there in serum/plasma?
Endogenous (e.g. glucose) or exogenous (e.g. ethanol)
Osmolarity calculation?
2(Na+ + K+) + urea + glucose
What is the osmolar gap?
The difference between osmolality and osmolarity
Why is the osmolar gap useful in metabolic acidosis?
If osmolarity is lower than osmolality we can assume there are extra unmeasured solutes that are dissolved
Normal range for serum osmolality?
275-295 mmol/kg
Normal range for Na+?
135-145mmol/l
What maintains Na+ as mainly an extracellular cation?
Na+/K+ ATPase
What would you see in symptomatic hyponatraemia?
N+V (<136mmol/l)
Confusion (<131mmol/l)
Seizures, pulmonary oedema (<125mmol/l)
Coma (<117mmol/l)
How do you determine whether it is a true hyponatraemia?
Using serum osmolality:
High-
Glucose/mannitol infusion
Normal-
Spurious
Drip arm sample
Pseudohyponatraemia
Low-
True hyponatraemia
What causes of pseudohyponatraemia are there?
Hyperlipidaemia
Paraproteinaemia
What would you be considering aetiology and treatment wise in a hypervolaemic hyponatraemic patient?
Three failures- heart, renal and liver
Treatment:
Fluid restrict and treat cause
What would you be considering aetiology and investigation wise in a euvolaemic hyponatraemic patient?
Hypothyroidism
Glucocorticoid insufficiency
SIADH
investigations:
TFTs
Short synacthen test
Paired urine and serum osmolality
What would you be considering diagnosis and treatment wise in a hypovolaemic hyponatraemic patient?
Diarrhoea
Vomiting
Diuretics
Salt losing nephropathy
Treatment
Fluid restoration with 5% dextrose
How does liver failure cause hyponatraemia?
There is poor breakdown of vasodilators like nitric oxide, these cause a low BP and subsequent ADH release causes water retention, which dilutes down sodium
What is the risk when treating hyponatraemia?
Rapid correction can lead to central pontine myelinolysis (locked in syndrome) therefore increase Na+ by 1mmol/l/hr
Why is hyponatraemia post surgery common?
Over hydration with hypotonic IV fluids
Transient increase in ADH due to stress of surgery
What is the lab criteria for SIADH?
True hyponatraemia
Clinically euvolaemic
Inappropriate high urine osmolality and increased renal sodium excretion (>20mmol/l)
Normal 9am cortisol and TFTs (diagnosis of exclusion)
Causes of SIADH?
Malignancy- small cell lung cancer (most common), pancreas, prostate, lymphoma)
CNS disorders- meningoencephalitis, haemorrhage, abscess
Chest- TB, pneumonia, abscess
Drugs- opiates, SSRIs, carbamazepine, PPIs
Treatment of SIADH?
Fluid restriction and treat cause, demeclocycline and tolvaptan induce a state of diabetes insipidus that may help
Symptoms of hypernatraemia?
Thirst -> confusion -> seizures + ataxia -> coma
What causes are there of hypovolaemic hypernatraemia?
GI loss- vomiting, diarrhoea
Skin loss- excessive sweating, burns
Renal loss- loop or osmotic
What causes are there of euvolaemic hypernatraemia?
Respiratory (tachypnoea)
Skin (sweating + fever)
Renal (DI)
What causes are there of hypervolaemic hypernatraemia?
Mineralocorticoid excess (Conn's syndrome) Hypertonic saline
What can rapid correction of hypernatraemia lead to?
Cerebral oedema
Clinical features of DI?
Hypernatraemia (lethargy, thirst, irritable, confusion, coma, fits)
Clinically euvolaemic
Polyuria and polydipsia
Urine:plasma osmolality <2
What is the difference between cranial and nephrogenic DI?
Cranial- lack of ADH
Nephrogenic- receptor defect (insensitivity)
Causes of cranial DI?
Surgery, trauma or tumours
Causes of nephrogenic DI?
Inherited channelopathies
Lithium, democlocycline
Hypercalcaemia
How is DI diagnosed?
8h fluid deprivation test:
Normal- urine conc >600mOsmol/kg
Primary polydipsia- urine conc 400-600
Cranial DI- urine only concentrates after desmopression
Nephrogenic- low concentration after desmopressin
Normal range of potassium?
3.5-5.5mmol/l
Causes of hypokalaemia?
Either depletion or shift into cells- rarely decreased intake
GI loss
Renal loss- hyperaldosteronism, excess cortisol, diuretics, osmotic diuresis
Redistribution into cells
Rare tubular acidosis or hypomagnesaemia
What are the 3 types of renal tubular acidosis and how are they different?
Type 1- most severe, distal failure of H+ excretion and subsequent acidosis and hypokalaemia (failed hydrogen potassium pumping)
Type 2- Milder, proximal failure to reabsorb bicarbonate, leads to acidosis and hyperkalaemia
Type 4- aldosterone deficiency or resistance (acidosis and hyperkalaemia)
Treatment of hypokalaemia?
Oral SandoK and monitoring potassium levels or if lower than 3.0 consider intravenous potassium chloride
Causes of hyperkalaemia?
Excessive intake-
oral, parenteral or stored blood transfusion
Transcellular movement (ICF>ECF)- acidosis, insulin shortage (DKA) and tissue damage/catabolic state
Decreased excretion- Acute renal failure (oliguric phase) CRF K-sparing diuretics (spironolactone) Mineralocorticoid deficiency (Addison's) NSAIDs, ACEi, ARBs
Treatment of hyperkalaemia?
10ml 10% calcium gluconate, 100mls 20% dextrose and 10 units insulin. Salbutamol useful as well
Normal blood pH range?
7.35-7.45
Normal blood CO2 range?
4.7-6kPa
Normal blood bicarbonate range?
22-30mmol/l
Normal blood O2 range?
10-13kPa
What are the steps in checking for an acidosis/alkalosis?
Check pH
CO2- does it fit with pH
Bicarbonate- does it fit with pH
Compensation- Any? Partial? Complete?
What would you see in a metabolic acidosis?
pH low, bicarb low, CO2 normal or low if compensated
Causes of metabolic acidosis?
Lactate build up in DKA
Renal tubular acidosis
Intestinal fistula
What would you see in a metabolic alkalosis?
Raised pH and bicarb, CO2 normal or raised if compensated
Causes of metabolic alkalosis?
Pyloric stenosis
Hypokalaemia
Ingestion of bicarb
What would you see in a respiratory acidosis?
Low pH, bicarb normal or raised if compensated, high CO2
Causes of resp acidosis?
Lung injury- pneumonia
COPD
Decreased ventilation- Morphine OD
What would you see in a resp alkalosis?
Raised pH, bicarb normal or low if compensated, low CO2
Causes of resp alkalosis?
Mechanical ventilation
Anxiety/panic attack
What is the anion gap?
Difference between total concentration of principal cations and anions - i.e. Concentration of unmeasured anions in plasma
Normal range for anion gap?
14-18mmol/l
Causes of elevated anion gap metabolic acidosis?
KULT
Ketoacidosis- diabetic, alcoholic, starvation
Uraemia- renal failure
Lactic acidosis
Toxins- ethylene glycol, methanol, paraldehyde, salicylate
Which LFTs are markers of liver cell damage?
ALT AST Alk Phos GGT Bilirubin
Which LFTs are markers of synthetic function?
Clotting (INR)
Albumin
Glucose
When are the aminotransferases (AST/ALT) raised?
When hepatocytes die
What would you see in terms of LFTs in alcoholic liver disease?
AST:ALT = 2:1
What would you see in terms of LFTs in viral liver disease?
AST:ALT = <1:1
When is ALP raised?
Cholestasis (intrahepatic or extrahepatic) and bone disease, very high in pregnancy
When is gamma GT (GGT) raised?
In chronic alcohol use
Bile duct disease
Metastases
Also used to confirm hepatic source of raised ALP
What are porphyrias?
Disorders caused by deficiency in enzymes, involved in haem biosynthesis, leading to build up of toxic haem precursors
What is the inheritance pattern of acute intermittent porphyria (AIP)?
Autosomal dominant
What causes AIP?
HMB (hydroxmethylbilane) synthase deficiency
Symptoms of AIP?
Neurovisceral- Abdo pain, seizures, psych, N+V, tachycardia, HTN, sensory loss, muscle weakness, constipation, incontinence, NO cutaneous manifestations
How is AIP diagnosed?
ALA + PBG in urine (‘Port wine urine’)
How do you treat AIP?
Avoid precipitating factors, analgesia, IV carbohydrate/haem arginate
What are the two types of acute poryphrias with skin lesions?
Hereditary coproporphyria (HCP) + Varegiate poryphria (VP) Same neurovisceral lesions with skin lesions
How do non-acute porphyrias present and what are the three types?
Skin lesions ONLY e.g. Congenital Erythopoietic porphyria (CEP) Erythropoietic protoporphyria (EPP) Porphyria Cutanea Tarda (PCT)
What is a typical feature of erythropoietic protoporphyria (EPP)?
Photosensitivity
Burning
Itching oedema following sun exposure
What causes PCT?
Uroporphyrinogen decarboxylase deficiency
Symptoms of PCT?
Cutaneous- vesicles (crusting, pigmented, superficial scarring) on sun exposed sites
How is PCT diagnosed?
Increased urinary uroporphyrins + coproporphyrins + ferritin
How is PCT treated?
Avoid precipitants (alcohol, hepatic compromise), phlebotomy
Name 5 hormones released by the hypothalamus?
GHRH GnRH TRH Dopamine CRH
What action does GHRH have on pituitary hormones?
Stimulates GH
What action does GnRH have on pituitary hormones?
Stimulates LH/FSH
What action does TRH have on pituitary hormones?
Stimulates TSH and prolactin
What action does dopamine have on pituitary hormones?
Inhibits prolactin
What action does CRH have on pituitary hormones?
Stimulates ACTH
What does a combined pituitary function test (CPFT) involve?
Administration of LHRH, TRH and insulin then measurement at 0, 30, 60, 90 and 120 minute levels of pituitary hormones
When is a CPFT indicated?
Assessment of all components of anterior pituitary function used particularly in pituitary tumours or following tumour treatment
When is a CPFT contraindicated?
IHD
Epilepsy
Untreated hypothyroidism
What is an easy way to assess whether a pituitary adenoma is likely to be benign or aggressive?
Size
Microadenoma <10mm usually benign
Macroadenoma >10mm usually aggressive
What can a pituitary adenoma compress and subsequently lead to?
Optic chiasm -> bitemporal hemianopia
Which hormones are released from the neurohypophysis (posterior pituitary gland)?
ADH
Oxytocin
What are the causes of excess ADH?
Lung paraneoplasia- SCC, pneumonia
Brain- traumatic injury, meningitis, primary or secondary tumours
Iatrogenic- SSRIs, amitryptilline, carbamazepine, PPIs
What is diabetes insipidus?
Increased diuresis due to either failure of production (neurogenic) or insensitivity (nephrogenic) to ADH, leading to decreased urine osmolality and increased serum osmolality
What would you suspect if TFTs showed a raised TSH and low T4?
Hypothyroidism
What would you suspect if TFTs showed a raised TSH and normal T4?
Treated hypothyroidism or sub-clinical
What would you suspect if TFTs showed a raised TSH and T4?
TSH secreting tumour or thyroid hormone resistance
What would you suspect if TFTs showed a low TSH and high T3 and T4?
Hyperthyroidism
What would you suspect if TFTs showed a low TSH and normal T3 and T4?
Subclinical hyperthyroidism
What would you suspect if TFTs showed a low TSH and low T4?
Central hypothyroidism (hypothalamic/pituitary disorder)
What would you suspect if TFTs showed a raised (then later decreased) TSH and low T3 and T4?
Sick euthyroidism. Body tries to shut down metabolism as thyroid gland has reduced output
What causes of high uptake hyperthyroidism are there?
Graves disease
Toxic multinodular goitre
Toxic adenoma (hot nodule on isotope scan)
What is F:M ratio of Graves?
9:1
What causes of low uptake hyperthyroidism are there?
Subacute De Quervains thyroiditis (self-limiting post-viral painful goitre)- initially hyper then hypo
Postpartum thyroiditis
What autoimmune causes of hypothyroidism are there?
Primary atrophic hypoT
Hashimotos
What non immune causes are there of hypothyroidism?
Iodine deficiency (mr. Worldwide)
Post-thyroidectomy/radioiodine
Drug-induced- antithyroid drugs, lithium, amiodarone
How does primary atrophic hypothyroidism differ from Hashimotos?
Primary atrophic- diffuse lymphocyte infiltration + atrophy. No goitre so small thyroid. No known antibodies
Hashimotos- Plasma cell infiltration + goitre, elderly females, initial hashitoxicosis, auto-antibody titres raised
Treatment of hyperthyroidism?
Depends on aetiology.
Low uptake- symptomatic with beta blockers, NSAIDs for De Quervains
High uptake- BB + antithyroid therapy (carbimazole/propylthiouracil)
Can also use radioiodine or surgery
Why is propylthiouracil rarely used nowadays?
Risk of aplastic anaemia
Treatment of hypothyroidism?
Thyroid replacement therapy
Most common type of thyroid neoplasia?
Papillary
5 subtypes of thyroid neoplasia?
Papillary- >60% Follicular- 25% Medullary- 5% Lymphoma- 5% Anaplastic- Rare
Treatment of papillary thyroid neoplasia?
Surgery +/- radioiodine and thyroxine to decrease TSH
What might you see on histology of papillary thyroid neoplasia?
Psammoma bodies
What is medullary thyroid neoplasia linked to?
MEN2 (they also produce calcitonin)
What are the three different types of multiple endocrine neoplasia?
MEN1 (3Ps)- Pituitary, pancreas (insuloma), parathyroid
MEN2a (2Ps1M)- Parathyroid, phaeochromocytoma, medullary (thyroid)
MEN2b (1P, 2Ms)- Phaeochromocytoma, medullary thyroid, mucocutaneous neuromas (+ marfanoid)
