Chem Path Flashcards
Normal blood pH
7.35-7.46
Causes of metabolic acidosis
o Increased H+ production e.g., DKA
o Decreased H+ excretion e.g., renal tubular acidosis
o Bicarbonate loss e.g., intestinal fistula
Causes of respiratory acidosis
o Decreased ventilation
o Poor lung perfusion
o Impaired gas exchange
Causes of metabolic alkalosis
o H+ loss e.g., pyloric stenosis
- Also a raised urea, creatinine, total protein (dehydration)
- Low potassium, low chloride
o Hypokalaemia
o Ingestion of bicarbonate
Causes of respiratory alkalosis
Hyperventilation due to:
o Voluntary e.g., anxiety
o Artificial ventilation
o Stimulation of respiratory centre
Cystic Fibrosis diagnostic Ix (in neonate)
High blood immune reactive trypsin (IRT)
If IRT >99.5th centile in 3 bloodspots –> do 4 panel DNA mutation analysis
• 2 mutations = CF
• 1 mutation = 28 panel analysis
• 0 mutations = may repeat IRT at 21-28 days if IRT>99.9th centile
Specificity & sensitivity calculations
Sensitivity = true positive / total disease present
Specificity = true negative / total disease absent
Predictive value calculations
Positive predictive value = true positive / total positive
- NOTE: PPV depends on disease prevalence/incidence too!
Negative predictive value = true negative / total negative
Presentation of Organic Acidurias in neonate
Unusual odour e.g. cheesy/sweaty smell (in isovaleric academia) Lethargy Feeding problems Truncal hypotonia / limb hypertonia Myoclonic jerks
Differences in neonatal kidneys
Low GFR for surface area:
- slow excretion of solute load
- limited Na+ available for H+ exchange
Short proximal tubule –> low reabsorptive capability (but is usually enough for small filtered load)
Short Loops of Henle/distal collecting duct –> reduced ability to concentrate urine
Distal tubule relatively unresponsive to aldosterone –> persistent loss of Na+
Causes of Hypernatraemia in neonates
Uncommon after 2 weeks
Usually dehydration
Rare causes:
- Salt poisoning
- Osmoregulatory dysfunction
Most important cause of HYPOnatraemia in neonate
Congenital adrenal hyperplasia
lack of 21 hydroxylase
- -> build up of 17-OH progesterone
- -> absence of aldosterone + cortisol
Signs/Sx: o Hyponatraemia o Hyperkalaemia o Marked volume depletion o (+ hypoglycaemia) o Ambiguous genitalia in female neonates o Growth acceleration in older child
Causes of high UNCONJUGATED bilirubin in neonate
Early rise:
- High level of synthesis (RBC breakdown)
- Haemolytic disease – ABO, Rhesus incompatibility
- G6PD deficiency
- Crigler-Najjar syndrome - Low rate of transport into liver and 3. Enhanced enterohepatic circulation
- Biliary atresia, choledocal cyst
- Ascending cholangitis in TPN
- Inherited metabolic disorders
Prolonged jaundice (<14 in term, >21 in preterm)
- Prenatal infection / sepsis / hepatitis
- Hypothyroidism – screened at day 6-8 (Guthrie?)
- Breast milk jaundice
Key features Acute intermittent porphyria
Neurovisceral attacks
- abdo pain
- SIADH & hyponatraemia
- seizures
- sensory loss / muscle weakness
NO SKIN LESIONS
Precipitated by:
- medications: barbiturates, steroids, anti-convulsants
- alcohol
- stress: surgery, infection
- reduced calorie intake
Other Acute porphyrias (not acute intermittent)
Hereditary Coproporphyria
Variegate Porphyria
Both have acute neurovisceral attacks + skin lesions
Non-acute porphyrias
Congenital eryrthopoietic porphyria
- only skin lesions: blistering, fragility, pigmentation, erosions
- associated with Myelodysplasic syndromes
Porphyria cutanea tarda
- skin lesions: vesicles on sun exposed areas, crusting, superficial scarring, pigmentation
- PCT-like syndrome can be caused by hexachlorobenezene
Erythropoietic protoporphyria (EPP)
- skin lesions: NO BLISTERS, photosensitivity, burning, itching oedema after sun exposure
- associated with myelodysplastic syndromes
Important requirement for urine samples if suspecting acute porphyria
Protect from light!
Otherwise, Porphyrinogens oxidised to porphyrins then –> activated porphyrins + O2
Ix results in sick euthyroid
o Low T4 (when severe)
o High normal TSH (later becomes low)
o Low T3 and reduced T3 action
Ix results in subclinical hypothyroidism
High TSH
Normal free T4
TPO autoantibodies - if positive, can predict future thyroid disease
Ix results in thyrotoxicosis
- Low TSH
- High free T4, free T3
- Technetium scan - identify specific cause e.g. single toxic adenoma
Hyperthyroid treatment options
Beta blocker (if pulse >100)
Radioactive iodine
- Do NOT use if active thyroid ophthalmopathy
Surgery
- +/- potassium perchlorate before hand to prevent iodide uptake
Thionamides - e.g. Carbimazole, Propylthiouracil
- Block & replace OR titration regimes
- NOTE: can cause agranulocytosis - warn pt to stop meds if any sore throat/fever and check FBC!
Vitamin Deficiencies
A/retinol - Colour blindness
D/cholecalciferol - Osteomalacia/rickets
E/tocopherol - Anaemia, neuropathy, ?malignany/IHD
K/phytomenadione - Defective clotting
C/ascorbate - Scurvy
Folate - megaloblastic anaemia, NTDs
Niacin - pellagra
Iron - hypo chromic anaemia Iodine - Goitre, hypothyroidism Zinc - dermatitis Copper - anaemia Fluoride - dental caries
Vitamin Deficiencies
A/retinol - Colour blindness
D/cholecalciferol - Osteomalacia/rickets
E/tocopherol - Anaemia, neuropathy, ?malignany/IHD
K/phytomenadione - Defective clotting
C/ascorbate - Scurvy
Folate - megaloblastic anaemia, NTDs
Niacin - pellagra
Iron - hypo chromic anaemia Iodine - Goitre, hypothyroidism Zinc - dermatitis Copper - anaemia Fluoride - dental caries
Disorders of protein malnutrition
Marasmus • Shrivelled • Growth retardation • Severe muscle wasting • No subcutaneous fat
Kwashiorkor • More common at times of famine – carbohydrate remains but protein content reduced • Scaling/ulcerated • Lethargic • Large liver, subcutaneous fat • Protein deficient • Oedematous
Causes of SIADH
- CNS pathology – stroke, haemorrhage, tumour
- Lung pathology – pneumonia (esp Legionella), pneumothorax
- Drugs – SRRIs, TCA, opiates, PPIs, carbamazepine
- Tumours
- Surgery
- Acute intermittent porphyria
Treatment of hyponatraemia
If hypovolaemic: Volume replacement, 0.9% saline
If euvolaemic: Fluid restrict <750ml/day + Abx infusions + Treat underlying cause
- E.g. hydrocortisone + fludrocortisone in Addison’s
- E.g. levothyroxine in hypothyroidism
- E.g. Demeclocycline or Tolvaptan in SIADH
If Hypervolaemic = Fluid restrict <750ml/day + Treat underlying cause + Abx infusions
If severe (reduced GCS, seizures) = hypertonic 3% saline + seek expert help
The risk of rapid increase in serum sodium?
Central Pontine Myelinolysis
should not increase Na by more than 8-10mmol/L in first 24 hours
Osmotic shifts cause stretching of BBB endothelial cells –> inflammatory signals
Presents with:
- quadriplegia
- dysarthria
- dysphagia
- seizures, coma, death
Management of HYPERnatraemia
- Fluid replacement – 5% Dextrose
- Treat underlying cause
- Take serial Na+ measurements every 4-6 hours
If also hypovolaemic, give 0.9% saline to correct ECF depletion (alongside 5% dextrose to correct water deficit)
ECG changes in HYPERkalaemia
- Peaked T waves (Early)
- Broad QRS
- Flat P-wave
- Prolonged PR (+ bradycardia)
- Sine wave (latest)
Management of HYPERkalaemia
Tx if ECG changes of K+ ?6.5
- 10ml 10% calcium gluconate
- 100ml 20% dextrose (previously 50ml 50% dextrose) + 10U insulin
- Nebulised salbutamol
- Treat underlying cause
Management of HYPOkalaemia
If K+ 3.0-3.5
• Oral potassium chloride – 2 x SandoK tablets TDS for 48 hours
• Recheck serum K+
If K+ <3.0
• IV potassium chloride
- Max rate 10mmol/hour
• Rates >20mmol/hour = irritating to peripheral veins
+ Tx underlying cause
Management of HYPOkalaemia
If K+ 3.0-3.5
• Oral potassium chloride – 2 x SandoK tablets TDS for 48 hours
• Recheck serum K+
If K+ <3.0
• IV potassium chloride
- Max rate 10mmol/hour
- Rates >20mmol/hour = irritating to peripheral veins
+ Tx underlying cause
Diagnostic findings in Conn’s syndrome
HTN + Low K+
High aldosterone:renin ratio (aldosterone suppresses renin)
Normal response to combined pituitary function test
Glucose drops <2mM then recovers Cortisol reaches 450-550nM (>400) Growth hormone >10IU/L LH, FSH, TSH >10IU/L Prolactin stimulation
Treatment of (functioning) prolactinoma
Urgent hydrocortisone (Fludrocortisone not needed - adrenals make aldosterone independent of hypothalamic-pituitary axis)
Other hormone replacement:
- levothyroxine
- oestrogen
- GH
- Dopamine agonist e.g., Cabergoline or Bromocriptine to shrink prolactinoma
Clinical features of Acromegaly
- Headaches
- hyperhidrosis
- Large hands “spade like”
- Prominent supraorbital ridges
- Increased interdental spaces
- Macroglossia
- Prognathism
- Bitemporal hemianopia
- Often presents alongside increased prolactin?
Diagnostic Ix for Acromegaly
IGF-1 measurement = raised
Oral glucose tolerance test = paradoxical growth hormone rise after glucose given
MRI pituitary = visualise any adenoma
Treatment of acromegaly
Trans-sphenoidal surgery (if no lateral growth or involvement of blood vessels) \+/- Pituitary radiotherapy D2 receptor agonist e.g. Cabergoline Somatostatin analogues e.g. Octreotide GH receptor antagonist e.g. Pegvisomant
Osmolality equation
- (Na+, K+) + (Cl-, HCO3-) + Urea + Glucose
* OR just 2 x (Na+, K+) + Urea + Glucose – since do not know anion levels!
Anion gap equation
Na + K - Cl – HCO3
Normal range = 16-20mM
Diagnostic findings in DKA
Hyperglycaemia >11.0mmol/L
Ketonaemia >3.0mmol/L OR significant ketonuria (2+ on dip)
Acidosis HCO3- <15.0mmol/L AND/OR venous pH <7.3
MOA of diabetes drugs
Gliptins e.g., sitagliptin = DPP-4 inhibitors
Thiazolidinediones / glitazones e.g., Pioglitazone = bind to peroxisome proliferator activated receptor-gamma in adipocytes –> maturation of fat cells + reduced circulating fat –> improved insulin sensitivity
Biguanides e.g. metformin = inhibit conversion of lactate to glucose in liver
T2DM diagnostic criteria
Fasting plasma glucose > 7.0mM OR
Glucose tolerance test (75 grams given at time 0) plasma glucose > 11.1mM at 2 hours OR
HbA1c > 48
NOTE: impaired glucose tolerance is 2-hour value 7.8-11.1mM OR HbA1c >42
Summary of adrenal disease
Addison’s
- low Na
- high K+
- hypotension
- Ix = short SynACTHen –> low cortisol
- Tx = corticosteroid replacement
Phaeo
- HTN
- Ix: urine + serum metanephrines (catecholamines, normetanephrines)
- Tx = alpha blockade, beta blockade, surgery
Conn’s
- high Na
- low K
- HTN
- Ix: HIGH aldosterone: renin ratio
- Tx: adrenalectomy OR aldosterone antagonist
Cushing’s
- centripetal obesity, inter scapular fat pad, bruising etc.
- DM, HTN
- low K
- Ix:
- - 9am + 12am plasma cortisol –> HIGH
- - low dose dexamethasone suppression test –> not suppressed
- - IPSS (pituitary sampling) to identify cause - Tx: Treat cause e.g. stop steroids, remove tumour
Normal GFR
120mL/min
Diagnostic criteria for AKI
- Increase in serum creatinine by >26mmol/L within 48 hours OR
- Increase in serum creatinine to 1.5x baseline within 7 days OR
- Urine output <0.5ml/kg/hour for 6 hours
Stages of AKI
Stage 1
- Increase in serum Cr by ≥26 micromol/L OR by 1.5 to 1.9x the ref serum Cr
- UO <0.5ml/kg/hour for 6-12 hours
Stage 2
- Increase in serum Cr by 2-2.9x ref serum Cr
- URO <0.5ml/kg/hour for ≥12 hours
Stage 3
- Increase in serum Cr by ≥354micromol/L OR ≥3x ref serum Cr
- UO <0.3ml/kg/hour for ≥24 hours OR anuria for ≥12 hours
Pre-renal causes of AKI
Generalised reduction in tissue perfusion or selective renal ischaemia
+ failure of adaptive mechanisms to maintain renal percussion
- true volume depletion
- hypotension
- oedematous states
- selective renal ischaemia
- drugs affecting glomerular blood flow - NSAIDs, calcineurin inhibitors, ACEi, ARB, diuretics
Renal causes of AKI
Abnormality of any part of nephron
• Vascular disease – vasculitis
• Glomerular disease – glomerulonephritis
• Tubular disease – acute tubular necrosis (most common!) from
untreated pre-renal AKI or endogenous/exogenous toxins
• Interstitial disease – analgesic nephropathy
Post-renal causes of AKI
Physical obstruction to urine flow
- Intra-renal obstruction
- Ureteric obstruction – bilateral
- Prostatic/urethral obstruction
- Blocked urinary catheter
Indications for emergency dialysis in AKI
- (Metabolic) acidosis
- Refractory hyperkalaemia
- Lithium, aspirin ‘intoxication’
- Pulmonary oedema
- Uraemic encephalopathy, pericarditis
Definition/Criteria for Chronic kidney disease
Abnormalities of kidney function ≥ 3 months with implications for health
Longstanding decline in GFR (<60) OR 1 of:
• Albuminuria / proteinuria
• Urine sediment abnormalities e.g., haematuria
• Electrolyte abnormalities
• Histological abnormality
• Structural abnormalities (on imaging)
• Hx kidney transplant
Stages of CKD
G1: GFR >90 with evidence of kidney damage
G2: GFR 60-89
G3a: GFR 45-59
G3b: GFR 30-44
G4: GFR 15-29
G5: GFR <15
Most common causes of CKD
- Diabetes!!
- Atherosclerotic renal disease
- HTN
- Chronic glomerulonephritis
- Infective or Obstructive nephropathy
- Polycystic kidney disease
Progression of Uraemic cardiomyopathy (in CKD)
LV hypertrophy
LV dilatation
LV dysfunction
Indications for dialysis in CKD
o Intractable hyperkalaemia o Acidosis o Uraemic Sx – nausea, pruritis, malaise o Therapy-resistant fluid overload o CKD Grade 5
Patterns of LFT abnormalities
High ALP + GGT (ALP»_space;) = biliary obstruction e.g. gallstones, HOP ca.
GGT > ALP = recent ETOH intake
ALP > GGT = pregnancy? osteomalacia (if PTH high), Paget’s disease (if osteocalcin high)
AST + ALT high = hepatocyte damage
- AST rises most (>ALT) = alcoholic hepatitis / cirrhosis
- ALT rises most (>AST) = viral hepatitis
Tumour markers
Ca125 = ovarian
Ca19-9 = pancreatic, cholangiocarcinoma
acid phosphatase / PSA = prostate
CEA = colorectal
AFP = testicular ca. (teratoma), hepatocellular ca.
Treatment of acute gout
NSAIDs
colchicine - inhibits polymerisation of tubular –> less neutrophil motility –> less inflammation
Glucocorticoids - oral or intra-articular injection
Do NOT attempt to alter plasma urate concentration - can cause further precipitation of crystals!
Microscopy of crystal arthropathies
Gout (monosodium urate)
- negative birefringence (yellow when parallel to compensator, blue when perpendicular)
- needle shaped
Pseudogout (calcium pyrophosphate)
- weak positive birefringence (blue when parallel to compensator)
- rod or Rhomboid shaped
Pathophysioloy & key features of Lesch Nyhan syndrome
X linked
Complete deficiency of H(G)RPT enzyme
No recycling of hypoxanthine or guanine to IMP/GMP
Normal at birth BUT then
- developmental delay, mental retardation
- spasticity
- hyperuricaemia
- choreiform movements ~1 year
- self mutilation, aged 1-16yrs (affects 85%)
Pathways of purine synthesis
De novo
- metabolically difficult
- inefficient
Salvage
- recycles purine catabolites
- predominates in most tissues EXCEPT bone marrow
- highly efficient
Rate limiting step of Purine Metabolism
PAT
- Negatively regulated by AMP & GMP (end products of purine synthesis)
- Also subject to positive feed-forward effect by PPRP
Transport of thyroid hormone
75% thyroid binding globulin
20% TBPA
5% Albumin
0.03% free T4
