Chemical Pathology Flashcards
Rise in Troponin is specific to heart but not specific to cause
Non MI myocardial injury:
- myocarditis
Multifactorial myocardial injury:
- pulmonary embolism
Serial measurement of cardiac Troponin
0, 3, 6 hours
If initial levels negative —> additional measurements
Still negative —> exclude AMI
Rise is bigger in MI than myocarditis
Chronic heart failure —> no rise/fall
Definition of MI
- Cardiac markers + symptoms / ECG/ imaging/ intracoronary thrombus
- at least one cardiac marker > 99th percentile of upper reference limit
5 types of MI
Type 1: secondary to plaque
Type 2: not due to ACS (coronary spasm, embolism)
Type 3: sudden cardiac death (no biomarker)
Type 4: procedure related (PCI)
Type 5: coronary artery bypass grafting
Approach to cardiac marker abnormality
- Test validity
- level and trend
- relationship too symptom
- exclude non-AMI cause
- consider AMI cause
- acute / long term treatment
- monitoring
Rising may not duet to AMI Late presentation of MI may not appear to be changing (near peak / gradual down) Analytical interference (use other instrument)
3 major natriuretic peptide
ANP (from atria):
—> response to pressure / volume overload —> natriuresis, oppose RAAS
BNP (from ventricle):
—> response to cardiac wall stretch —> natriuresis, reduce preload
—> BNP + NTproBNP (byproduct)
—> diagnose ***heart failure who present acutely with dyspnea
—> identify cardiac involvement
—> prognostic marker in HF, ACS (high BNP —> poorer prognosis)
—> monitor drug therapy
CNP (vascular endothelium):
—> regulate vascular tone
Criteria for valid Therapeutic Drug Monitoring (TDM)
- Poor correlation between dose and effect
- Narrow therapeutic window
- Absence of good clinical marker of effect
- Good correlation between plasma concentration and effect
Drugs need TDM
Digoxin
- 2 compartment
- high volume of distribution —> distribute mainly in tissue
- blood concentration correlate with effect after 6-8 hours
- collection time (minimum 8 hours, prefer 12 hours)
- renal excreted
- 0.5-2.0 ng/mL (critical value: 2.5)
- toxicity: arrhythmia, nausea, vomiting
- **- hypokalaemia, hypomagnesemia, hypercalcemia, impaired renal function enhance toxicity
- activated charcoal, Digibind (Digoxin-specific antibody), haemodialysis not effective since distribute in tissue
- immunoassays may not be accurate: Interference: Digoxin-like immunoreactive substance (DLIS), Megdigoxin, steroid, Spironolactone
Pharmacogenetics of Clopidogrel
- pro-drug —> convetered to active metabolite (inhibit ADP P2Y12 and plate activation)
- 2C19:
*1 —> wild type
*2 —> no activity
3 —> no activity
(2 and *3 account for almost all poor metabolisers in Asian) - 2 defective copies of allele may not achieve therapeutic effect
—> increase dose / switch to other drugs - 1 defective copy —> increase dose
Urine analysis
- Macroscopic:
- colour: red —> haemoglobin, myoglobin, drugs, food
- turbidity
- volume - Microscopic:
- casts (ligh chains)
- crystals
- bacterial staining / cultrue
- chyle (lymph due to inflammation of glomerulus) - Chemical analysis (urine dipstick)
- limitations: pathologic vs non-pathologic cause of abnormal urine dipstick
- false-positive vs false-negative
Urine pregnancy test
Lower limit of detection (high sensitivity)
Urine hCG: 25 mIU/mL
Blood hCG:
- Non-pregnant: <5
- 0.2-1 week: 5-50 mIU/L
- Every week increase 10x
False positive:
- early miscarriage
- missed reaction time (sit for too long —> do not wait till +ve)
- drugs: hCG shot for infertility treatment
- faint evaporation line
- abuse of drugs
Urine sample collection
- spot
- timed (24 hour: first void in morning discarded, subsequent collect every void)
- midstream
- Creatinine clearance
- 24 hour urine collection CrCl:
urine creatinine x urine volume / plasma creatinine x time
Cerebrospinal fluid
- from Choroid plexus
- clear fluid with NO cells
- precious sample
- procedure for CSF collection
1. Four tubes under aseptic technique (needle into spine)
2. Each tube 2-4ml
3. Send promptly within 1 hour
4. Do not refrigerate
Analysis:
- colour/ appearance: blood, turbidity, xanthochromia
- open pressure measurement
- chemical analysis (lactate)
- immunological (antibodies)
- anatomical pathology (cytology)
- high protein —> life-threatening —> protein leak through BBB
- low glucose —> consumed by bacteria
Pleural fluid
- 30ml normally
Chemical analysis:
- pH
- LDH
- protein
- TAG (chylothorax)
Transudate = total protein < 30g/L
- **Exudate: (1 of 3 criteria)
- pleural fluid:serum total protein > 0.5
- pleural fluid:serum LDH > 0.6
- pleural fluid LDH > 2/3 upper normal limit of LDH
Pleural adenosine deaminases (ADA) activity: good test
- Tuberculosis: high
- Empyema: low
Factors affecting result interpretation
- Pre-analytical
- patients factors (correct patients, age, gender, diet, drugs)
- sampling factors (storage time, sampling time, specimen type) - Analytical
- correct test on correct specimen
- performance of test (accuracy, imprecision, sensitivity, specificity) - Post-analytical
- transcription, computer data uploading
- appropriate reference interval
Reference interval
- **Reference interval: represent central 95% of reference individuals
- Values derived from distribution of results obtained from reference population (healthy individuals)
- usually 2 values (upper and lower reference limit)
Reference individuals —> population —> sample group —> values —> distribution —> limits —> intervals
- Parametric: Mean +/- 2 SD (95.4% within 2SD, assume Gaussian distribution)
- Non-parametric: 2.5th and 97.5 percentile (95% included, no assumption of distribution)
Blood analyses requiring partitioning of reference intervals
Age: Growth hormone
Gender: Testosterone, oestrogen
Posture: Renin, aldosterone
Diet: glucose, TAG
Inter vs Intra-individual variation
Intra:
- biological variation: e.g. progesterone level
Inter:
- between individuals
Narrow intra-individual variation —> inter-individual less sensitive than intra-individual variation (睇inter-individual無意思, 睇intra-individual先有用)
Clinical decision limits
- **- dividing lines between normal and diseased
- **- consensus value / predictive value
- usually one value, without confidence interval
- may change with time (reference intervals will not)
- can be distinct from reference limits
- useful for integrating test results for diagnosis and clinical management
- Bayesian approach (e.g. Troponin) —> based on:
- definition
- pathogenesis
- sensitivity of test
- specificity of test
- prevalence
- clinical costs for misclassification - Epidemiological approach (e.g. cholesterol, glucose) —> based on:
- population studies
- national guidelines / consensus
- outcomes studies showing different level of survival with concentrations above or below limit - Pathophysiological approach —> based on:
- critical values —> life threatening situation
- arbitrary
- clinical experience
- without support of statistical mean
Positive predictive value, Negative predictive value, Sensitivity, Specificity
PPV = True positive / All positive
NPV = True negative / All negative
Sensitivity = True positive / All disease —> ability to pick up all diseased people
—> high sensitivity —> high NPV (very few false negative)
Specificity = True negative / All healthy —> ability to exclude normal people
—> high specificity —> high PPV (very few false positive)
Likelihood ratio
LR+ = P(+ve test in diseased) / P(+ve test in normal people)
—> Sensitivity / 1-Specificity
LR- = P(-ve test in diseased) / P(-ve test in normal people)
—> 1-Sensitivity / Specificity
Receiver Operating Characteristic Curve (ROC)
Performance of 2 different tests can be compared
—> by plotting sensitivity against (1-specificity)
- Better the test curve lies above and left
- Larger AUC
