Organ Function Testing PDF

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Organ Function Testing...

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Organ Function Testing, Screening and Therapeutic Drug Monitoring Uses of Biochemical Tests:  Diagnosis – e.g. a specific tests sensitive to a disease provides conclusive evidence towards certain condition  Management o Progression of disease o Response to treatment o Recurrence of disease  Screening – detection in asymptomatic individuals o Population – e.g. newborn screening o Selected groups – e.g. obese patients for type 2 diabetes mellitus o Individual – familial hypercholesterolemia Biomarkers - e.g. genetic, proteins, enzymes, molecules anything with a detectable change  Biochemical tests use biomarkers  Usually measure in blood (easy to take) but can be in urine, faeces or CSF  Biomarkers can be enzymes, other proteins, metabolites or hormones  Ions or gases are often also measured in clinical biochemistry An example of how serum proteins / enzymes can be used as biomarkers In normal tissue the cell membrane is intact and enzyme escapes due to normal cell turnover. When the membrane is damaged high levels of this enzyme are released out of the tissue and into the blood stream. Once in the blood stream it is now detectable Problems with this approach  Unsure of the basal level, reference ranges help but individuals can be different  Increased cell number can lead to increased enzyme presence. Doesn’t have to be damage  Anything that increases the levels of enzyme will also increase the level of it in the blood =, again not related to damage Serum proteins / enzymes as biomarkers  Increased serum enzyme activity does not always mean cell damage o Maybe hyper proliferation o May be induction (synthesis of more enzyme) o Some instances of induction can be diagnostically useful.  Same argument applies to non-enzyme proteins in the serum e.g. albumin o Many of these are normally secreted Ideal protein biomarkers should be:  Tissue specific  Rapid release in response to damage and not too short a half life  Very low in serum of normal individual  Easily measured with clear universal reference values  If these criteria are difficult to achieve use a battery of tests to make a profile. Metabolites as biomarkers – products of metabolism

They are useful to assess the function of the organ that produces them, however many of them aren’t organ specific. The concentration in serum may depend on uptake by other tissues and / or excretion by the kidney. Metabolites are metabolically useful, tend to be made for a reason, because of this they may get taken up. E.g. if a cell is lysed it will release loads of glucose and pyruvate. These aren’t useful as markers as other cells will take them up and use it. The various assays of serum biomarkers – should be simple, cheap and rapid  Spectrophotometric methods measure the activity of serum diagnostic enzyme. o The colour change in response to a reaction. Add a reagent to sample and colour change occurs. o Normally used for enzymes! o The beer lambert law expressed as IU/l (international units per litre)  Immunoassay will measure the amount of enzyme or other protein e.g. mg/l o E.g. Elisa using antibodies o This quantifies amount, not activity  Metabolites are expressed as concentration and are usually measured by Spectrophotometric methods Reference ranges are commonly used to identify abnormal results Population-based reference ranges are the most common means of establishing a range. It uses the local population and eliminates some social, genetic and environmental variables such as age gender race diet and genetics As well as defining established variables exclusions should be made e.g for risk factors such as obesity and hypertension. For drugs use e.g. alcohol and oral contraceptives and for certain physiological conditions such as pregnancy, stress and excessive exercise. How to make a reference range  Gather values o Patients consent o Sample collection o Specimen storage and analysis o Partition if necessary  Inspect and apply data o Easiest if data are normally distributed (bell shaped curve around the mean)  A result greater than 1.96 S.D. above below the mean is considered abnormal  This is 95% of population in normal

Advantages of reference ranges

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Simple – is the value within the range? Easily sourced – websites, textbook, report forms o Beware of variations, groups, hospitals, local population Easily utilised – but sometimes without due thought

Disadvantages  Statistical significance may not reflect clinical significance  May be derived from inappropriate population  Biological variability – 2.5% of people will be out of the range just because that is where they lie within the normal distribution Effectiveness of tests – needed when creating a new test How good is a particular test at providing diagnosis and does an abnormal result actually mean anything? If we had a gold standard test that always gives the correct results possible results are  True positive: positive test and subject has disease  False positive: positive test and subject doesn’t have disease  True negative: negative test and subject doesn’t have disease  False negative: negative test and subject has disease – worst case Sensitivity = The proportion of patients who have the disease who give a positive test. (How good the test is at correctly identifying people with the disease)

Specificity = the proportion of patients without the disease that give a negative test (how good the test is at identifying patients without disease)

In an ideal world for a gold standard test you would have 100% for both. Always right!! Aim for >90% Raising the cut off will increase the specificity as false positives will reduce but there may be many false negatives and the sensitivity will fall

Applications of these tests Newborn screening – heel prick test  Population screen must be highly sensitive (detect all disease), highly sensitive don’t want any false negatives  Outcome is always further investigation o Can tolerate false positives, better than false negative o However, these may causes distress  What it can test for

Testing for cystic fibrosis  In babies with CF mucus can block the ducts from the pancreas to the small intestine

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o Immunoreactive trypsin (IRT) levels increase Increased IRT in blood can be detected after 1-2 weeks with heel-prick test using an immune assay (measures concentration in blood) Not all babies with IRT will have CF (false positive) Further investigation by sweat testing or genetic analysis

Therapeutic drug monitoring – common application  Necessary when drugs have a narrow therapeutic window e.g. warfarin too much bleed to death, too little still at risk o Wide and narrow therapeutic windows  Assume relationship between concentration of the drug in the blood and clinical effect...