Clinical Pathology use of laboratory tests to diagnose disease

Indications: to confirm a clinical impression - example, in infection, you perform blood test to establish diagnosis - there are certain laboratory examinations which are very distinctive for a particular disease to monitor therapy example in diabetes, to find out sugar content of the drugs to establish prognosis - tumor marker 1. DIAGNOSIS DEPENDS ON HISTORY determination listening and observing the patient are the to screen or detect disease - screening Hepa best procedures for information gathering to examinations formulate a differential diagnosis always be mindful of your patients comfort Terminal Competencies and dignity; treat patient as a human being *In doing clinical laboratory examinations, you are instead of making them like laboratory expected to have certain competencies as follows: experiments. identification of appropriate examinations for diagnosis, confirmation and guide to 2. LABORATORY MEDICINE IS AN ADJUNCT management TO DIAGNOSIS interpretation and translation of laboratory do not depend on laboratory alone, still you examinations in the light of patients depend on the knowledge you gained from medical problem med school. promotion of the understanding and clarification of pathophysiology or natural 3. LABORATORY EXAMINATION RESULTS ARE NOT INFALLIBLE history of disease as reflected by the clinical pathology data machines sometimes could give you wrong results recognition of pitfalls, problems and limitations of laboratory data there are problems occurring between the pathologist and the clinician appreciation of the importance of examinations for efficient and costeffective medical and health care delivery INTERPRETATION OF LABORATORY TEST result is much more complicated than * use laboratory wisely to document the impression simply comparing the test results against a * all in all, in clinical examination you have to so-called normal range, labelling the test choose the best examination for your patient: value normal or abnormal according to the - some of laboratory examinations are normal range limits then fitting the result expensive into patterns that indicate certain diseases. - not all laboratory examinations are the laboratory examinations is a infalliable. confirmatory test which tells you to confirm the diagnosis. It is not the lab examinations Medical models that give you diagnosis but your history. ANATOMY - learn where all the bits are PHYSIOLOGY AND BIOCHEMISTRY - find out how they work

PATHOLOGY -observe the sort of things that go wrong CLINICAL MEDICINE - note carefully the signs and symptoms MEDICINE - readjust physiology and suppress pathology SURGERY -intervene by repairing anatomy and removing pathology

Basic Considerations

1. Sensitivity the ability of the test to detect patients with some specific disease ( i.e. , how 6. Normal (reference) ranges often false negative results are most important in laboratory examinations encountered ). Gaussian (homogenous symmetric) value In considering specimens, it is the ability distribution of the analytical procedure to measure small amounts of a component in a Problems derived from use: specimen. 1. Clinically normal persons with undetected or sub-clinical disease may be included 2. Specificity 2. Statistical reliability of sample size describes how well test abnormality is 3. Source of sample population from which restricted to those persons who have the normal range has been calculated may not be disease in question (i.e., how often false representative of the population to be tested. positive results are produced). (larger sample size, the better) In the specimens, is the ability of an 4. Normal values obtained by one analytical analytical procedure to measure accurately method may be inappropriately used with one component in a specimen without another method. interference by other also present 5. Population values may not be randomly distributed and be skewed toward one end. high specificity is a lot better than high sensitivity Physiologic Variables 3. Predictive Value normal metabolic alteration age dramatizes the fact that the smaller the sex number of persons with a certain disease race in the population being tested, the lower will be the proportion of persons with change in posture abnormal test result who will be biologic diurnal effects abnormal because they have the disease in pregnancy question. It is employed to evaluate a positive result Effects of Medications drug- induced injury to organ functions 4. Accuracy most common is the liver because most of correctness of a measurement, or the the drugs are metabolized in the liver. closeness with which the measurement drug competition effects comes to the true value - affinity of the drugs expressed quantitatively by the mean error drug interference with analytical methods which is the difference between the average of a series of test results and the true result Effects of Hospital Working Conditions intravenous fluids running at the time of 5. Reproducible (PRECISION OR INHERENT extraction ERROR) effect of heparin flushes measures how closely the laboratory can drug administrations approach the same answer when the test defective communication between performed repeatedly on the same physician and laboratory specimens

expressed mathematically by the standard deviation or by the coefficient of variance used for quality assurance

Serum Proteins transferrin Plasma: blood minus formed elements hemopexin Serum: blood minus formed elements and vit. D binding globulin fibrinogen (What kind of information is obtained from protein Serum proteins: albumin and globulin fractionation?) serum protein + lipids = lipoproteins Classification According to Functions serum protein + carbohydrate = I. Acute Phase Reactants (Complements) glycoproteins haptoglobulin total serum proteins = 6.5 -8.0 ceruloplasmin gms/100ml (wherein albumin is 4-6gms/100ml and globulins: C-reactive proteins 1-3gms/100ml) antithrombin III II. Carrier Proteins (Immunoglobulins) Methods of Fractionating Serum Proteins prealbumin, albumin a. "salting out" techinique transferin b. chemical fractionation hemopexin c. ultracentrifugation TBG, CBG (transcortin) d. electrophoresis e. immunoassay Globulins radial immunodiffusion Alpha 2 immunephelometry haptoglobulin Laurell "rocket" ceruloplasmin electroimmunodiffusion macroglobulin immunofluorometry Alpha 1 radioimmunoassay a1-antitrypsin f. immunoelectrophoresis TBG transcortin (LDL) Albumin Functions a1 fetoprotein maintains serum oncotic pressure a1 lipoprotein transport of substances dissolved in plasma c1 inhibitor bilirubin Gamma globulins fatty acid Beta Globulins cortisol b1 transferrin thyroxin b1 CompC C3 drugs (b1) hemopexin sulfonamides b2 lipoptrotein barbiturates comp c1q, c2 salicylates Globulin Functions active role in immunologic mechanisms immunoglobulins complement acute phase reactants transport system for substances haptoglobulin

pattern) decrease albumin, moderate increased gamma globulin polyclonal gammopathy IV. Monoclonal Gammopathy (M-spike, paraprotenemia) decrease albumin, thin narrow-based spike at gamma seen in MM, Waldenstrom macroglobulinemia idiopathic monoclonal gammopathy

Indications for Serum Protein Electrophoresis Suspected multiple myeloma, Waldenstrom's macroglobulinemia, primary amyloidosis, or related disorder Unexplained peripheral neuropathy (not attributed to longstanding diabetes mellitus, toxin exposure, chemotherapy, etc.) New-onset anemia associated with renal failure or insufficiency and bone pain. Back pain in which multiple myeloma is suspected. Hypercalcemia attributed to possible Typical Electrophoretic Patterns malignancy (eg. Associated weight loss, I. Acute Reaction/Stress/Immediate fatigue, bone pain, abnormal bleeding) Response Pattern Rouleaux formations noted on peripheral decreased albumin, elevated a2 blood smear globulin Renal insufficiency with associated serum II. Chronic Inflammatory Pattern protein elevation slight to moderate decrease albumin Unexplained pathologic fracture or lytic slight elevation to N a2 globulin region lesion identified on radiograph slight to moderate elevated gamma Bence Jones proteinuria globulin Acute Phase Reaction Proteins III. Hepatic Cirrhosis Pattern (Far advanced synthesized in the liver by stimulation of

cytokines increased in inflammation a1, a2, haptoglobulin and ceruloplasmin if with increase in gamma fractions**, considered as chronic inflammation

Hypogammaglobulinemia may result from lack of production, excessive loss of immunoglobulins, or both. Congenital disorders affecting B-cell development can result in complete or partial absence of one or more Ig isotypes. The classic form of this type of disorder is Bruton gammaglobulinemia, also known as Xlinked agammaglobulinemia(XLA) IgA deficiency is the most common antibody deficiency syndrome, followed by common variable immunodeficiency (CVID). Extracorporeal Albumin Leakage Alpha 1-antitrypsin deficiency (a1-antitrypsin Protein leakage from urine or GIT in nephrotic syndrome increased a2 fraction deficiency, A1AD or simply Alpha-1) is an autosomal co-dominant genetic disorder caused by because both macroglobulin and haptoglobulin do not leak and remain in the defective production of alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity in the blood and blood lungs, and deposition of excessive abnormal A1AR protein in liver cells.

Lipoproteins Polyclonal increase chylomicrons chronic inflammation and cirrhosis very low density lipoprotein (VDL) Monoclonal increase low density lipoprotein disease that produce an increase in the high density lipoprotein gamma-globulin level include Hodgkin's disease, malignant Serum Cholesterol lymphoma, chronic lymphocytic major component of LDL and minority leukemia, granulomatous diseases, component of HDL/VLDL connective tissue diseases, liver associated with risk of diseases, multiple myeloma, ATHEROSCEROSIS (Framingham Study) Waldenstrom's macroglobulinemia, and Relative CHD Risk Total Serum Cholesterol amyloidosis. mg/100ml mmol/L - linking (bridging) beta-gamma bridging ( - bridging) on average risk 150 3.9 serum protein electrophoresis is touted Average risk 225 5.85 as being virtually pathognomonic for 2x average risk 260 6.7 hepatic disease. 3x average risk 300 7.75 Multiple Myeloma Mprotein appears as a narrow spike in the National Cholesterol Education Program gamma, beta or alpha2 regions. Criteria to Screen CHD M-protein level is usually greater than Total LDL 3g/dL Cholesterol Cholesterol skeletal lesions (eg. Lytic lesions, diffuse (mg/100ml) osteopenia, vertebral compression fractures) Desirable Less than 200 Less than 130 are present in 80% of patients. (5.15mmol) (3.36) Diagnosis is requires 10 to 15 percent plasma cell involvement on bone marrow Borderline 200-239 (5.6 130-159 (3.36 biopsy. 6.18) 4.11) Anemia, pancytopenia, hypercalcemia, and High total More than 240 More than 160 renal disease may be present. (6.20) (4.14) Low Density Lipoprotein better correlation with risk of ATHEROSCEROSIS

FRIEDWALD FORMULA LDL = Total cholesterol minus (HDL- Trigylcerides/ 5) High Density Lipoproteins strong inverse correlation with risk of atherosclerosis for every decrease of 20mg/100ml of HDL double the risk for ATHEROSCEROSIS

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