Clinical Information

Kindly click any of the tests below for more information. For information on tests not listed here, kindly contact the relevant Manager under Our Operations Team or view our Medical Articles page.

 

Full Blood Count
The interpretation of the indices measured is complex and the notes below are given as a brief and general description only. If there are significant abnormalities detected when measuring these indices then examination of a peripheral blood film is required to complete the interpretation.

  1. Haemoglobin (Hb)
    Anaemia is defined as haemoglobin below normal for age and gender. Further investigation of the cause of anaemia is guided by clinical features, blood film and red cell indices (MCV, MCH, MCHC). The Hb is elevated in erythrocytosis.
  2. Red Cell Count (RCC)
    Interpretation is required to be made in conjunction with the other red cell parameters below.
  3. Packed Cell Volume (PCV)
    PCV is reduced in anaemia and increased in erythrocytosis. In patients with erythrocytosis the PCV correlates with blood viscosity.
  4. Mean Cell Volume (MCV)
    Macrocytosis (high MCV) is found in:
    • Megaloblastic, aplastic, dyserythropoietic and sideroblastic anaemias
    • Myelodysplastic syndromes, myeloma; liver disease, alcohol excess
    • Chronic hypoxic lung disease
    • Myxoedema; following renal transplant
    • Cytotoxic drug therapy particularly hydroxyurea, therapy with Zidovudine (AZT).

    Microcytosis (low MCV) is found in:
    • Iron deficiency
    • Anaemia of chronic disease
    • Haemoglobinopathies (especially the thalassaemias).
  5. Mean Cell Haemoglobin (MCH)
    Arithmetically, MCH is Hb divided by RCC. The MCH is increased in macrocytic anaemias and decreased in microcytic anaemias. If the MCH is significantly abnormal then a blood film should also be requested.
  6. Mean Cell Haemoglobin Concentration (MCHC)
    Arithmetically, MCHC is Hb divided by PCV. There is a rough correlation between low MCHC and hypochromia and between high MCHC and the presence of spherocytes.
  7. Red Cell Distribution Width (RDW)
    The RDW may assist in the classification of anaemia, in association with the blood film, and the other red cell indices (MCV, MCH and MCHC). The RDW gives a quantitative assessment of the degree of variation in red cell size / volume (anisocytosis).
  8. White Cell Count (WCC/TWDC)
    The interpretation is required to be made in conjunction with the differential count of white cells below.
     
    1. Neutrophils
      Neutrophilia (increased) may be caused by:
      • Physiological stress e.g. physical, emotional, pregnancy.
      • Infection especially bacterial or fungal.
      • Inflammation e.g. connective tissue disease, arthritis.
      • Tissue necrosis e.g. myocardial infarction, carcinoma.
      • Blood loss - both acute and chronic.
      • Haemolytic anaemia.
      • Myeloproliferative disorders.
      • Splenic atrophy/absence.
      • Drug therapy e.g. corticosteroids, cytokines, lithium.

      Neutropenia (decreased) may be caused by:
      • Decreased production

      • Drug reactions such as cytotoxic drugs (usually pancytopenia) or NSAID, Sulphonamides, Carbimazole, Clopidogrel, Clozapine.
      • Bone marrow failure (usually pancytopenia), acute leukaemia, myelodysplasia.
      • Megaloblastic anaemia (usually pancytopenia)
      • Chronic idiopathic neutropenia.
      • Hereditary/Constitutional such as cyclic neutropenia, Schwachman syndrome, Chediak-Higashi syndrome, Diamond-Blackfan syndrome

        Increased destruction and/or margination
      • Autoimmune diseases such as SLE, rheumatoid arthritis
      • Drug reactions e.g. Captopril, Penicillins
      • Hypersplenism
      • Haemodialysis
      • Idiopathic

        Decreased production and increased destruction
      • Viral infection e.g. infectious mononucleosis, HIV
      • Bacterial infections e.g. Septicaemia, typhoid fever (The neutrophil count is variable in severe bacterial infection, but neutropenia is common, especially in neonates and in patients with Gram-negative septicaemia).
      • Protozoal infection e.g. malaria
      • Hairy Cell Leukaemia
    2. Lymphocytes
      Lymphocytosis (increased) may be caused by:
      • Mononucleosis syndromes such as infectious mononucleosis, CMV infection, Toxoplasmosis
      • Other viral infections
      • Chronic lymphocytic leukaemia, prolymphocytic leukaemia, lymphoma (non-Hodgkin’s), Hairy Cell Leukaemia
      • Splenic atrophy/absence following physical trauma

      Lymphocytopenia (decreased) may be caused by:
      • Bacterial infection
      • Early stage of viral infection
      • Carcinoma
      • Irradiation
      • Drugs especially corticosteroids and cytotoxics
      • HIV infection
      • Hodgkin’s disease
      • Malnutrition
      • Renal Failure
      • SLE
      • Cushing’s syndrome
      • Sarcoidosis
      • Protein losing enteropathy
    3. Monocytes
      Usually low numbers – monocytosis (increased) may be associated with acute or chronic bacterial infection, carcinoma, Hodgkin’s disease, cytokine administration, splenic atrophy/absence or monocytic leukaemias.
    4. Basophils
      Usually low numbers – basophilia (increased) may be associated with myeloproliferative disorders or in reactive disorders such as hypothyroidism, ulcerative colitis, hypersensitivity states and together with idiopathic hypereosinophilic syndrome.
    5. Eosinophils
      Usually absent or low numbers – eosinophillia (increased) is usually associated with allergic reactions to drugs or conditions such as eczema, asthma, food allergy and psoriasis. Eosinophillia may also be seen with some parasitic infections and with Aspergillosis.
    6. Platelets
      Thrombocytosis (increased numbers) may be caused by:
      • Polycythemia Vera
      • Post-Splenectomy syndrome
      • Primary thrombocytosis
      • Certain malignancies
      • Early CML
      • Anaemia

      Thrombocytopenia (decreased numbers) may be caused by:
      • Increased usage as in disseminated intravascular coagulation
      • In association with haemorrhagic disease such as dengue or haemolytic anaemia
      • Idiopathic Thrombocytopenic Purpura (ITP)
      • Leukemia
      • Prosthetic heart valve
      • Massive blood transfusion
      • Chemotherapy

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Erythrocyte Sedimentation Rate (ESR)
ESR is a non-specific indicator of inflammatory and neoplastic disease (C-reactive protein is a more sensitive early indicator of an acute phase response). A normal ESR does not exclude active disease.
The ESR increases with age, is raised in pregnancy and anaemia; mild to moderate elevations should be interpreted with caution in these situations. It is increased in acute and chronic inflammatory disease and in neoplastic disease.
The ESR may be very high (>100 mm in 1 hour) in multiple myeloma, tuberculosis and temporal arthritis.
A low ESR (<1 mm in 1 hour) may be seen in polycythaemia rubra vera and sickle cell disease.

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Renal Function Tests

  1. Sodium
    Sodium concentration is dependent on the state of hydration, body sodium content and water shifts between plasma and other body fluid compartments. Intravenous therapy with isotonic saline may cause hypernatraemia and volume replacement with dextrose may cause hyponatraemia. Hyponatraemia occurs in a small percentage of patients on diuretic therapy, particularly the elderly. Severe hyperlipidaemia or hyperproteinaemia may cause 'pseudohyponatraemia'. Sodium is retained with mineralocorticoid excess and lost with mineralocorticoid deficiency, gastrointestinal and renal loss, or excessive sweating. Hyponatraemia as a result of fluid retention (dilutional hyponatraemia) is seen in renal and cardiac disease and with SIADH. Urine sodium estimation may assist in interpretation.
  2. Potassium
    Increased levels are usually found in acidosis, tissue damage, renal failure and mineralocorticoid deficiency. Decreased levels are found in association with loop or thiazide diuretic therapy, vomiting or diarrhoea, alkalosis, during treatment of acidosis, and with mineralocorticoid excess. Haemolysis during collection, delay in separation, refrigeration of unseparated blood, marked leucocytosis and thrombocytosis, and muscle activity of limb immediately prior to venepuncture may cause a misleading increase in potassium. As potassium is commonly raised because of red cell leakage after venepuncture, it is important that unexpected hyperkalaemia is verified by a repeat (fresh) sample if clinically indicated.
  3. Chloride
    Hyponatraemia and metabolic alkalosis are associated with hypochloraemia. Hypernatraemia and metabolic acidosis, due to renal tubular acidosis or bicarbonate loss, are associated with hyperchloraemia. An increased anion gap indicates accumulation of an anion other than chloride (e.g. lactate, hydroxybutyrate); this usually occurs with metabolic acidosis.
  4. Urea
    Increased levels are seen with reduced glomerular filtration due to renal or pre-renal disease, bleeding into the gastrointestinal tract and hypercatabolic states.
    Reduced values are seen in pregnancy, with water retention, with reduced synthesis as a result of decreased protein intake, severe liver disease, or urea-cycle defects.
  5. Uric Acid
    The likelihood of gout is low if the serum urate concentration is repeatedly below 0.42mmol/L. The risk of developing gout is three times greater if the serum urate concentration is consistently above 0.42 mmol/L. However, a raised serum urate level alone is insufficient to diagnose gout. Impaired renal function, pregnancy-induced hypertension, diuretics, fasting, hyperlactataemia, hyperketonaemia and low dose salicylates can all produce increased urate levels. Hypouricaemia is seen in patients with a low purine intake, in SIADH, with hypouricaemic drugs (e.g. allopurinol) and in the rare condition of xanthinuria.
  6. Creatinine
    Increased creatinine levels occur in conditions which decrease the glomerular filtration rate. These may be pre-renal (e.g. hypovolaemia, hypotension), renal or post-renal (e.g. obstruction). Levels are lower in patients with a reduced muscle mass (e.g. the elderly) and this may conceal impairment of renal function.
    Please refer to MediTalk Client Circular No 14 - Routine Reporting of eGFR to read about eGFR reporting.
  7. Calcium
    Total calcium should not be used for evaluation of patients. In most situations, corrected calcium is used which accounts for the main binding protein's (albumin) concentration. Ionised calcium is only required if complexed calcium is likely to be very high (e.g. during massive transfusion), if pH is abnormal or if an abnormality in calcium is marginal. Artefactual decrease in calcium occurs if EDTA, unbalanced heparin or oxalate is used as an anticoagulant. As a hypercalcaemic result may be artifactual (especially if potassium is unexpectedly raised) it is important that unexpected reduced corrected calcium results are verified by a repeat (fresh) sample if clinically indicated.
  8. Phosphate
    Increased phosphate levels are found in response to low parathyroid hormone levels (e.g. hypoparathyroidism, hypercalcaemia due to malignancy and other non-parathyroid causes) and in renal failure. Decreased levels of phosphate are usually found in patients with primary hyperparathyroidism, in some cases of hypercalcaemia associated with malignancy, in renal tubular disorders and in patients using magnesium and aluminium containing antacids. Levels may be decreased during prolonged intravenous therapy if phosphate supplementation is inadequate. Phosphate levels may also be decreased following a carbohydrate-rich meal, due to cellular uptake of phosphate. Numerous other conditions can affect serum phosphate levels. As a raised phosphate result may be artifactual (especially if potassium is unexpectedly raised) it is important that unexpected raised phosphate results are verified by a repeat (fresh) sample if clinically indicated.

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Liver Function Tests

  1. Total Serum Protein
    Total protein is measured together with albumin in order to calculate the concentration of the globulin fraction. The interpretation of total protein concentration depends on the levels of albumin and immunoglobulins, which are the only proteins present in serum in sufficient concentration to significantly alter total protein levels. Increased levels also occur after excessive venous stasis during blood collection and in dehydration.
  2. Albumin
    Decreased levels may be associated with overhydration, chronic liver disease, protein losing disorders (e.g. nephrotic syndrome, protein-losing enteropathy), malnutrition, and shifts into the extravascular space (e.g. burns). Decreased levels may also be seen as part of an acute phase response. Increased levels may be seen with dehydration. Increases above the true level may occur with excessive use of tourniquet for sample collection, and with some methods that also measure acute phase reactants. Levels may be up to 15% higher if the specimen is collected with the patient erect rather than supine. In severe hypoalbuminaemia, non-immunological methods significantly overestimate the level of albumin.
  3. Globulin
    Levels are increased with chronic inflammation, infection, autoimmune disease, liver disease, and paraproteinaemia. Levels are decreased in protein-losing enteropathy, humoral immunodeficiency and sometimes in the nephrotic syndrome.
  4. Total Bilirubin
    Total bilirubin comprises unconjugated, conjugated and delta bilirubin, whereas direct bilirubin comprises conjugated and delta bilirubin. In most cases total bilirubin measurement only is adequate. High levels of total and direct bilirubin are seen with hepatocellular disease or biliary disease (intra- or extra-hepatic). Delta bilirubin, which is covalently bound to albumin, has a longer half-life in the circulation than the other bilirubins and may cause bilirubin elevation for some time after the others have returned to normal. Isolated elevation of unconjugated bilirubin (that is elevated total bilirubin with normal direct bilirubin) occurs when the rate of production exceeds the rate of conjugation.

    It is seen in haemolysis and in megaloblastic anaemia, but the commonest cause is the Gilbert syndrome, in which there is a non-pathogenic impairment of bilirubin conjugation. Physiological jaundice in neonates is due to elevated unconjugated bilirubin. Normal levels of bilirubin may be present in uncomplicated cirrhosis, early in the course of fulminant liver failure, or with hepatic metastases until the disease is advanced.
    Yellow skin colour with normal bilirubin may be due to carotenaemia.
  5. ALP
    Increased levels in liver disease (particularly in association with cholestasis), bone disease (with increased osteoblastic activity e.g. Paget’s disease), some bony metastases (especially prostate and breast), and at times in malignancy without liver or bone metastases (Regan isoenzyme). ALP may also be elevated in some gastrointestinal diseases or due to a macroenzyme. Alkaline phosphatase isoenzymes are rarely necessary to identify the source of an elevated ALP. Marked but transient elevation of ALP may be seen in children, probably attributable to viral infection. Abnormal dentition and fragile bones with decreased ALP characterise the autosomal recessive disease hypophosphatasia.
  6. AST (SGOT)
    Increased levels are found with hepatocellular disease.
    The AST/ALT ratio is typically > 1 in alcoholic liver disease and < 1 in non-alcoholic liver disease.
    Although AST levels are increased with cardiac and skeletal muscle disease, more specific tests are available in these situations.
    Haemolysis during collection or refrigeration of unseparated blood may cause an artefactual increase.
  7. ALT (SGPT)
    Increased ALT levels are associated with hepatocellular damage. ALT is more specific for hepatocellular damage than AST or LD are and remains elevated for longer, due to its longer half-life. The AST/ALT ratio is typically > 1 in alcoholic liver disease and < 1 in non-alcoholic liver disease. ALT may be slightly elevated in skeletal muscle disease but the degree of elevation is much less than for AST and CK.
  8. GGT
    Increased levels are found in cholestatic liver disease and in hepatocellular disease when there is an element of cholestasis. Levels are increased in diabetes with chronic intake of excess alcohol and with certain drugs (especially phenytoin) as a result of enzyme induction. Pancreatitis and prostatitis may also be associated with increased levels. Levels may be normal early in the course of acute hepatocellular damage e.g. acute viral hepatitis, paracetamol hepatotoxicity.

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Glucose
Please refer to Diabetes Mellitus & Glycaemic Control.

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Lipid Studies

  1. Total Cholesterol, Triglycerides, HDL and LDL
    This profile is for the investigation of lipid status in suspected hyperlipidaemia and in monitoring the efficacy of lipid lowering treatment. It also provides an assessment of risk for atherosclerosis, especially coronary artery disease.
    Low levels of HDL and high levels of LDL cholesterol are associated with an increased risk of atherosclerotic vascular disease.
    National guidelines generally specify specific targets. Desired lipid levels for reducing the risk of cardiac disease vary greatly from country to country even though most studies conducted by committees and working parties include many racial groups. Gribbles is currently using the widely recognized ideal targets for lipid levels as specified by the National Cholesterol Education Program (NCEP) based on their Adult Treatment Program version III (ATPIII). Full details, including the variations in desired levels according to the presence of risk factors can be obtained here.
    LDL levels are reduced for up to 8 weeks with acute illness (e.g. myocardial infarction, acute infection) and assays should not be performed during this time.
  2. Apolipoproteins
    Apo A1 and apo B may be measured as an alternative to HDL and LDL cholesterol respectively in the assessment of atherosclerosis risk factors, and may offer better prediction of risk.
    Apo B together with LDL cholesterol can be used to define hyperapobetalipoproteinaemia, a condition associated with small dense LDL and increased risk of atherosclerosis.
    Apo A1 and apo B are very low in Tangier disease and abetalipoproteinaemia (plus hypobetalipoproteinaemia) respectively.
    Decreased apo A1 and increased apo B or apo (a) are associated with an increased risk of atherosclerosis.
  3. Lipoprotein (a)
    Lp (a) is an independent risk factor for atherosclerosis and may be indicated in the assessment of a patient with premature coronary or cerebral arterial disease, especially if there is a suggestive family history.
    Raised Lp (a) is associated with increased vascular risk. Homozygous apoE2 may result in type III hyperlipidaemia.

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Urine FEME
Urine is subjected to the chemical screening tests below.

  1. pH
    Inability to acidify urine may indicate distal renal tubular acidosis.
  2. Specific Gravity
    This measures urine concentration.
  3. Protein
    > 300 mg/L suggests a glomerular protein leak or inflammatory exudate along the urinary tract and should be followed up with a microalbumin test. Please refer to Microalbumin for further information on this test.
  4. Glucose
    A positive result indicates hyperglycaemia at the time of urine formation, or renal glucosuria.
    Hypoglycaemic coma may be present when urine shows glucosuria from earlier hyperglycaemia. Glucosuria is not a reliable indicator of gestational diabetes and the test should not be used for this purpose.
  5. Ketones
    In a diabetic, positive ketones indicate ketoacidosis. If lactic acidosis is also present, the ketone reaction may be inappropriately weak.
  6. Bilirubin
    A negative result in an apparently jaundiced person suggests unconjugated hyperbilirubinaemia (haemolysis, Gilbert syndrome) or carotenaemia.
    A positive result is found in hepatocellular or obstructive jaundice.
  7. Blood
    A positive test for blood may be due to red cells from inflammation, trauma, or tumour of the renal tract.
    Contamination of urine from vaginal bleeding may also be responsible.
    If no red cells are seen on microscopy, it indicates haemoglobinuria or myoglobinuria.
    A negative test with red urine indicates presence of a coloured compound e.g. beetroot, porphyrins.
  8. Leucocytes
    (Leucocyte esterase) - A positive result indicates the presence of neutrophils.
  9. Microscopy
    This is performed to identify and count the types of cells, casts, crystals and other components, such as bacteria and mucous, that can be present in urine.

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RPR (VDRL)
RPR (rapid plasma regain) test is a simple, non specific test for syphilis. A positive test result suggests either past or present exposure to syphilis. Biological false positives may be found in pregnancy; transiently in measles, chicken pox; chronically in cirrhosis, SLE, the phospholipid antibody syndrome, leprosy. All positive RPR tests are routinely followed by a confirmatory and specific test for syphilis called TPHA.

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Hepatitis

  1. Hepatitis B surface Antigen (HBsAg)
    Detected in the serum of patients with Hepatitis B virus infection 6 - 16 weeks after exposure. If HBs Ag is positive then Hepatitis Be Antigen (HBeAg) should be determined. HBeAg is an indicator of viral replication & infectivity of the patient. The presence of HBe Antibodies may indicate reduced infectivity and possible resolution of infection.

    Hepatitis B core Antibody (Anti-HBc) develops soon after the appearance of HBs Ag especially in patients with acute Hepatitis B infection and is present in virtually all chronic Hepatitis B carriers. It is the only serological marker during the “window period" of an acute infection and after previous Hepatitis B virus infection.

    The Hepatitis B virus results in a chronic carrier state in 90% - 95% of infections acquired in childhood especially as a result of vertical transmission, and in 5% - 10% of adult infections.

    Table 1: Interpretation of Hepatitis B results

    Test
     
    Results
    Interpretation

    HBsAg
    Anti-HBcore
    Anti-HBs

     

    Negative
    Negative
    Negative
     

    Susceptible
     

    HBsAg
    Anti-HBcore
    Anti-HBs

     

    Negative
    Negative
    Positive
     

    Immune due to vaccination
     

    HBsAg
    Anti-HBcore
    Anti-HBs

     

    Negative
    Positive
    Positive
     

    Immune due to natural infection
     

    HBsAg
    Anti-HBcore
    IgM anti HBcore
    Anti-HBs

     

    Positive
    Positive
    Positive
    Negative
     

    Acutely infected
     

    HBsAg
    Anti-HBcore
    IgM anti HBcore
    Anti-HBs

     

    Positive
    Positive
    Negative
    Negative
     

    Chronically infected
     

    HBsAg
    Anti-HBcore
    Anti-HBs

     

    Negative
    Positive
    Negative
     

    Four possible interpretations
    possible*
     

    * Four Interpretations:
    1. May be recovering from acute HBV infection.
    2. May be distantly immune, but the test may not be sensitive enough to detect a very low level anti-HBs in serum.
    3. May be susceptible with false positive anti HBcore
    4. May be chronically infected and have an undetectable level of HBsAg present in the serum.



    For more information on Hepatitis B, please read our MediTalk Client Circular No 10 - Hepatitis B.
  2. Hepatitis C
    The Hepatitis C Virus is a single-stranded RNA virus and is the cause of > 90% of transfusion-associated hepatitis. The virus may be transmitted via the parental route through blood or blood products. Sexual transmission, vertical transmission and transmissions through the saliva are other possible routes of infection.
    Chronic infections occur in 50% - 70% of cases and 20% - 25% of these develop antibodies. Hepatocellular carcinoma may develop from 7 to 23 years after acute infections.
    Anti-HCV antibody is detectable in < 50% of patients during an acute infection, and in some patients do not develop at all. It may persist for many years following resolution and in chronic diseases. Sero - conversion has been shown to occur in 10 - 39 weeks following blood transfusion or 4 - 32 weeks after clinical symptoms appear. Anti-HCV may be undetectable in some chronic carriers.

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Thyroid Function Tests

Table 2: Interpretation Matrix for Thyroid Function

   
High T4
 
Normal FT4
 
Low FT4

High TSH
 

In vivo/in vitro artefact
Pituitary hyperthyroidism
[TSHoma]Thyroid Hormone resistance
 

Mild thyroid failure (primary)
(also termed subclinical hypothyroidism and diminished thyroid reserve)
 

Primary hypothyroidism
 

Normal TSH
 

As above. Sampling within 6 hours of thyroxine dose.
 

Normal (in patients taking thyroxine, TSH>3mU/L may indicate subtle under-replacement)
 

Pituitary or hypothalamic hypothyroidism. Severe non-thyroidal illness
 

Low TSH
 

Hyperthyroidism (for this diagnosis, TSH must be suppressed rather than just low)
 

Subclinical hyperthyroidism
Subtle thyroxine over-replacement
Thyroid autonomy(multinodular goitre or autonomous functioning thyroid nodule)
Non-thyroidal illness
 

Pituitary or hypothalamic hypothyroidism
Severe non-thyroidal illness
 

 

  1. Hyperthyroidism may be caused by:
    • Graves disease
    • Multinodular goiter
    • Autonomously functioning single thyroid nodule (adenoma)
    • Thyroiditis e.g. subacute, postpartum or lymphocytic
    • Factitious hyperthyroidism i.e. thyroid hormone ingestion
    • Functioning thyroid carcinoma (follicular carcinoma)
    • HCG-mediated e.g. hyperemesis gravidarum or trophoblastic disease
    • Foetal and neonatal hyperthyroidism (TSH-receptor-antibody-mediated)
    • Struma ovarii
    • TSH secreting pituitary tumour
    • Partial (pituitary-selective) thyroid hormone resistance
  2. Hypothyroidism may be caused by:
    • Autoimmune lymphocytic thyroiditis e.g. atrophic thyroiditis, classic Hashimoto’s disease
    • Post ablative therapy (i.e. radioiodine (RAI) therapy, thyroidectomy)
    • Transient e.g. subacute thyroiditis, postpartum thyoriditis, early post-ablative therapy (RAI, subtotal thyroidectomy)
    • Drug induced e.g. thionamide, lithium, amiodarone, interferon, drugs that interfere with thyroxine absorption in treated hypothyroidism (iron salts, cholestyramine, sucralfate)
    • Iodine associated i.e. iodine-deficiency disease or iodine-induced
    • Infiltrative e.g. Reidel’s thyroiditis, scleroderma, amyloid disease, haemochromatosis
    • Neonatal or congenital e.g. thyroid agenesis/ectopia, genetic disorders of TSH, TSH receptor, thyroid peroxidase, thyroglobulin, pendrin and transplacental passage of blocking TSH-receptor antibody
    • Secondary e.g. pituitary or hypothalamic disease
    • Thyroid hormone resistance

For more information on Thyroid Function tests, please read our MediTalk Client Circular No 3 - Interferences in the Measurement of TSH and Free Thyroid Hormones.

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Rheumatoid Factor
Rheumatoid factor is elevated in patients with rheumatoid arthritis as well as in a number of other inflammatory conditions such as TB, syphilis and malignancy. There is now a more specific test for rheumatoid arthritis called anti-CCP (anti-cyclic citrullinated peptide antibody). In patients who are known to have rheumatoid arthritis or those who demonstrate unexpectedly raised levels of RF, a measurement of anti-CCP is recommended.

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HIV

  1. HIV Ag/Ab Screening Assay
    The HIV screening assay performed by Gribbles Pathology is known as a “combo” assay. It detects not only antibodies to HIV which are generally produced 3 to 4 weeks after exposure, but also p24 antigen which can be present in detectable amounts at 2 weeks post exposure. This combination enables detection of an infected individual at the earliest possible moment by minimising the “window period” between infection and detection.
  2. Western Blot Assay
    This is a confirmatory assay for HIV I/II antibody. A positive Western Blot is generally regarded as conclusive for a HIV infection. Negative tests do not necessarily rule out HIV infection, because there is an interval between HIV infection and the appearance of measurable anti-HIV antibodies (called the "window period"). If the screening test is positive and Western Blot is negative, then the Western Blot should be repeated in 2 – 3 weeks.
  3. HIV-1 Viral Load Assay
    Viral load means the quantity of HIV-1 RNA present in the blood. This assay measures the amount of HIV-1 RNA in a small amount of plasma.
    This test is used in conjunction with clinical presentation and other laboratory markers as an indicator of disease prognosis and for use as an aid in assessing viral response to antiretroviral treatment as measured by changes in plasma HIV-1 levels.

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Cancer Markers
Tumor markers are substances either produced by neoplastic tissue (e.g. CA 125) or are normally occurring organ specific substances which as a result of neoplastic activity are released into the circulation (e.g. PSA).

  1. AFP (Alpha Fetoprotein)
    Raised AFP may be associated with viral hepatitis, cirrhosis and neoplasia (especially hepatoma). A repeat of this marker in a few weeks is suggested to see if there is a rising titre. Most elevations found in non-neoplastic disease are often transient, whereas with neoplastic disease they remain elevated or rise continuously.
  2. ß2M (ß2 Microglobulin)
    ß2M is the light chain of the HLA-A,-B and-C major histocompatibility complex antigens and occurs on the surface of nucleated cells. It is abundant on lymphocytes, monocytes and on many tumour cell lines. Elevated serum levels, in the presence of normal glomerular filtration rate suggest increased production as may be seen in lymphoproliferative disorders such as multiple myeloma, chronic lymphocytic leukaemia, Hodgkin’s disease, non Hodgkin’s lymphoma, SLE, rheumatoid arthritis, Sjogren’s syndrome, Crohn’s disease and certain viral infections, including CMV, non A and non B hepatitis and infectious mononucleosis. As ß2M is of low molecular weight it is considered a sensitive means for diagnosing proximal tubule dysfunction with increased urinary excretion observed in a wide variety of conditions including upper urinary tract infections, kidney transplantation and nephrotoxicity resulting from exposure to heavy metals such as cadmium and mercury as well as cyclosporine, aminoglycoside or cis-platinum therapy.
  3. CA 125 (Cancer Antigen 125)
    Approximately 75% of patients with ovarian carcinoma have elevated levels of CA 125. It is however, also found in non malignant conditions such as pericarditis, cirrhosis, severe hepatic necrosis, endometriosis, first trimester pregnancy, and ovarian cysts. Mild elevations may be seen during menstruation. Non ovarian malignancies which are reported to show elevations include uterine carcinoma, hepatoma, pancreatic adenocarcinoma, lung and endometrial cancer.
  4. CA19.9 (Cancer Antigen 19.9)
    CA 19.9 is elevated in pancreatic and gastrointestinal malignancies. It is also elevated in a number of benign conditions including cholecystitis, cirrhosis, renal failure and may be mildly elevated in normal individuals.
  5. CA 15.3 (Cancer Antigen 15.3)
    Patients with confirmed breast cancer frequently have raised levels of CA 15.3. Elevated levels are also associated with non mammary malignancies such as lung, colon, pancreas, hepatoma, ovary, cervix and endometrium. It is also raised in some benign conditions of the ovary and breast. A repeat of this marker in a few weeks is suggested to see if there is a rising titre. Most elevations found in non-neoplastic disease are often transient, whereas with neoplastic disease they remain elevated or rise continuously. A negative test does not necessarily exclude the presence of disease
  6. CEA (Carcinoembryonic Antigen)
    Borderline values of CEA may occur due to heavy smoking and chronic inflammation. Elevated CEA may be associated with primary colorectal cancer or other malignancies including breast, gastrointestinal tract, liver, lung, ovarian, pancreatic and prostate cancers. A repeat of this marker in a few weeks is suggested to see if there is a rising titre. Most elevations are found in non-neoplastic disease and are often transient, whereas with neoplastic disease they remain elevated or rise continuously.
  7. Catacholamines
    Urinary catacholamine excretion is used in the diagnosis of phaeochromocytoma (increased adrenaline and/or noradrenaline), neuroblastoma and ganglioneuroma (increased dopamine). Excretion of adrenaline and noradrenaline is usually increased in phaeochromocytoma, particularly after a hypertensive paroxysm. Excretion may also be increased in malignant hypertension and with severe stress. Some drugs may interfere with the assay – please note on the request form the drugs patient may be taking.
  8. EBV EA & EBV VCA IgA
    There is a strong and constant association of undifferentiated carcinoma of the nasopharynx with the Epstein - Barr virus (EBV). Reactivation of the virus in the nasopharynx is accompanied by synthesis of EBV related IgA antibodies, and is believed to lead to carcinogenesis in some patients. The most useful cancers markers for the NPC are Anti-VCA (Viral Capsid Antigen) IgA and Anti-EA (Early Antigen) IgA. Combined use of the VCA and EA specific antibody is recommended for the diagnosis of NPC, due to the sensitivity of VCA, and increased specificity of EA. High titres and rising titre are particularly significant, and NPC should be actively excluded in these patients.
  9. PSA (Prostatic Specific Antigen)
    PSA is produced in the prostate, and is useful in the diagnosis of prostatic cancer as well as for monitoring patients for tumour recurrence and metastases. The diagnostic sensitivity increases when used together with measurement of free PSA (fPSA).
    Studies have shown that the ratio of free/total PSA is useful to further distinguish those patients with abnormal prostate glands. Cancer patients tend to produce more bound PSA and therefore have a low ratio while those with benign disease produce more of the free form and have an elevated ratio. To calculate the ratio the laboratory performs a measurement of total PSA and a separate measurement for “free” PSA.
    Free/total PSA ratio is of most benefit for those patients with values of total PSA within the range of 2-10 ug/L. At levels below 2 ug/L the ratio does not give meaningful information and at levels above 10 it is already highly likely that the patient has prostatic carcinoma.



    Note that between the ranges of 7 - 25% of free/total PSA there is still an overlap of clinical findings. There is no advantage in measuring free PSA by itself.
    Although free/total PSA enhances the ability to select patients for further investigations there is still no single biochemical test which will rule in or rule out carcinoma of the prostate. In patients in whom there is a high index of suspicion, free/total PSA appears to offer advantages over PSA measurement alone, especially in those patients with mild elevations in total PSA.

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Diabetes Mellitus & Glycaemic Control
Glucose reference ranges are in line with guidelines of the American Diabetes Association. These guidelines have been adopted by the Malaysian Endocrine Society. (Reference Diabetes Care 27:S5-S10, 2004)

A brief summary of the guidelines is:

  1. Fasting Glucose(Ideally after 10 hour fast)
    • Fasting glucose < 5.6 mmol/L ? Normal fasting glucose
    • Fasting glucose 5.6 – 6.9 mmol/L ? IFG (Impaired fasting glucose) and recommend 75g OGTT
    • Fasting glucose > 7.0 mmol/L on more than 1 occasion or on 1 occasion together with symptoms of diabetes ? Diabetes
  2. Random Glucose
    • Random glucose = 11.1 mmol/L on more than 1 occasion or on 1 occasion together with symptoms of diabetes ? Diabetes
    • Random glucose is 5.6 – 11.0 mmol/L, then recommend 75g OGTT.
  3. Glucose Tolerance Test (75g)
    • 2 hour post load glucose < 7.8 mmol/L ? Normal glucose tolerance
    • 2 hour post load glucose 7.8–11.0 mmol/L ? IGT (Impaired glucose tolerance)
    • 2 hour post load glucose = 11.1 mmol/L ? Diabetes


Criteria for the diagnosis of diabetes mellitus
Symptoms of diabetes plus casual plasma glucose concentration = 11.1 mmol/L. Casual is defined as any time of day without regard to time since patient’s last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.

OR

FPG = 7.0 mmol/L. Fasting is defined as no caloric intake for at least 8 hrs.

OR

2 hour post load glucose = 11.1 mmol/L during an OGTT. The test should use a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.


Gestational Diabetes

  1. One-step approach
    Perform a diagnostic OGTT without prior plasma or serum glucose screening. The one-step approach may be cost-effective in high-risk patients or populations and diagnosis is as noted under diagnosis of Gestational Diabetes Mellitus (GDM) with a 75 g glucose load is as noted above.
  2. Two-step approach
    Perform an initial screening by measuring the plasma or serum glucose concentration 1 hour after a 50g oral glucose load (glucose challenge test - GCT) and perform a diagnostic OGTT on that subset of women exceeding the glucose threshold value on the GCT.
    Note: For the glucose challenge test (GCT), the patient is not required to fast and is given a 50g glucose load. Only one blood is drawn at 1 hour post loading.
    When the two-step approach is used, a glucose threshold = 7.8 mmol/L identifies ~ 80% of women with GDM, and the yield is further increased to 90% by using a cutoff of = 7.2 mmol/L.

HbA1c Classifications
The HbA1c guidelines used are those adopted by the Malaysian Endocrine and Metabolic Society and are the same guidelines as that adopted by the International Diabetes Federation in 2002. The Singapore Endocrine Society has also adopted the same guidelines.


Haemoglobin A1c (%)
 

Glucose Control Index
 

< 6.1
 

Non Diabetic Range
 

6.1 - 6.4
Diabetic with good control

6.5 - 7.5
 

Diabetic with satisfactory control
 

> 7.5
 

Diabetic with poor control
 


Note:** HbA1c less than 6.1% does not necessarily exclude diabetes.

For more information on Diabetes Mellitus, please read our MediTalk Client Circular No 12 - Diabetes Mellitus (Targets for Control).

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Microalbumin
A serious prognostic sign of this complication of diabetes is the development of a persistent proteinuria or macroproteinuria. Before this occurs, there is detectable microproteinuria. This stage of diabetic renal disease is referred to as incipient diabetic nephropathy. Macroalbuminuria is irreversible whereas it has been suggested that, in well-controlled diabetes, microalbuminuria is reversible. It is thus apparent that microalbuminuria is an important predictor of diabetic nephropathy.
The term “microalbuminuria”, which has been used to describe albuminuria, is somewhat misleading, as the albumin is of normal molecular mass. Urine albumin is elevated in the nephrotic syndrome, in other conditions with increased glomerular permeability (e.g. glomerulonephritis) and in urinary tract inflammation.

In a spot urine (first void morning sample) the normal albumin creatinine ratio (ACR) range is <3.5 (female) and <2.5 (male) mg albumin/mmol creatinine, while ratios in the range 3.5–25.0 mg/mmol are consistent with microalbuminuria. ACR values of >25.0 mg/mmol are likely to reflect overt proteinuria. In a timed urine collection (24 hour or overnight 8 hour collection), microalbuminuria is defined as being an albumin excretion rate (AER) of 20–200 ug/min measured. Excretion rates of >200 ug/min are considered to be evidence of macroalbuminuria, and this is most likely irreversible.

There are no special dietary requirements prior to sample collection. A first void morning specimen is the sample of choice for spot albumin:creatinine ratio (ACR). It is important to remember that exercise increases excretion rate and so at least 1 hour of rest is advised before collection of spot urine. The albumin excretion rate utilises either a 24 hour or overnight 8 hour timed urine collection. If an 8 hour collection is used it is important that the collection includes the first morning void. It is essential that the period of collection be accurately noted on the request form.

The recommended procedure for an overnight urine collection is as follows:

  1. Prior to going to bed empty the bladder and note the time (do not save this urine).
  2. Save all the urine passed during the night into the container provided.
  3. On rising in the morning empty the bladder again (saving this urine) and note the time.

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eGFR
Please refer to MediTalk Client Circular No 14 - Routine Reporting of eGFR for eGFR information.

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Helicobacter pylori
Testing Regime

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Semen Analysis
Male factors are the sole cause or a contributory factor of infertility. Semen analysis is the single most important method of assessing sperm quality. It provides information of four essential parameters: sperm presence, members, motility and morphology. There is normally great variability in the quality of semen because of factors like stress, illness, drugs and waned abstinence period, and patient may be azoospermia to normospermia in successive ejaculations. 2 specimens taken two weeks apart is suggested.

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Cervical Cytology
Pap Smear
The term CIN was introduced by Richart in 1968 to emphasize the spectrum and continuum of dysplastic changes involving the stratified epithelium of the cervical transformation zone. The changes reflect an increasingly disordered development and maturation as well as nuclear abnormalities and range in order of severity from CIN I (mild dysplasia) to CIN II (moderate dysplasia) and CIN III (severe dysplasia). Other terms which were previously used in this context are anaplasia, atypical or precancerous epithelium and borderline lesions.

Biological Behaviour of CIN Lesions
Many studies have shown that between 20% - 30% of CIN I and II lesions progress to a more severe grade of dysplasia. In addition approximately 20% - 70% of patients with CIN III develop invasive cancer when followed up for up to 20 years. When HPV alone is reported in routine cervical smears, 14% of the patients have histological evidence of CIN and another 10% will develop CIN over the next 3 years.

Terminology
We follow the Bethesda classification. The Bethesda system (TBS) is a system for reporting cervical or vaginal cytologic diagnoses, used for reporting Pap smear results. It was introduced in 1988, and revised in 1991 and 2001. The name comes from the location (Bethesda, Maryland) of the conference that established the system.

The terms you may encounter in a cytology report include the below. 
 
Inflammatory nuclear changes. 
 
Dyskaryosis (abnormal nucleus), inclusive of mild dyskaryosis (CIN I), moderate dyskaryosis (CIN II) & severe dyskaryosis (CIN III and some invasive cancers). 
 
Borderline abnormalities. A repeat smear should be recommended if the abnormalities are mild. 
 
Atypia, a term which should be avoided as its meaning range from dyskaryosis, borderline abnormalities and inflammatory or reactive changes. 
 
Metaplasia, metaplastic cells are obtained from the cervical transformation zone and are a normal cellular component of the cervical smear.

Accuracy of the Cervical Pap Smear
Studies have shown that a single smear will not detect 20% of CIN and 50% of invasive cancer. The diagnostic accuracy rate of cervical smear depends on the cellularity which has to be representative of the lesion, proper smearing technique, fixation, staining and cytologic interpretation. Every step of the process is vital. Inadequate cellular sampling has been found to be responsible for 30% - 60% of high grade dysplasia that are picked up on second screening. It is calculated that the degree of protection from future invasive cancer developing in 10 years is about 60% with one cervical smear. It has therefore been recommended that there should be a Screening Programme. This has been instituted as a Population based Programme in British Columbia, Iceland and Finland. The incidence of cervical cancers in these countries has fallen by 60% - 80% and cervical cancer mortality has fallen by 30% - 80%.

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Dengue
There are 4 serotypes of the dengue virus and infection by any of the serotypes leads to a similar spectrum of illness and lasting immunity to the infecting serotype but not to the other three. The individual non-protective antibodies cross-react with the other serotypes.
Laboratory diagnosis of dengue infection includes virus isolation, antigen detection, serology, and molecular methods. In addition, a clinical diagnosis of DHF can be made in the presence of fever, haemorrhagic tendencies, thrombocytopenia (platelets = 100,000/cmm) and haemoconcentration. Virus isolation and antigen detection are most successful during viraemia which usually last 3 - 5 days and coincides with fever.
IgM antibodies appear around the 5th day of the fever and last for 2 - 3 months. IgG antibodies are detected from the 14th day in primary infections and 2nd day in secondary infections and are usually detectable for life. Three serological tests are widely used:

  1. HI (Hemagglutin Inhibition Test) ? Detects a mixture of IgM and IgG antibody and cross reacts with other serotypes. Paired titres are tested 7 days apart.
  2. IgM antibody enzyme immunoassay ? False positive due to cross-reaction with other viruses may occur. Sensitivity is in the region of 80% and specificity 99%.
  3. Dengue Blot Test ? Rapid test for IgG antibody, but is usually negative in primary infections.

For more information on Dengue, please read our MediTalk Client Circular No 1 - Dengue.

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Thalassaemia
Thalassaemia is an inherited disorder in which one or more globin chains comprising a haemoglobin molecules is synthesized at a reduced rate. It can be found in any population of people but is most common in the Chinese and Malays in Malaysia, people from the South East Asia, Mediterranean & the Middle East.

Laboratory Tests for Diagnosing Thalassaemia
• FBP-Hb, PCV, MCV, MCH

 
MCV < 76 fl
MCH < 27
PBF: Microcytic,
Hypochromic
Commonly due to
Thalassaemia or
Iron deficiency
 
• Reticulocyte smear - for "H" inclusions for α° Thal 



• Hb electrophoresis or HPLC - for β thal, HbE, HbS,HbCoSp, HbH,Hb Barts, HbNY, HbD 



• S. Ferritin: High in Thalassaemia & multiply transfused persons
• DNA studies for α° thalassaemia



Suggested Flow for Screening those with a Low MCV, MCH
 


Cascade studies:
When a person is identified with thalassaemia, screening their blood relatives would identify more of those with thalassaemia.

Cascade Screening:
More cost effective than population screening. Screen the patient's parents, siblings, children and other blood relatives of those with thalassaemia. Spouse can be screened for thalassaemia to assess the risk for thalassaemia major.


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