Biochemical markers for diagnosis of diseases and follow up

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Biochemical markers for diagnosis of diseases and follow up Foundation Block Dr. Usman Ghani Lecture objectives Upon completion of this lecture, the students should be able to: Comprehend the importance
Biochemical markers for diagnosis of diseases and follow up Foundation Block Dr. Usman Ghani Lecture objectives Upon completion of this lecture, the students should be able to: Comprehend the importance and diagnostic qualities of various biomarkers Understand the importance of different biomarkers in the diagnosis, treatment and follow up of a disease. Recognize the types of biomarkers and their use in specific diseases such as heart, cancer, liver, kidney and pancreatic diseases. Overview What is a biomarker? Diagnosis and prognosis Plasma and tissue-specific biomarkers Factors affecting serum biomarker levels Qualities of a good biomarker Types: Enzymes, proteins, hormones Enzymes: Amylase, lipase, trypsinogen, ALT, AST Proteins: Cystatin C, BNP, a-fetoprotein, PSA Hormones: Anti-Mullerian hormone What is a biomarker? A biological molecule found in blood, other body fluids, or tissues that indicates a normal or abnormal process such as a disease or a condition A biomarker is measured to follow up a disease or treatment diagnosis and prognosis Diagnosis: Identification of a disease from its signs and symptoms Prognosis: The future outcome of a disease Most common body fluids for measurement of biomarkers are: Serum Plasma Urine Some biomarkers are either: Plasma-specific or Tissue-specific Plasma-specific biomarkers Normally present in plasma Perform their functions in blood High level of activity in plasma than in tissue cells Examples: blood clotting enzymes (thrombin), cholinesterase, etc. Tissue-specific biomarkers Present inside the cell Conc. is lower in plasma Released into the body fluids in high conc. due to: cell damage defective cell membrane Intracellular enzymes are present only in their cells of origin Some are secretory enzymes that are secreted by salivary glands, gastric mucosa and pancreas In disease, plasma levels of secretory enzymes increase when their cells are damaged The diagnosis of organ disease is done by measurement of enzymes of that tissue Factors affecting serum biomarker levels Cell damage Rate of biomarker synthesis and clearance Enzyme inhibitors Glucose deficiency Localized hypoxia (less oxygen) Ischemia (obstruction of blood vessels) Necrosis Tissue infarction due to ischemic necrosis Myocardial infarction Qualities of a good biomarker A good biomarker should be: Able to accurately diagnose a disease Able to accurately predict prognosis of a disease Compliant with treatment follow up Easily obtainable from blood, urine, etc. Qualities of a good biomarker assay A good biomarker assay should be rapid to deliver results faster Sensitive Ability of an assay to detect small quantities of a marker Specific Ability of an assay to detect only the marker of interest Types of biomarkers Enzymes Hormones Proteins Enzymes as biomarkers Enzymes are clinically used for the diagnosis and prognosis of various diseases Examples include: Amylase, Lipase Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Amylase and Lipase Acute pancreatitis is the inflammation of pancreas caused by: Obstruction of the pancreatic duct Gallstones Alcohol abuse Abnormal release and premature activation of pancreatic enzymes (for example amylase, lipase) Diagnosis conducted by measuring pancreatic enzymes Amylase Elevated serum amylase level is a diagnostic indicator of acute pancreatitis Amylase level greater than 10 times the upper limit indicates acute pancreatitis The test has low specificity because elevated serum amylase level is also present in other diseases Amylase appears in the serum within 2-12 hours after abdominal pain Free amylase (unbound form) is rapidly cleared by the kidneys Lipase Serum lipase has higher specificity than serum amylase It appears in plasma within 4-8 hours and remains for 8-14 days Measurement of amylase and lipase give 90-95% accuracy in the diagnosis of acute pancreatitis and abdominal pain High serum ALT and AST levels in liver diseases are due to: Alcohol abuse Medication Chronic hepatitis B and C Steatosis and steatohepatitis Autoimmune hepatitis Wilson s disease a1-antitrypsin deficiency Malignancy Poisons and infectious agents Alanine aminotransferase (ALT) Mostly present in liver Small amounts in heart More specific for liver disease than AST Major diagnosis: liver disease Aspartate aminotransferase (AST) Widely distributed in heart, liver, skeletal muscle, kidney Small amounts in erythrocytes High serum activity of AST found in: Liver disease, heart disease, skeletal muscle disease, hemolysis Major diagnosis: liver and muscle diseases Serum enzymes used in the assessment of liver function: Markers used in hepatocellular necrosis Alanine aminotransferases Aspartate aminotransferases Proteins as biomarkers Cystatin C B-type natriuretic peptide (BNP) Tumor markers a-fetoprotein Prostate Specific Antigen (PSA) Cystatin C A cysteine protease inhibitor mainly produced by all nucleated cells of the body Useful biomarker for measuring glomerular filtration rate (GFR) in assessing kidney function and failure Unlike creatinine, its serum conc. is independent of gender, age or muscle mass Abnormally high serum levels of cystatin C indicates kidney failure Clinically useful marker for detecting: early kidney disease, monitoring kidney transplantation and acute kidney injury B-type natriuretic peptide (BNP) A peptide secreted mainly in the cardiac ventricles in response to cardiac expansion and pressure overload High serum levels are observed in congestive heart failure In some pulmonary diseases, BNP levels are high but not as high as in heart failure BNP helps differentiate between pulmonary disease and heart failure An important marker for the diagnosis and prognosis of congestive heart failure Currently being investigated as a screening biomarker for heart disease Tumor markers A molecule secreted by a tumor that is measured for diagnosis and management of a tumor a-fetoprotein Prostate specific antigen (PSA) a-fetoprotein In newborn babies a-fetoprotein levels are very low High conc. are observed in: Hepatocellular carcinomas (hepatoma) Testicular carcinomas GI tract carcinomas However, high serum levels are also found in benign (non-cancerous) conditions e.g. hepatitis High conc. are not always suggestive of a tumor Prostate Specific Antigen (PSA) A serine protease enzyme also called kallikrein III, seminin Produced by prostate gland Liquefies ejaculate High serum PSA levels are observed in prostate cancer Less specific in diagnosis High serum levels are also observed in benign prostatic hypertrophy (enlarged prostate gland) Hormones as biomarkers Anti-Mullerian hormone (AMH) A polypeptide hormone involved in sexual differentiation of male embryo In females it is produced by ovaries Prevents premature depletion of ovarian follicles Appears to be a best marker for estimating egg cell reserve in the ovaries Only growing follicles produce AMH Plasma AMH levels strongly correlate with number of growing follicles Helps assess female fertility Take-home messages Biomarkers are used for diagnosis, prognosis and follow up of diseases A biomarker should exhibit good diagnostic and prognostic values Examples of biomarkers used in different disease will help understand their qualities and limitations References What are biomarkers? Kyle Strimbu and Jorge A. Tavel, Curr Opin HIV AIDS November ; 5 (6): Biomarkers: Potential uses and limitations. Richard Mayeux. J. Amer. Soc. Exp. Neuro Therap. Vol. 1, , April 2004
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