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Clinical chemistry, chemical pathology and medical biochemistry is the area of clinical pathology that is generally concerned with analysis of bodily fluids. Originated in the 19th century with simple chemistry test of blood and urine Disorders of Protein Metabolism: Non-protein nitrogenous compounds (Urea, uric acid & amino acids): 3 lectures › Their normal plasma levels › Disease states associated with their increased and decreased levels in the plasma. Plasma Proteins: › Normal and abnormal levels of plasma proteins and diseases associated with increased and decreased levels. › Immunochemistry › Components of the immune system. Diseases associated with disorders in the immune system, multiple myeloma, systemic lupus erythromatosis, heavychain diseases, macroglobulinemia etc. Clinical Enzymology › Changes in enzymatic activity in disease states Hemoglobin › Normal and types of abnormal hemoglobins. › Pathological cases associated with abnormal hemoglobin, e.g., thalassemia, sickle cell anemia etc. Disorders of Lipid Metabolism › Hyper and hypolipoproteinemia. › Atherosclerosis & lipidoses. › Fatty liver Disorders of Electrolytes, Blood Gases &Acidbase Balance › Sodium, potassium, chloride & their diagnostic value. › Gas transport in the blood (Oxygen & CO2). › Blood pH and its regulation. › Acidosis and alkalosis (Metabolic and respiratory) & Pathological conditions associated with each condition. Blood analysis: › Electrophoretic separation of plasma proteins. › Electrophoretic separation of plasma lipoproteins. Estimation of serum enzymes: › LDH and its isoenzymes. › CPK and its isoenzymes. Ornithine carbamoyl transferase. › › › › 5-nucleotidase. Isocitric dehydrogenase. Sorbitol dehydrogenase. Glucose-6-P dehydrogenase. Aldolase › Leucine aminopeptidase. › Aspartate and Alanine Aminotransferases AST and ALT. Serum electrolytes: › Chloride sodium, Potassium, Calcium, Magnesium, Phosphorus. Urine Analysis: › Porphyrins. › Urobilinogen, Amino Levulinic Acid (ALA) Clinical Biochemistry, 2nd Edition, 2008, R. Luxton. Clinical Biochemistry made ridiculously simple, 2010, Stephen Goldberg. Clinical Biochemistry; An illustrated color text, 2008, Allan Gaw, Michael J. Murphy, Robert A. Group 1: Disorders that give rise to Intoxication Group 2: Disorders involving energy metabolism. Group 3: Disorders involving complex molecules. (Proposed by JM Saudubray-2002) This group includes IEM that lead to acute or progressive intoxication from accumulation of toxic compounds proximal to metabolic block. Includes (Cont): Congenital Urea Cycle Defects › Arginosuccinate Lyase Def › Ornithine Carbamyl Transferase Def Sugar Intolerance › Galactosaemia › Hereditary Fructose Intolerance Includes: Aminoacidopathies e.g: › Phenylketoneuria (PKU) › Maple Syrup Urine Disease (MSUD) › Tyrosinaemia type I Organic acidaemias e.g. › Methylmalonic acidaemia (MMA) › Propionic Acidaemia › Isovaleric Acidaemia This group consists of IEM with symptoms due at least partly to a deficiency of energy production or utilization. They result from a defect in the: › › › › Liver Myocardium Brain Muscle Includes: Hypoglycaemic disorders › Gluconeogenesis defects › Glycogenosis defects › Hyperinsulinism Fatty Acid Oxidation Disorders Includes (Cont) Congenital Lactic Acidaemias › Pyruvate carboxylase deficiency › Krebs Citric Cycle defects › Mitochondrial Respiratory Chain defects This group includes diseases that involve defects in the synthesis or the catabolism of complex molecules. These diseases are: Progressive Permanent Independent of intercurrent events Not amenable to treatment. Includes: Lysosomal Disorders Peroxisomal Disorders Golgi Apparatus Disorders Inborn Errors of Cholesterol Synthesis Carbohydrate metabolism › Glycogen storage diseases › Galactosemia › Hereditary fructose intolerance various galactose-1-phosphate uridyle transferase, galactose kinase fructose bisphosphate aldolase Amino acid metabolism › Phenylketonuria › Alkaptonuria › Maple syrup urine disease phenylalanine hydroxylase homogentisic acid oxidase branched chain ketoacid hydroxylase Lipid metabolism › Hyper and hypo lipoproteinemia Steroid metabolism › Congenital adrenal hyperplasia various 21-hydroxylase Purine metabolism › Gout various › Lesch-Nyhan syndrome HGPRT (hypoxanthine-guanine phosphoribosyl transferase) Lysosomal storage disease › Tay-sachs disease…….. › Gaucher’s disease…….. hexosaminidase A glycosylceramidase Cell transport defects › Cystinuria………. › Renal glycosuria………. › Renal tubular acidosis…. amino acid transport glucose transport hydrogen ion transport About 5 million children die in the first month of life in developing countries Four million children are born with some congenital anomaly. WHO Almost 27 - 30 % of babies dying of SIDS are now proved to be having some Inborn Errors of Metabolism (IEM). About 5 to 15 % of all sick neonates in NICU are expected to have some IEM WHO a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product IEM arises from a damaged gene which leads to abnormal enzyme. May be autosomal or sex-linked. May be recessive or dominant in expression. Heterozygote will have both normal and abnormal alleles. But homozygote will have two alleles the same on each chromosome. An accumulation of the substrate before the enzyme defect*. A decrease in the amount of the product is observed. An increased concentration of the alternative metabolites*. A decrease or absence of the enzyme activity. Screening for IEM who do not have the symptoms Investigations of the patient with symptoms of the IEM May be carried out in three stages: a. Diagnosis of Broad Category: Saudubray et al (2002)* suggested a battery of simple and routine tests for identification of the broad category of the disorders. These tests include plasma electrolytes, ABGs, blood ammonia and lactic acid etc. *Saudubray JM, Nasoogne MC, Lonlay PD, Touati G. Clinical approach to inherited metabolic disorders in neonates: an overview. Smin Neonatol 2002; 7: 3-15. May be carried out in three stages: b. Diagnosis of the exact disorder • It requires very sophisticated equipment e.g. HPLC, tandem mass spectrometry, GC-MS and ion exchange chromatography. May be carried out in three stages: b. Diagnosis of the exact disorder (cont) • These techniques also require elaborate infrastructure of trained manpower, proper back-up service for the instruments and regular supply of reagents. May be carried out in three stages: b. Diagnosis of the exact disorder (cont) • AKU hospital has taken an initiative to establish the first-ever lab in the country for the pin-point diagnosis of some of the IEM. May be carried out in three stages: c. Determination of deficient enzyme or protein Although a few laboratories in the world provide this facility, this is only of academic and research interest. Diagnosis of the genetic defect provides another promising pathway for some of these disorders.