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Clinical Biochemistry

The document discusses the importance of clinical biochemistry in hospital laboratory investigations, highlighting its role in diagnosing various medical conditions, particularly diabetes mellitus. It outlines the processes of carbohydrate digestion, absorption, and the hormonal regulation of blood glucose levels, as well as the biochemical disturbances associated with diabetes. Additionally, it addresses methods for glucose monitoring and the significance of various tests in clinical practice.

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Clinical Biochemistry AASER ABDELAZIM Professor Medical Biochemistry and Molecular Biology FAIMER fellow 2021 (Medical education) Clinical Chemistry consultant amabdalazim@ub.edu.sa 8/15/23 1 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 2 1. Clinical biochemical tests comprise over1/3 of all hospital laboratory investigations 2. Most biochemical tests are now performed at the site of clinic especially during major operations like transplantation not only in clinical biochemistry labs. 3. Most laboratories are now computerized and use: q The par-coding for specimens q Automated methods in analysis This leads to: A. High degrees of productivity . B. Improves the quality of service. C. Allow direct access to the results by clinicians. A. INTRODUCTION
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 3 History Clinical examination Diagnostic services Imaging Physiological tests ECG, EEG, lung functions Lab services Hematology Histopathology Immunology Microbiology Clinical biochemistry Core tests Emergency tests Specialized tests B. Place of clinical biochemistry in medicine
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 4 Core tests commonly requested by physician e.g., U, LFTs and Es (Urea, liver function tests electrolytes) Core tests 1. Not all labs introduce the service but it restricted only to some reference centers 2. Needed to diagnose rare diseases Specialized tests 1. Done immediately 2. Results taken on call 3. Need to work out of normal hours of lab. 4. All labs should perform theses tests. Emergency tests Core biochemical tests Sodium, potassium, chloride, bicarbonates Urea, creatinine Calcium, phosphates Total proteins, albumins Bilirubin, alkaline phosphatase ALT, AST T4, TSH ɣ-GT, CK Blood gases Amylase Specialized tests Emergency tests Hormones Urea and electrolytes Special proteins Blood glucose Trace elements Blood gases Vitamins Paracetamol Drugs Salicylates Lipids and lipoproteins Calcium DNA analysis Amylase
Clinical biochemical laboratory qBiochemical tests are used for diagnosis, monitoring, treatment, screening and for prognosis. q core biochemical tests are performed in every biochemistry laboratory. qSpecialized biochemical tests are preferred to be performed in larger departments. q laboratory personnel should be able to select the perfect type of tests and interpret the results based on his knowledge. 8/15/23 5 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 6 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 7 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 1 By Aaser M. Abdelazim, PhD Assistant professor of Biochemistry and Molecular biology
A tour in carbohydrates metabolism Digestion Absorption Metabolism 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 8
Digestion of carbohydrates 60% of our food [starch, glycogen, sucrose, lactose, and cellulose] Salivary α-amylase (pH 6-7) Mouth stomach Pancreas Pancreatic α-amylase (pH 7.1) Maltose /isomaltose/starch dextrins Maltose /isomaltose Small intestine Lactase/sucrase/maltase/α-dextrinase Cocktail of sugars [monosacchrides] We have not β-glucosidase so cellulose passes as such 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 9
Absorption of carbohydrates GLUCOSE – GALACTOSE-FRUCTOSE Jejunum Portal vein GLUCOSE Active transport system SGLT-1 Na-K pump Faster than passive Need ATP From lumen to intestinal cells Passive transport system GLUTs No need ATP From lumen to intestinal cells GLUT-5 Form intestinal /renal /liver cells /β-cells to circulation GLUT-2 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 10
GLUCOSE – GALACTOSE-FRUCTOSE Portal vein GLUCOSE Fate of absorbed sugars OXIDATION STORAGE CONVERSION Glycogen Glycolysis- Krebs MAJOR PATHWAY Uronic acid Detoxification NADPH Ribose HMP-shunt Lactose Glucosamine Galactose amine Fructose Glycogenesis Lipids Lipogenesis 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 11
Blood glucose Fasting (70-110mg/dl) One hour (120-150 mg/dl) Two hours(70-140 mg/dl) Dietary carbohydrates Liver glycogen Amino acids and non carbohydrate-substance Absorption Gluconeogenesis Glycogenolysis BLOOD GLUCOSE HORMONAL REGULATION HEPATIC REGULATION RENAL REGULATION INSULIN Glucagon Growth Glucocorticoids Catecholamines 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 12
BLOOD GLUCOSE HORMONAL REGULATION Glucagon Growth H Glucocorticoids Catecholamines INSULIN Glucose uptake Glucose oxidation Glycogenesis + + + Lipogenesis + Glycogenolysis Gluconeogenesis - - Glycogenolysis Gluconeogenesis + + GLUCAGON Catecholamine Gluconeogenesis + Gluconeogenesis Glucose uptake + - Glucocorticoids Insulin action at cell mem Glucose uptake - - Growth H THYROID H Glycolysis / Gluconeogenesis + ?! 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 13
Condition Insulin Level Insulin Level (SI Units*) Fasting < 25 mIU/L < 174 pmol/L 30 minutes after glucose administration 30-230 mIU/L 208-1597 pmol/L 1 hour after glucose administration 18-276 mIU/L 125-1917 pmol/L 2 hour after glucose administration 16-166 mIU/L 111-1153 pmol/L ≥3 hours after glucose administration < 25 mIU/L < 174 pmol/L *SI unit: conversional units x 6.945 NORMAL INSULIN LEVELS 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 14
BLOOD GLUCOSE HEPATIC REGULATION AFTER MEAL FASTING Glycogenolysis Gluconeogenesis + + Ketogenesis + BRAIN Add sugar to blood BRAIN MUSCLES ADIPOSE LIVER PORTAL Lipids Glucose-6-P Glycogen Lipogenesis Glycogenesis 40% of glucose Circulation Insulin secretion + 60% of glucose LIVER Glucokinase + HYPERGLYCEMIA Glucose uptake 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 15
BLOOD GLUCOSE RENAL REGULATION LOW RENAL THRESHOLD HIGH RENAL THRESHOLD URINE RENAL THRESHOLD 180 mg/dl 100 mg/dl Diabetes innocence 20% of pregnant 220 mg/dl Elderly people Diabetes associated renal damage 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 16
Diabetes mellitus: Is a family disorder characterized by hyperglycemia Etiology: Type Etiology Type I 1. ᵦ- cell destruction lead to absolute insulin deficiency 2. Immune mediated 3. Idiopathic Type II May range from predominantly insulin resistance with relative insulin deficiency to a predominantly Secretory defect with insulin resistance. Gestational diabetes (GDM) Similar to type II; it is diabetes that diagnosed in pregnancy as pregnancy is associated with increase tissue cells resistance to insulin; the hyperglycemia of GDM diminishes after delivery and other cases develop type II diabetes. Other specific types 1. Genetic defect of beta cells functions 2. Genetic defect in insulin action 3. Diseases of exocrine pancreas (cystic fibrosis) 4. Endocrinopathies (cushing’s syndrome) 5. Drug – or – chemical induced (protease inhibitors or glucocorticoids) 6. Infections 7. Uncommon forms of immune- mediated diabetes 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 17
DIABETES MELLITUS Biochemical disturbances in Diabetes Mellitus Syndrome Disease LIPIDS PROTEINS HYPERGLYCEMIA CARBOHYDRATES DYSLIPIDEMIA DYSPROTEINEMIA Relative /absolute deficiency of INSULIN Chronic metabolic disorder 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 18
Biochemical disturbances in Diabetes Mellitus CARBOHYDRATES GLUCNEOGENESIS GLYCOGENOLYSIS Glucose uptake Intracellular glucose POLYPHAGIA HYPERGLYCEMIA 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 19
Biochemical disturbances in Diabetes Mellitus HYPERGLYCEMIA Glucose >renal threshold Plasma osmolality Dehydration Intra cellular water POLYDEPSIA Brain dehydration Hyperglycemic hyperosmolar coma Loss of water POLYUREA Loss of water soluble vitamins and minerals GLUCOSURIA 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 20
8/15/23 21 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Glucose homeostasis
8/15/23 22 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Action of insulin
8/15/23 23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Development of diabetic ketoacidosis:
Blood Glucose (Blood sugar) Normal level = 70 – 110 mg/dl I- Hyperglycemia •Diabetes mellitus •Gestational diabetes GDM(24th- 28th week) •Acromegaly •Acute stress (response to trauma, heart attack, stroke) •Chronic renal failure •Cushing syndrome (excess glucocorticoids) •Hyperthyroidism •Pancreatitis •Pancreatic tumors •Excess food intake •Drugs (corticosteroids, tricyclic antidepressants, diuretics, epinephrine, estrogen, Lithium, phenytoin, Salicylates.) 8/15/23 24 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
II- Hypoglycemia Hypoglycemia in Diabetic patients 1. Patients taking blood glucose lowering medications q Excess dose of insulin q High dose of sulfonylurea q Extra dose of Meglitinides. 1. Increase the activity or the exercise 2. Excess drinking of alcohols. Hypoglycemia in non Diabetic patients Reactive hypoglycemia (postprandial, after meal) Fasting (post absorptive) 8/15/23 25 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
1) Some people that were sensitive to normal release of epinephrine. 2) Deficiency in Glucagon secretion. 3) Gastric surgery (rapid passage of food to intestine). Diagnosed from blood samples lower than 50 mg/dl 1. Alcohols: especially binge drinking(depletion of pyruvate and Oxaloacetate) 2. Critical illness: (hepatocellular damage, renal insufficiency , sepsis, starvation ) 3. Hormonal deficiency:(cortisol, GH, Glucagon, epinepherine ) 4. Tumors :(insulinoma: tumor of B – cells ) 5. Drugs:(salicylates in large dose, Pentamedines (pneuomenia treatment),Quinine(malaria ttt) ) 8/15/23 26 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Appears after 3-4 hrs after meals
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 27 1- Babies from diabetic mothers. 2- In born error of metabolism. A. Glycogen storage diseases. B. Galactosemia Etiology: New born with risk of hypoglycemia 12% New born without risk of hypoglycemia 88%
The clinical effect of hypoglycemia Catecholamin es and glucagon starts to face the problem Starts to enter in coma Brian damage Coma 8/15/23 28 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 29 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology (1) Oral glucose in conscious patients: If patient can swallow, give sweet drink, sweets, or glucose tablets (2) Oral glucose in comatose patients: If patient unable to swallow, jam or any available glucose gel smeared on inside the cheeks (3) i.m Glucagon: May be given to comatose patients (4) i.v Glucose: Treatment of choice in comatose patients
1. Blood sugar 2. Urine sugar 3. Glycated HB 4. Glycated proteins 1- Venous blood 2- Capillary blood RBCs level is less than plasma level due to less water contents of RBCs G soluble in water 1) Separated rapidly 2) Rapid transported to lab. 3) Cooling of samples 4) Add sod. Fluoride to inhibit glycolysis 1) Fasting 2) Random 3) Timed interval (glucose tolerance) 8/15/23 30 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Precautions Samples Types of Samples Monitoring
ORAL GLUCOSE TOLERANCE TEST 8/15/23 31 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 1) Mild or no DM symptoms 2) Glucose absorbance and utilization 3) Renal threshold (note next slide) 4) Persistent glycosuria 5) Pregnant woman with family history of diabetes Indications 1) Let patient to be fasted for not more than 12 hours 2) Measure fasting blood glucose level (0) time and register the results. 3) Give the patient 75 gm of sugar in about 400-500 ml water orally. 4) Every hour take blood and urine samples for determination of glucose draw the oral glucose tolerance curve
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 32 Remarks on The curve: 1. Ascending limb: explains the glucose absorbance 2. Descending limb: explains glucose utilization and insulin response 3. Usually glucose does not appears in urine until it be over the threshold level 4. Diabetes diagnosed from FBG= >126 and at least one sample > 200 after the 1st 30 minutes 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours Max level=120-150 mg /dl Fasting level = 70-110 mg/dl Renal threshold of glucose = 180 mg/dl Hypoglycemic response/insulin overshoot Usually max value (after one hour) = 1.5 time fasting value Ascending limb Descending limb Return to fasting level ORAL GLUCOSE TOLERANCE curve
Renal threshold of glucose It is the blood glucose level above which glucose appear in urine Average =180 mg/dl 1 mmol/L = 18 mg/dl 1. Persons of diabetes innocence 2. In 20% of pregnant females 1. Elderly people due to reduced GFR 2. Diabetes associated with renal damage 8/15/23 33 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Renal threshold of glucose Low renal threshold High renal threshold 100 mg/dl 220 mg/dl
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 34 Types of oral glucose tolerance curves: 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours 300 400 500 (1) Severe diabetic curve: Urine: Time 0 1 2 Glucose + ++ +++ Ketones Trace Trace Trace Renal threshold
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 35 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours (2) Mild diabetic curve: Urine: Time 0 1 2 Glucose 0 0 0 Ketones 0 0 0 Renal threshold
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 36 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours (3) Hypoglycemic curve: (4)Flat curve: blood glucose fails to rise normally after glucose load Occurs in; malapsorption, myxodema, hypopitutrism Urine: Time 0 1 2 Glucose 0 0 0 Ketones 0 0 0 Urine: Time 0 1 2 Glucose 0 0 0 Ketones 0 0 0
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 37 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours (5) Renal glucosuria curve: it resemble normal curve while we can find glucose in urine. Urine: Time 0 1 2 Glucose 0 + ++ Ketones 0 0 0 Renal threshold Renal threshold (6)Lag storage curve: FBG level is normal, after 30 minutes of glucose load the level be up renal threshold , then the level falls sharply in less than 2 hours Occurs in; after gasterectomy; due to rapid passage of glucose to intestine, severe liver diseases when no glucose is used in glycogenesis and all Glc goes directly to blood, rare in thyrotoxicosis due to rapid absorption of glucose. Urine: Time 0 1 2 Glucose 0 + 0 Ketones 0 0 0
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 38 Remarks on OGTT in children Point Comments Indications of the test in children üDiabetic child with equivocal fasting or random level. üHypoglycemic child üTo exclude excess Growth H. üCystic fibrosis üFor the following conditions [polycystic ovary, strong family history, obesity and fatty liver disease] Precautions qOnly when blood glucose level 5.6 to < 7.o mmol/L. qDon’t performed in patients with thyroid dysfunctions, under physical stress e.g post surgery, hypokalemic periodic paralysis. Side effect Many child feel nauseated or vasovagal symptoms. Preparation of patient qEnsure that the child has had an adequate carbohydrate diet for at least 5 days before the test (150g/day). qAvoid prolonged fasting of child (only for 4 hour night fast) allow him to drink water with no sweet drinks. qPhysical exercise is not allowed before or during the test. qYou should perform the test at morning. Protocol 1. Measure the fasting level. 2. Prepare glucose load as following § Liquid contains 0.66 g /mL of anhydrous glucose (the dose is 2.64 ml/Kg body weight with maximum dose 113 ml.) you can add water up to 200 ml volume. § Anhydrous glucose (dose 1.75 g/kg body weight) maxium dose 75 g § Rapilose contains 75 g of glucose in 300 mL for child of weight less than 43 Kg . 3. Child should take the glucose load with in 5 minutes. 4. Take the second blood sample after 2 hours.
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 39
Biochemical disturbances in Diabetes Mellitus PROTEINS Depletion of glucose as source of energy Breakdown of tissue proteins Infection Muscle wasting Poor healing 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 40
Biochemical disturbances in Diabetes Mellitus LIPIDS Depletion of glucose as source of energy Lipolysis Hyperlipidemia Loss of weight Fatty acid oxidation Acetyl CoA Ketogenesis /ketosis Ketotic coma Hyperkalemia 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 41
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 42 Diabetes mellitus: Is a family disorder characterized by hyperglycemia Etiology: Type Etiology Type I 1. ᵦ- cell destruction lead to absolute insulin deficiency 2. Immune mediated 3. Idiopathic Type II May range from predominantly insulin resistance with relative insulin deficiency to a predominantly Secretory defect with insulin resistance. Gestational diabetes (GDM) Similar to type II; it is diabetes that diagnosed in pregnancy as pregnancy is associated with increase tissue cells resistance to insulin; the hyperglycemia of GDM diminishes after delivery and other cases develop type II diabetes. Other specific types 1. Genetic defect of beta cells functions 2. Genetic defect in insulin action 3. Diseases of exocrine pancreas (cystic fibrosis) 4. Endocrinopathies (cushing’s syndrome) 5. Drug – or – chemical induced (protease inhibitors or glucocorticoids) 6. Infections 7. Uncommon forms of immune- mediated diabetes
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 43 Insulin dependant diabetes mellitus (IDDM) versus non-insulin dependant diabetes mellitus NIDDM Main features IDDM NIDDM Epidemiology: 1. Frequency in northern Europe 2. Predominance 0.02-0.4 % N. European Caucasian 1-3 % World wide; lowest in rural areas of developing countries Clinical characteristics: 1. Age 2. Weight 3. Onset 4. Ketosis 5. Endogenous insulin 6. HLA associations 7. islets cells antibodies < 30yrs Low Rapid Common Low / absent Yes Yes >40yrs Normal / increase Slow Under stress normal / high No No Pathophysiology: 1. Etiology 2. Genetic association 3. Environmental factors Autoimmune destruction of ᵦ- cells Polygenic Viruses and toxins are implicated. Unclear/ impaired insulin secretion and insulin resistance. Strong Obesity and physical inactivity
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 44 Criteria for diagnosis of diabetes mellitus: Reference range for blood glucose level(mg/dl) Normal Impaired OGTT Indication of diabetes Fasting blood glucose (mg/dl) 70-110 100-125 >126 Two- hours postprandial blood glucose (mg/dl) < 140 140-200 > 200 Criteria for diagnosis and monitoring of DM Notes (1) Symptoms of diabetes + random plasma glucose >200 (mg/dl or 11.1 mmol/l) Random: means any time of day. Symptoms: include polyuria, polydipsia, polyphagia, unexplained weight loss. (2) Fasting plasma glucose (FPG) > 126 mg/dl (7 mmol/l) Fasting: means no caloric intake for at least 8 hours. Not more 12 hours. (3) two-hours post load glucose >200 mg/dl (> 11.1 mmol/l) During OGGT using 75 g anhydrous glucose dissolved in water. (4) Glycated hemoglobin (HBA1c) > 12% of normal Hb and fructosamine and microalbuminuria (30-200 mg/l) index of early affection of kidney in diabetes (diabetic nephropathy) HBA1c: index over 2-3 months; fructosamine index over 2-3 weeks; microalbuminuria normally (20-30 mg/l urine)
WHO Criteria for diagnosis of diabetes mellitus and impaired glucose tolerance (IGT) : RANDOM GLUCOSE SAMPLE (MMOL/L) Diabetes unlikely Diabetes uncertain Diabetes likely Venous plasma < 5.5 5.5 -less 11 11 Venous blood < 4.4 4.4 -less 10 10 Capillary plasma < 5.5 5.5 - less 12.2 12.2 Capillary blood < 4.4 4.4 – less 11.1 11.1 likely= confirmed Uncertain = unconfirmed unlikely-= discarded 1 mmol/L = 18 mg/dl STANDARDIZED OGGT (MMOL/L) Diabetes IGT Venous plasma Fasting >7.8 < 7.8 2 hrs >11.1 7.8 - < 11.1 Venous blood Fasting >6.7 < 6.7 2 hrs >10.0 6.7 - < 10.0 Capillary plasma Fasting >7.8 < 7.8 2 hrs >12.2 7.8 - < 12.2 Capillary blood Fasting > 6.7 < 6.7 2 hrs > 11.1 6.7 - < 11.1 8/15/23 45 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 46
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 47
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 48
8/15/23 49 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Case study 1
8/15/23 50 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 1
8/15/23 51 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Case study 2
Answer of Case study 2 Requests Explanation (1) The most likely diagnosis Diabetic ketoacidosis – infection can accelerate the appearance of such condition. (2) Bedside tests help in confirmed diagnosis 1. Blood glucose level will help in the treatment. 2. Urine samples for ketone bodies. (3) Laboratory tests requested 1. Urea and electrolytes can help us to check renal conditions. 2. Serum sodium and potassium levels for checking of hyperkalemia. 3. Acid base balance tests for detection the severity of acidosis. 4. Sputum sample for microbiology to confirm presence of infection. 8/15/23 52 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 53 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Case study 3
8/15/23 54 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 3
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 55 2 Aaser Abdelazim, PhD Assistant professor of Medical Biochemistry and Molecular Biology amabdalazim@ub.edu.sa
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 56 1. Sequelae of lipid determination 2. Major points during sampling for lipid profile. 3. Plasma appearance
A. Sequelae of lipids determinations 1. Coronary heart diseases(CHD) 2. Acute pancreatitis 3. Failure to grow and weakness 4. Cataract 8/15/23 57 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Diagnose Major points for sampling for blood lipid profile:- 1) Patient should be fasted at least12 hours before sampling 2) Test should not performed during acute illness 3) Test should not performed on hospitalized patients until 2-3 months of illness 4) Blood lipids affected by body posture, drugs, smoking and alcohol 5) Samples should not heparinized 6) Plasma or serum Samples should be separated as soon as possible 7) Body weight should be remain constant at least for 2-3 weeks 8) Abnormal results should be confirmed before change the type of therapy
(1) Plasma appearance 8/15/23 58 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Clear Turbid Cloudy to opaque Creamy layer appeared on the surface of the plasma within 4 hours TG <200 mg/dl TG~300 mg/dl TG >600 mg/dl CM present
Lipid profile 8/15/23 59 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 60 (1) Serum Total Cholesterol (N= 130-220 mg/dl) 1. Used to monitoring the CHD 2. Monitoring other lipoprotein disorders 1. Idiopathic hypercholesterolemia 2. Hyperlipoproteinemia 3. Chronic renal failure 4. Smoking 5. Hypothyroidism 6. Obstructive liver diseases 7. Pregnancy 8. Pancreatic diseases include DM 1. Hyperthyroidism 2. Malnutrition 3. Severe liver cell damage 4. Chronic anemia LOW CHOLESTEROL
(2) Serum HDL-Cholesterol (N=30-75 mg/dl ) (levels >60 mg/dl good indication –ve CHD) 1.Vigorous exercise 2.Some familial lipoproteins disorders 3.Mild alcohol intake 4.Estrogen treatment 5.Insulin treatment 6.Increase clearance of TG 1. Nephrosis 2. Chronic liver diseases 3. Stress 4. Obesity 5. Smoking 6. Lack of exercise 7. Hyperthyroidism 8. DM 9. Familial LCAT deficiency 8/15/23 61 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology High HDL-CH low HDL-CH
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 62 Risk factor for CHD = Every 1 mg/dl decrease in HDL increases the risk of CHD by 2-3% Risk factor Low :3.3-4.4 Average: 4.4-7.1 Moderate: 7.1-11 High:>11 Interpretation for Risk factor Total cholesterol HDL-cholesterol NOTE: Now there are many applications on mobile stores can calculate this risk factor
1. Idiopathic hypercholesterolemia 2. Hyperlipoproteinemia 3. Chronic renal failure 4. Smoking 5. Hypothyroidism 6. Obstructive liver diseases 7. Pregnancy 8. Pancreatic diseases include DM 9. Diet reach in cholesterol, saturated FA 10. antihypertensive B blocker drugs 1. Oral estrogen 2. Sever illness 3. A betalipoproteinemia 8/15/23 63 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology High (3) Serum LDL-Cholesterol (N=65-175mg/dl) low
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 64 Determination of LDL-cholesterol level 1. Total Cholesterol= HDL+VLDL+LDL (in lab we can measure TC,HDL,TG but neither LDL nor VLDL ) 2. Major amount of TG present in VLDL= 5 times the amount of CL so we can calculate the amount of CL in VLDL by TG/5 Friedwald formula: LDL=(HDL+TG/5)-Total CL
(4) Serum Triglycerides (N=40-160 mg/dl) 1. Idiopathic hypercholesterolemia 2. Hyperlipoproteinemia 3. Chronic renal failure 4. Smoking 5. Hypothyroidism 6. Obstructive liver diseases 7. Pregnancy 8. Pancreatic diseases include DM 1. TG should be measured after 12 hours 2. fasting serum levels are 5% higher than plasma 3. While HDL is the same at fasting and after meal 4. TGs are not strong predictors for atherosclerosis and CHD Precautions 8/15/23 65 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology mg/dl=88.4 mmol/L High triglycerides
Lipid Desirable Borderline High risk Total Cholesterol <200 200-239 240 HDL- Cholesterol 60 35-45 <35 LDL- Cholesterol 60-130 130-159 160-189 Triglycerides <150 150-199 200-499 Lipid profile interpretation All data in the table measured by mg/dl 8/15/23 66 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 67 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology LIPOPROTEINS METABOLISM DISORDERS [A]: Introduction to lipoprotein structure
Apolipoprotein Molecular weight Site of synthesis Functions A-I 28,000 Intestines, liver Activates LCAT A-II 17,000 Intestines, liver B100 549,000 Liver 1. Triglycerides and cholesterol transport. 2. Binds to LDL receptors. B48 264,000 Intestines Triglycerides transport. C-I 6600 Liver Activates LCAT C-II 8850 Liver Activates LPL C-III 8800 Liver Inhibits LPL E 34,000 Intestines, liver and macrophage Binds to LDL receptors and other liver receptors. [b]: Properties of human apolipoproteins 8/15/23 68 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
Lipoprotein Apolipoproteins Properties Functions Chylomicrons B48, A-I, C-II and E qLargest lipoprotein. qSynthesized in gut after meal. qNot present in normal fasting plasma. It is the main carrier of dietary triglycerides. VLDL B100, C-II and E Synthesized in liver Main carrier of endogenous triglycerides. LDL B100 Generated from VLDL in circulation. The main carrier of cholesterol. HDL A-I and A-II The smallest type It has a protective function. It takes cholesterol from extra hepatic tissues to liver for excretion. [c]: Properties of human apolipoproteins 8/15/23 69 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
[d]: Composition of blood lipoproteins Components Chylomicro ns VLDL IDL LDL HDL Triglycerides 85% 55% 26% 10% 8% Proteins 2% 9% 11% 20% 45% Apolipoproteins B, C, E B, C, E B,E B A, C, E Cholesterol 1% 7% 8% 10% 5% Cholesterol ester 2% 10% 30% 35% 15% Phospholipids 8% 20% 23% 20% 25% 8/15/23 70 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology NOTE: The highest cholesterol concentration is present in LDL, highest triglycerides is present in chylomicrons, highest protein concentration is present in HDL, highest phospholipids concentration is present in HDL.
8/15/23 71 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology [e]: lipoproteins metabolism
8/15/23 72 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology [f]: LDL and its receptors
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 73 [g]: clinical disorders of lipid metabolism (dyslipidemias) Genetic causes Secondary causes Disorder Genetic defect Fredrickson Risk (1) Lipoprotein lipase deficiency Reduced the activity of LPL I Pancreatitis (2) Apo C-II deficiency Inability to synthesis Apo C-II the cofactor for LPL I Pancreatitis (3) Familial hypercholesterolemia Reduced the number of functional LDL receptors IIa or IIb CHD (4) Familial hypertriglyceridemia Single gene defect IV or V (5) Familial combined hyperlipidemia Single gene defect IIa, IIb, IV or V CHD (6) A betalipoproteinemia Inability to synthesize ApoB Normal Deficiency of fat soluble vitamins and neurological defects (7) An alphalipoproteinemia (Tangier disease) Inability to synthesize ApoA Normal Storage of cholesteryl ester in abnormal places and neurological defects A. Genetic causes of dyslipidemias
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 74 A. Secondary causes of dyslipidemias Disorder Dominant lipid that affected (1) Diabetes mellitus Triglyceride (2) Excess alcohol intake (3) Chronic renal failure (4) Drugs as (thiazide diuretics, nonselective B-blockers ) (5) Hypothyroidism Cholesterol (6) A betalipoproteinemia (7) Nephrotic syndrome
8/15/23 75 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology [h]: Frederickson (WHO) classification of dyslipidemias NOTE: Fredrickson classification of dyslipidemias based on the appearance of fasting plasma samples after standing for 12 hrs at 4 ºC then determination of its cholesterol and triglycerides content.
8/15/23 76 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Conversion factors 1. Cholesterol = x38.66 2. Glucose_____ x18.016 3. Triglycerides _____ x 87.5 4. BUN_____x2.808 5. Urea___-x6.006 6. Uric acid _____x 59.48 Case study 1
8/15/23 77 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 1
8/15/23 78 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
8/15/23 79 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Case study 2
8/15/23 80 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 2
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 81 3
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 82 Body fluid compartments: 1. An average person weighting 70 kg; contains 42 liters of water. 2. ECF can be classified into plasma fluid and interstitial fluids. 3. Inlet; oral or I/V injection fluids. 4. Outlet; through urine or respiration or evaporation from skin. Inlet Extracellular fluids Intracellular fluids Outlet Normal
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 83 Fluid loss consequences Intracellular loss Extracellular loss Cellular dysfunctions, coma 1) Circulatory collapse 2) Renal failure 3) Shock Normal Normal Over hydration Dehydration
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 84 Points Dehydration Over hydration Pulse Increase Normal BP Decrease Normal / increase Skin trugor Decrease Increase Eyeball Soft/sunken Normal Mucous membrane Dry Normal Urine output Decrease Normal/decrease Consciousness Decrease Decrease Clinical disorders of severe hydration disorders:
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 85 Electrolytes: Na+ qNa is the main extracellular cation. qHighest solute concentration in plasma so it mainly used to determine plasma osmolality qConcentration of Na may be changed due to the change in Na conc. Itself or due to the change in water conc. K+ Proteins/ phosphates Cl-/ HCO3- Osmolality: Movement of water between body compartments keeps osmolality the same Osmol. qOsmolality of a solution = mmol of solutes/kg solvents (water). qNormal osmolality of serum and other body fluids except urine = 285 mmol/kg. qSerum osmolality (mmol/kg)= 2x serum conc. (mmol/l); this formula use only if the serum urea and glucose are within the reference range or the highest values should be added to correct the calculated osmolality. qOsmaolal gap: is the difference between calculated and measured osmolality. Osmol.
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 86 Water and sodium balance: Unregulated Other ways of water loss are: qFistulae qDiarrhea qVomiting Regulated by AVP Water intake (0.5-5 liters/day) Depends on the daily habits Body distribution (42 liters)
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 87 0.5 ml/min (decrease water excretion) AVP (ADH) (Arginine vasopressin) Posterior pituitary Hypothalamus 15 ml/min (increase water excretion) H2O Solute conc. Low (Low osmolality ) Solute conc. High (High osmolality ) Regulation of water balance by AVP:
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 88 Sodium balance: Sodium intake 100-300 mmol/day In health total body level do not changed if the intake between 5-750 mmol/dy Body distribution (3700 mmol) for 70 kg man Na losses in diarrhea are usually fatal in infants
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 89 Adrenal cortex Renin Angiotensinogen Angiotensin II Angiotensin I Aldosterone Angiotensin II Angiotensin I Angiotensinogen Renin Aldosterone Aldosterone reduces sodium loss at the expense of K&H in response to low blood pressure Sodium regulation by Aldosterone: Atrial natriuretic peptide increase Na loss by increase urinary sodium loss. Na retention in response of falling of BP Na loss in response to increase BP
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 90 Regulation of volume: H2O Na/Cl Are mainly present in ECF They held water outside the cell qSo the amount of Na determine the volume of the compartment (ECF). qAldosterone and AVP mainly interacts to keep ECF. H2O Patients with loss of fluids due to vomiting or diarrhea in GIT infections without intake of Na or water become fluid depleted. So Aldosterone secretion is increase to retain any salts during fluid therapy in the same time AVP ensures water retain too. This rises ECF osmolality. ECF loss
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 91 HYPERNATREMIA Definition: increase serum sodium above 135-145 mmol/l Before analyzing a patient sample for serum sodium many considerations should be taken: 1.Is this patient lost fluids? 2.Is the volume of ECF reduced? 3.If there is a fluids loss is this loss water or water with sodium? 4.Is the patient has given the appreciate fluid therapy or ingested sodium slats? When these questions have been answered the type of hypernatremia can be addressed and the treatment become easy.
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 92 Assessing the cause of hypernatremia: A patient become hypernatremic because of: 1.Water depletion 2.Water and sodium depletion 3.Excess sodium intake or retention in ECF 4.Very rare in cases of renal failure when kidneys unable to secretes Na. [Na+] [Na+] (a) ECF and ICF are reduced (b) ECF slightly expanded and ICF is normal
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 93 HYPERNATREMIA Na content normal& H2O decreased Na content decreased& H2O very decreased Na content increased& H2O normal Decrease H2O intake Renal water loss (diabetes insipidus) Excessive sweating or diarrhea in children Osmotic diuresis (diabetes mellitus) Conn’s syndrome Cushing’s syndrome Na+ administration Urine maximally concentrated & reduce urine volume Urine not be concentrated Normal or increased volume
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 94 HYPONATREMIA DEFINITION: Is a significant fall in serum sodium concentration below the range 135-145 mmol/l. CAUSES: 1. Water retention: more water in the ECF lead to dilute Na. 2. Loss of Sodium: for ECF e.g. (vomiting, fistulae). [Na]
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 95 HYPONATRAEMIA WITH WATER RETINTION Oedematous Non-oedematous Water excretion water intake e.g. Nephrotic syndrome e.g. Inappropriate I/V saline Water excretion water intake e.g. Renal failure, So-called syndrome of inappropriate antiduresis (SIAD) e.g. Compulsive water drinking
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 96 4
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 97 qDrug effect is assessed by observing patients clinical state. qTherapeutic drug monitoring (TDM) is : measurement of drug concentration in plasma, or saliva as a mean for calculation of drug dosage adequacy. qThe curve will give information about: 1) Half life of the drug. 2)Volume of drug distribution which estimate the correct dose once or several times doses. THERAPEUTIC DRUG MONITORING (TDM): Figure (1): Concentration of drug in plasma
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 98 Sampling for TDM Before taking the samples for TDM important things should be taken in mind like: 1)Ask the patient about the compliance (is the prescribed drug accurate for the compliance ?). 2)Check for drug interaction. 3)Note the doses and time of last dose. 4)Take the sample at appropriate time (the best time to take the sample is just before the dose this known as trough concentration). INTERPERTATION OF DRUG LEVELS qHigher or lower levels than the expected depend on the compliance and changes occurring with other drug or in kidneys and liver. qCumulative reports are very useful for the comparison between levels. qEach drug has a population reference range with minimal toxicity and maximal therapeutic effect and the therapeutic dose for a patient may be toxic to the other.
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 99 Drugs for which TDM is appropriate Although many drugs are prescribed in the specialists units only small groups of them need to be measured and need TDM most of them have a low therapeutic index means that toxic dose not far from therapeutic dose (table 1 show them) Drug Reason for TDM Notes Toxicity Interactions Compliance Phenytoin √ √ √ Has saturable kinetics Digoxin √ √ √ Highly depend on renal functions Theophylline √ √ √ Has low therapeutic index (common toxicity) Methotrexate √ If slowly excreted patients need folate Cyclosporin √ Nephrotoxic (need to measure Creatinine ) Carbamazapine √ √ √ Risk of a plastic anemia and fetal anomalies like Primidone √ Metabolized to phenobarbitone and both should be measured Phenobarbitone √ Can cause depression of CNS and PNS Gentamycin and other √ Both peak and trough concentration should be measured
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 100 Drug Medical use Phenytoin Is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures, partial seizures, but not absence seizures. Digoxin Digoxin is occasionally used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication. Theophylline known as 1,3-dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. Methotrexate It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid via dihydrofolate reductase. Cyclosporin Is an immunosuppressant drug widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells. Carbamazapine used in the treatment of epilepsy and neuropathic pain. It may be used in schizophrenia along with other medications and as a second line agent in bipolar disorder. Primidone Is an anticonvulsant of the barbiturate class. Phenobarbitone is a medication recommended by the World Health Organization for the treatment of certain types of epilepsy. Gentamycin and other aminoglycosides It is an antibiotic used to treat several types of bacterial infections, This include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis.
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 101 Common causes of sub-therapeutic or toxic levels Sub-therapeutic levels Toxic levels 1. Non compliance 2. Dose too low 3. Malabsorption 4. Rapid metabolism 1. Overdose 2. Dose too high 3. Dose too frequent 4. Impaired renal function 5. Reduced hepatic metabolism
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 102 DRUG INTERACTIONS qInterference of one drug with the metabolism and excretion of the other; on the other hand addition of one drug will alter the plasma concentration of the another. qIn these circumstances it is useful to lower the dose or discontinue the drug for a time. EXAMPLE: Patients with chronic asthma controlled on THEOPHYLLINE usually develop a sever chest infection, the patients in this case were prescribed ERYTHROMYCIN which will interfere with theophylline inducing tachycardia and dizziness. So we enforced to stop theophylline for two days and once the infection was clear; the original dose of theophylline will restart. Absorption Distribution Metabolism Excretion Affected drug Interacting drug (s) Increase decrease Interacting drug (s) Increase plasma level of affected drug decrease plasma level of affected drug
8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 103 Answer of Case study 1 Case study 1

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Clinical Biochemistry

  • 1.
    Clinical Biochemistry AASER ABDELAZIM ProfessorMedical Biochemistry and Molecular Biology FAIMER fellow 2021 (Medical education) Clinical Chemistry consultant amabdalazim@ub.edu.sa 8/15/23 1 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 2.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 2 1. Clinical biochemical tests comprise over1/3 of all hospital laboratory investigations 2. Most biochemical tests are now performed at the site of clinic especially during major operations like transplantation not only in clinical biochemistry labs. 3. Most laboratories are now computerized and use: q The par-coding for specimens q Automated methods in analysis This leads to: A. High degrees of productivity . B. Improves the quality of service. C. Allow direct access to the results by clinicians. A. INTRODUCTION
  • 3.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 3 History Clinical examination Diagnostic services Imaging Physiological tests ECG, EEG, lung functions Lab services Hematology Histopathology Immunology Microbiology Clinical biochemistry Core tests Emergency tests Specialized tests B. Place of clinical biochemistry in medicine
  • 4.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 4 Core tests commonly requested by physician e.g., U, LFTs and Es (Urea, liver function tests electrolytes) Core tests 1. Not all labs introduce the service but it restricted only to some reference centers 2. Needed to diagnose rare diseases Specialized tests 1. Done immediately 2. Results taken on call 3. Need to work out of normal hours of lab. 4. All labs should perform theses tests. Emergency tests Core biochemical tests Sodium, potassium, chloride, bicarbonates Urea, creatinine Calcium, phosphates Total proteins, albumins Bilirubin, alkaline phosphatase ALT, AST T4, TSH ɣ-GT, CK Blood gases Amylase Specialized tests Emergency tests Hormones Urea and electrolytes Special proteins Blood glucose Trace elements Blood gases Vitamins Paracetamol Drugs Salicylates Lipids and lipoproteins Calcium DNA analysis Amylase
  • 5.
    Clinical biochemical laboratory qBiochemicaltests are used for diagnosis, monitoring, treatment, screening and for prognosis. q core biochemical tests are performed in every biochemistry laboratory. qSpecialized biochemical tests are preferred to be performed in larger departments. q laboratory personnel should be able to select the perfect type of tests and interpret the results based on his knowledge. 8/15/23 5 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 6.
    8/15/23 6 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology
  • 7.
    8/15/23 7 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology 1 By Aaser M. Abdelazim, PhD Assistant professor of Biochemistry and Molecular biology
  • 8.
    A tour incarbohydrates metabolism Digestion Absorption Metabolism 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 8
  • 9.
    Digestion of carbohydrates 60% ofour food [starch, glycogen, sucrose, lactose, and cellulose] Salivary α-amylase (pH 6-7) Mouth stomach Pancreas Pancreatic α-amylase (pH 7.1) Maltose /isomaltose/starch dextrins Maltose /isomaltose Small intestine Lactase/sucrase/maltase/α-dextrinase Cocktail of sugars [monosacchrides] We have not β-glucosidase so cellulose passes as such 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 9
  • 10.
    Absorption of carbohydrates GLUCOSE –GALACTOSE-FRUCTOSE Jejunum Portal vein GLUCOSE Active transport system SGLT-1 Na-K pump Faster than passive Need ATP From lumen to intestinal cells Passive transport system GLUTs No need ATP From lumen to intestinal cells GLUT-5 Form intestinal /renal /liver cells /β-cells to circulation GLUT-2 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 10
  • 11.
    GLUCOSE – GALACTOSE-FRUCTOSE Portalvein GLUCOSE Fate of absorbed sugars OXIDATION STORAGE CONVERSION Glycogen Glycolysis- Krebs MAJOR PATHWAY Uronic acid Detoxification NADPH Ribose HMP-shunt Lactose Glucosamine Galactose amine Fructose Glycogenesis Lipids Lipogenesis 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 11
  • 12.
    Blood glucose Fasting (70-110mg/dl) Onehour (120-150 mg/dl) Two hours(70-140 mg/dl) Dietary carbohydrates Liver glycogen Amino acids and non carbohydrate-substance Absorption Gluconeogenesis Glycogenolysis BLOOD GLUCOSE HORMONAL REGULATION HEPATIC REGULATION RENAL REGULATION INSULIN Glucagon Growth Glucocorticoids Catecholamines 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 12
  • 13.
    BLOOD GLUCOSE HORMONAL REGULATION Glucagon Growth H Glucocorticoids CatecholaminesINSULIN Glucose uptake Glucose oxidation Glycogenesis + + + Lipogenesis + Glycogenolysis Gluconeogenesis - - Glycogenolysis Gluconeogenesis + + GLUCAGON Catecholamine Gluconeogenesis + Gluconeogenesis Glucose uptake + - Glucocorticoids Insulin action at cell mem Glucose uptake - - Growth H THYROID H Glycolysis / Gluconeogenesis + ?! 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 13
  • 14.
    Condition Insulin Level InsulinLevel (SI Units*) Fasting < 25 mIU/L < 174 pmol/L 30 minutes after glucose administration 30-230 mIU/L 208-1597 pmol/L 1 hour after glucose administration 18-276 mIU/L 125-1917 pmol/L 2 hour after glucose administration 16-166 mIU/L 111-1153 pmol/L ≥3 hours after glucose administration < 25 mIU/L < 174 pmol/L *SI unit: conversional units x 6.945 NORMAL INSULIN LEVELS 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 14
  • 15.
    BLOOD GLUCOSE HEPATIC REGULATION AFTER MEAL FASTING Glycogenolysis Gluconeogenesis + + Ketogenesis + BRAIN Addsugar to blood BRAIN MUSCLES ADIPOSE LIVER PORTAL Lipids Glucose-6-P Glycogen Lipogenesis Glycogenesis 40% of glucose Circulation Insulin secretion + 60% of glucose LIVER Glucokinase + HYPERGLYCEMIA Glucose uptake 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 15
  • 16.
    BLOOD GLUCOSE RENAL REGULATION LOW RENALTHRESHOLD HIGH RENAL THRESHOLD URINE RENAL THRESHOLD 180 mg/dl 100 mg/dl Diabetes innocence 20% of pregnant 220 mg/dl Elderly people Diabetes associated renal damage 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 16
  • 17.
    Diabetes mellitus: Is afamily disorder characterized by hyperglycemia Etiology: Type Etiology Type I 1. ᵦ- cell destruction lead to absolute insulin deficiency 2. Immune mediated 3. Idiopathic Type II May range from predominantly insulin resistance with relative insulin deficiency to a predominantly Secretory defect with insulin resistance. Gestational diabetes (GDM) Similar to type II; it is diabetes that diagnosed in pregnancy as pregnancy is associated with increase tissue cells resistance to insulin; the hyperglycemia of GDM diminishes after delivery and other cases develop type II diabetes. Other specific types 1. Genetic defect of beta cells functions 2. Genetic defect in insulin action 3. Diseases of exocrine pancreas (cystic fibrosis) 4. Endocrinopathies (cushing’s syndrome) 5. Drug – or – chemical induced (protease inhibitors or glucocorticoids) 6. Infections 7. Uncommon forms of immune- mediated diabetes 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 17
  • 18.
    DIABETES MELLITUS Biochemical disturbancesin Diabetes Mellitus Syndrome Disease LIPIDS PROTEINS HYPERGLYCEMIA CARBOHYDRATES DYSLIPIDEMIA DYSPROTEINEMIA Relative /absolute deficiency of INSULIN Chronic metabolic disorder 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 18
  • 19.
    Biochemical disturbances inDiabetes Mellitus CARBOHYDRATES GLUCNEOGENESIS GLYCOGENOLYSIS Glucose uptake Intracellular glucose POLYPHAGIA HYPERGLYCEMIA 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 19
  • 20.
    Biochemical disturbances inDiabetes Mellitus HYPERGLYCEMIA Glucose >renal threshold Plasma osmolality Dehydration Intra cellular water POLYDEPSIA Brain dehydration Hyperglycemic hyperosmolar coma Loss of water POLYUREA Loss of water soluble vitamins and minerals GLUCOSURIA 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 20
  • 21.
    8/15/23 21 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Glucose homeostasis
  • 22.
    8/15/23 22 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Action of insulin
  • 23.
    8/15/23 23 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Development of diabetic ketoacidosis:
  • 24.
    Blood Glucose (Bloodsugar) Normal level = 70 – 110 mg/dl I- Hyperglycemia •Diabetes mellitus •Gestational diabetes GDM(24th- 28th week) •Acromegaly •Acute stress (response to trauma, heart attack, stroke) •Chronic renal failure •Cushing syndrome (excess glucocorticoids) •Hyperthyroidism •Pancreatitis •Pancreatic tumors •Excess food intake •Drugs (corticosteroids, tricyclic antidepressants, diuretics, epinephrine, estrogen, Lithium, phenytoin, Salicylates.) 8/15/23 24 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 25.
    II- Hypoglycemia Hypoglycemia inDiabetic patients 1. Patients taking blood glucose lowering medications q Excess dose of insulin q High dose of sulfonylurea q Extra dose of Meglitinides. 1. Increase the activity or the exercise 2. Excess drinking of alcohols. Hypoglycemia in non Diabetic patients Reactive hypoglycemia (postprandial, after meal) Fasting (post absorptive) 8/15/23 25 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 26.
    1) Some peoplethat were sensitive to normal release of epinephrine. 2) Deficiency in Glucagon secretion. 3) Gastric surgery (rapid passage of food to intestine). Diagnosed from blood samples lower than 50 mg/dl 1. Alcohols: especially binge drinking(depletion of pyruvate and Oxaloacetate) 2. Critical illness: (hepatocellular damage, renal insufficiency , sepsis, starvation ) 3. Hormonal deficiency:(cortisol, GH, Glucagon, epinepherine ) 4. Tumors :(insulinoma: tumor of B – cells ) 5. Drugs:(salicylates in large dose, Pentamedines (pneuomenia treatment),Quinine(malaria ttt) ) 8/15/23 26 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Appears after 3-4 hrs after meals
  • 27.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 27 1- Babies from diabetic mothers. 2- In born error of metabolism. A. Glycogen storage diseases. B. Galactosemia Etiology: New born with risk of hypoglycemia 12% New born without risk of hypoglycemia 88%
  • 28.
    The clinical effectof hypoglycemia Catecholamin es and glucagon starts to face the problem Starts to enter in coma Brian damage Coma 8/15/23 28 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 29.
    8/15/23 29 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology (1) Oral glucose in conscious patients: If patient can swallow, give sweet drink, sweets, or glucose tablets (2) Oral glucose in comatose patients: If patient unable to swallow, jam or any available glucose gel smeared on inside the cheeks (3) i.m Glucagon: May be given to comatose patients (4) i.v Glucose: Treatment of choice in comatose patients
  • 30.
    1. Blood sugar 2.Urine sugar 3. Glycated HB 4. Glycated proteins 1- Venous blood 2- Capillary blood RBCs level is less than plasma level due to less water contents of RBCs G soluble in water 1) Separated rapidly 2) Rapid transported to lab. 3) Cooling of samples 4) Add sod. Fluoride to inhibit glycolysis 1) Fasting 2) Random 3) Timed interval (glucose tolerance) 8/15/23 30 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Precautions Samples Types of Samples Monitoring
  • 31.
    ORAL GLUCOSE TOLERANCETEST 8/15/23 31 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 1) Mild or no DM symptoms 2) Glucose absorbance and utilization 3) Renal threshold (note next slide) 4) Persistent glycosuria 5) Pregnant woman with family history of diabetes Indications 1) Let patient to be fasted for not more than 12 hours 2) Measure fasting blood glucose level (0) time and register the results. 3) Give the patient 75 gm of sugar in about 400-500 ml water orally. 4) Every hour take blood and urine samples for determination of glucose draw the oral glucose tolerance curve
  • 32.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 32 Remarks on The curve: 1. Ascending limb: explains the glucose absorbance 2. Descending limb: explains glucose utilization and insulin response 3. Usually glucose does not appears in urine until it be over the threshold level 4. Diabetes diagnosed from FBG= >126 and at least one sample > 200 after the 1st 30 minutes 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours Max level=120-150 mg /dl Fasting level = 70-110 mg/dl Renal threshold of glucose = 180 mg/dl Hypoglycemic response/insulin overshoot Usually max value (after one hour) = 1.5 time fasting value Ascending limb Descending limb Return to fasting level ORAL GLUCOSE TOLERANCE curve
  • 33.
    Renal threshold ofglucose It is the blood glucose level above which glucose appear in urine Average =180 mg/dl 1 mmol/L = 18 mg/dl 1. Persons of diabetes innocence 2. In 20% of pregnant females 1. Elderly people due to reduced GFR 2. Diabetes associated with renal damage 8/15/23 33 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Renal threshold of glucose Low renal threshold High renal threshold 100 mg/dl 220 mg/dl
  • 34.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 34 Types of oral glucose tolerance curves: 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours 300 400 500 (1) Severe diabetic curve: Urine: Time 0 1 2 Glucose + ++ +++ Ketones Trace Trace Trace Renal threshold
  • 35.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 35 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours (2) Mild diabetic curve: Urine: Time 0 1 2 Glucose 0 0 0 Ketones 0 0 0 Renal threshold
  • 36.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 36 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours (3) Hypoglycemic curve: (4)Flat curve: blood glucose fails to rise normally after glucose load Occurs in; malapsorption, myxodema, hypopitutrism Urine: Time 0 1 2 Glucose 0 0 0 Ketones 0 0 0 Urine: Time 0 1 2 Glucose 0 0 0 Ketones 0 0 0
  • 37.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 37 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours 50 200 180 100 1 3 2 0 150 Blood glucose mg /dl Hours (5) Renal glucosuria curve: it resemble normal curve while we can find glucose in urine. Urine: Time 0 1 2 Glucose 0 + ++ Ketones 0 0 0 Renal threshold Renal threshold (6)Lag storage curve: FBG level is normal, after 30 minutes of glucose load the level be up renal threshold , then the level falls sharply in less than 2 hours Occurs in; after gasterectomy; due to rapid passage of glucose to intestine, severe liver diseases when no glucose is used in glycogenesis and all Glc goes directly to blood, rare in thyrotoxicosis due to rapid absorption of glucose. Urine: Time 0 1 2 Glucose 0 + 0 Ketones 0 0 0
  • 38.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 38 Remarks on OGTT in children Point Comments Indications of the test in children üDiabetic child with equivocal fasting or random level. üHypoglycemic child üTo exclude excess Growth H. üCystic fibrosis üFor the following conditions [polycystic ovary, strong family history, obesity and fatty liver disease] Precautions qOnly when blood glucose level 5.6 to < 7.o mmol/L. qDon’t performed in patients with thyroid dysfunctions, under physical stress e.g post surgery, hypokalemic periodic paralysis. Side effect Many child feel nauseated or vasovagal symptoms. Preparation of patient qEnsure that the child has had an adequate carbohydrate diet for at least 5 days before the test (150g/day). qAvoid prolonged fasting of child (only for 4 hour night fast) allow him to drink water with no sweet drinks. qPhysical exercise is not allowed before or during the test. qYou should perform the test at morning. Protocol 1. Measure the fasting level. 2. Prepare glucose load as following § Liquid contains 0.66 g /mL of anhydrous glucose (the dose is 2.64 ml/Kg body weight with maximum dose 113 ml.) you can add water up to 200 ml volume. § Anhydrous glucose (dose 1.75 g/kg body weight) maxium dose 75 g § Rapilose contains 75 g of glucose in 300 mL for child of weight less than 43 Kg . 3. Child should take the glucose load with in 5 minutes. 4. Take the second blood sample after 2 hours.
  • 39.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 39
  • 40.
    Biochemical disturbances inDiabetes Mellitus PROTEINS Depletion of glucose as source of energy Breakdown of tissue proteins Infection Muscle wasting Poor healing 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 40
  • 41.
    Biochemical disturbances inDiabetes Mellitus LIPIDS Depletion of glucose as source of energy Lipolysis Hyperlipidemia Loss of weight Fatty acid oxidation Acetyl CoA Ketogenesis /ketosis Ketotic coma Hyperkalemia 8/15/23 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology 41
  • 42.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 42 Diabetes mellitus: Is a family disorder characterized by hyperglycemia Etiology: Type Etiology Type I 1. ᵦ- cell destruction lead to absolute insulin deficiency 2. Immune mediated 3. Idiopathic Type II May range from predominantly insulin resistance with relative insulin deficiency to a predominantly Secretory defect with insulin resistance. Gestational diabetes (GDM) Similar to type II; it is diabetes that diagnosed in pregnancy as pregnancy is associated with increase tissue cells resistance to insulin; the hyperglycemia of GDM diminishes after delivery and other cases develop type II diabetes. Other specific types 1. Genetic defect of beta cells functions 2. Genetic defect in insulin action 3. Diseases of exocrine pancreas (cystic fibrosis) 4. Endocrinopathies (cushing’s syndrome) 5. Drug – or – chemical induced (protease inhibitors or glucocorticoids) 6. Infections 7. Uncommon forms of immune- mediated diabetes
  • 43.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 43 Insulin dependant diabetes mellitus (IDDM) versus non-insulin dependant diabetes mellitus NIDDM Main features IDDM NIDDM Epidemiology: 1. Frequency in northern Europe 2. Predominance 0.02-0.4 % N. European Caucasian 1-3 % World wide; lowest in rural areas of developing countries Clinical characteristics: 1. Age 2. Weight 3. Onset 4. Ketosis 5. Endogenous insulin 6. HLA associations 7. islets cells antibodies < 30yrs Low Rapid Common Low / absent Yes Yes >40yrs Normal / increase Slow Under stress normal / high No No Pathophysiology: 1. Etiology 2. Genetic association 3. Environmental factors Autoimmune destruction of ᵦ- cells Polygenic Viruses and toxins are implicated. Unclear/ impaired insulin secretion and insulin resistance. Strong Obesity and physical inactivity
  • 44.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 44 Criteria for diagnosis of diabetes mellitus: Reference range for blood glucose level(mg/dl) Normal Impaired OGTT Indication of diabetes Fasting blood glucose (mg/dl) 70-110 100-125 >126 Two- hours postprandial blood glucose (mg/dl) < 140 140-200 > 200 Criteria for diagnosis and monitoring of DM Notes (1) Symptoms of diabetes + random plasma glucose >200 (mg/dl or 11.1 mmol/l) Random: means any time of day. Symptoms: include polyuria, polydipsia, polyphagia, unexplained weight loss. (2) Fasting plasma glucose (FPG) > 126 mg/dl (7 mmol/l) Fasting: means no caloric intake for at least 8 hours. Not more 12 hours. (3) two-hours post load glucose >200 mg/dl (> 11.1 mmol/l) During OGGT using 75 g anhydrous glucose dissolved in water. (4) Glycated hemoglobin (HBA1c) > 12% of normal Hb and fructosamine and microalbuminuria (30-200 mg/l) index of early affection of kidney in diabetes (diabetic nephropathy) HBA1c: index over 2-3 months; fructosamine index over 2-3 weeks; microalbuminuria normally (20-30 mg/l urine)
  • 45.
    WHO Criteria fordiagnosis of diabetes mellitus and impaired glucose tolerance (IGT) : RANDOM GLUCOSE SAMPLE (MMOL/L) Diabetes unlikely Diabetes uncertain Diabetes likely Venous plasma < 5.5 5.5 -less 11 11 Venous blood < 4.4 4.4 -less 10 10 Capillary plasma < 5.5 5.5 - less 12.2 12.2 Capillary blood < 4.4 4.4 – less 11.1 11.1 likely= confirmed Uncertain = unconfirmed unlikely-= discarded 1 mmol/L = 18 mg/dl STANDARDIZED OGGT (MMOL/L) Diabetes IGT Venous plasma Fasting >7.8 < 7.8 2 hrs >11.1 7.8 - < 11.1 Venous blood Fasting >6.7 < 6.7 2 hrs >10.0 6.7 - < 10.0 Capillary plasma Fasting >7.8 < 7.8 2 hrs >12.2 7.8 - < 12.2 Capillary blood Fasting > 6.7 < 6.7 2 hrs > 11.1 6.7 - < 11.1 8/15/23 45 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 46.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 46
  • 47.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 47
  • 48.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 48
  • 49.
    8/15/23 49 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Case study 1
  • 50.
    8/15/23 50 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 1
  • 51.
    8/15/23 51 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Case study 2
  • 52.
    Answer of Casestudy 2 Requests Explanation (1) The most likely diagnosis Diabetic ketoacidosis – infection can accelerate the appearance of such condition. (2) Bedside tests help in confirmed diagnosis 1. Blood glucose level will help in the treatment. 2. Urine samples for ketone bodies. (3) Laboratory tests requested 1. Urea and electrolytes can help us to check renal conditions. 2. Serum sodium and potassium levels for checking of hyperkalemia. 3. Acid base balance tests for detection the severity of acidosis. 4. Sputum sample for microbiology to confirm presence of infection. 8/15/23 52 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 53.
    8/15/23 53 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Case study 3
  • 54.
    8/15/23 54 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 3
  • 55.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 55 2 Aaser Abdelazim, PhD Assistant professor of Medical Biochemistry and Molecular Biology amabdalazim@ub.edu.sa
  • 56.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 56 1. Sequelae of lipid determination 2. Major points during sampling for lipid profile. 3. Plasma appearance
  • 57.
    A. Sequelae oflipids determinations 1. Coronary heart diseases(CHD) 2. Acute pancreatitis 3. Failure to grow and weakness 4. Cataract 8/15/23 57 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Diagnose Major points for sampling for blood lipid profile:- 1) Patient should be fasted at least12 hours before sampling 2) Test should not performed during acute illness 3) Test should not performed on hospitalized patients until 2-3 months of illness 4) Blood lipids affected by body posture, drugs, smoking and alcohol 5) Samples should not heparinized 6) Plasma or serum Samples should be separated as soon as possible 7) Body weight should be remain constant at least for 2-3 weeks 8) Abnormal results should be confirmed before change the type of therapy
  • 58.
    (1) Plasma appearance 8/15/2358 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology Clear Turbid Cloudy to opaque Creamy layer appeared on the surface of the plasma within 4 hours TG <200 mg/dl TG~300 mg/dl TG >600 mg/dl CM present
  • 59.
    Lipid profile 8/15/23 59 AaserAbdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 60.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 60 (1) Serum Total Cholesterol (N= 130-220 mg/dl) 1. Used to monitoring the CHD 2. Monitoring other lipoprotein disorders 1. Idiopathic hypercholesterolemia 2. Hyperlipoproteinemia 3. Chronic renal failure 4. Smoking 5. Hypothyroidism 6. Obstructive liver diseases 7. Pregnancy 8. Pancreatic diseases include DM 1. Hyperthyroidism 2. Malnutrition 3. Severe liver cell damage 4. Chronic anemia LOW CHOLESTEROL
  • 61.
    (2) Serum HDL-Cholesterol(N=30-75 mg/dl ) (levels >60 mg/dl good indication –ve CHD) 1.Vigorous exercise 2.Some familial lipoproteins disorders 3.Mild alcohol intake 4.Estrogen treatment 5.Insulin treatment 6.Increase clearance of TG 1. Nephrosis 2. Chronic liver diseases 3. Stress 4. Obesity 5. Smoking 6. Lack of exercise 7. Hyperthyroidism 8. DM 9. Familial LCAT deficiency 8/15/23 61 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology High HDL-CH low HDL-CH
  • 62.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 62 Risk factor for CHD = Every 1 mg/dl decrease in HDL increases the risk of CHD by 2-3% Risk factor Low :3.3-4.4 Average: 4.4-7.1 Moderate: 7.1-11 High:>11 Interpretation for Risk factor Total cholesterol HDL-cholesterol NOTE: Now there are many applications on mobile stores can calculate this risk factor
  • 63.
    1. Idiopathic hypercholesterolemia 2.Hyperlipoproteinemia 3. Chronic renal failure 4. Smoking 5. Hypothyroidism 6. Obstructive liver diseases 7. Pregnancy 8. Pancreatic diseases include DM 9. Diet reach in cholesterol, saturated FA 10. antihypertensive B blocker drugs 1. Oral estrogen 2. Sever illness 3. A betalipoproteinemia 8/15/23 63 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology High (3) Serum LDL-Cholesterol (N=65-175mg/dl) low
  • 64.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 64 Determination of LDL-cholesterol level 1. Total Cholesterol= HDL+VLDL+LDL (in lab we can measure TC,HDL,TG but neither LDL nor VLDL ) 2. Major amount of TG present in VLDL= 5 times the amount of CL so we can calculate the amount of CL in VLDL by TG/5 Friedwald formula: LDL=(HDL+TG/5)-Total CL
  • 65.
    (4) Serum Triglycerides(N=40-160 mg/dl) 1. Idiopathic hypercholesterolemia 2. Hyperlipoproteinemia 3. Chronic renal failure 4. Smoking 5. Hypothyroidism 6. Obstructive liver diseases 7. Pregnancy 8. Pancreatic diseases include DM 1. TG should be measured after 12 hours 2. fasting serum levels are 5% higher than plasma 3. While HDL is the same at fasting and after meal 4. TGs are not strong predictors for atherosclerosis and CHD Precautions 8/15/23 65 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology mg/dl=88.4 mmol/L High triglycerides
  • 66.
    Lipid Desirable BorderlineHigh risk Total Cholesterol <200 200-239 240 HDL- Cholesterol 60 35-45 <35 LDL- Cholesterol 60-130 130-159 160-189 Triglycerides <150 150-199 200-499 Lipid profile interpretation All data in the table measured by mg/dl 8/15/23 66 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 67.
    8/15/23 67 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology LIPOPROTEINS METABOLISM DISORDERS [A]: Introduction to lipoprotein structure
  • 68.
    Apolipoprotein Molecular weightSite of synthesis Functions A-I 28,000 Intestines, liver Activates LCAT A-II 17,000 Intestines, liver B100 549,000 Liver 1. Triglycerides and cholesterol transport. 2. Binds to LDL receptors. B48 264,000 Intestines Triglycerides transport. C-I 6600 Liver Activates LCAT C-II 8850 Liver Activates LPL C-III 8800 Liver Inhibits LPL E 34,000 Intestines, liver and macrophage Binds to LDL receptors and other liver receptors. [b]: Properties of human apolipoproteins 8/15/23 68 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 69.
    Lipoprotein Apolipoproteins PropertiesFunctions Chylomicrons B48, A-I, C-II and E qLargest lipoprotein. qSynthesized in gut after meal. qNot present in normal fasting plasma. It is the main carrier of dietary triglycerides. VLDL B100, C-II and E Synthesized in liver Main carrier of endogenous triglycerides. LDL B100 Generated from VLDL in circulation. The main carrier of cholesterol. HDL A-I and A-II The smallest type It has a protective function. It takes cholesterol from extra hepatic tissues to liver for excretion. [c]: Properties of human apolipoproteins 8/15/23 69 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology
  • 70.
    [d]: Composition ofblood lipoproteins Components Chylomicro ns VLDL IDL LDL HDL Triglycerides 85% 55% 26% 10% 8% Proteins 2% 9% 11% 20% 45% Apolipoproteins B, C, E B, C, E B,E B A, C, E Cholesterol 1% 7% 8% 10% 5% Cholesterol ester 2% 10% 30% 35% 15% Phospholipids 8% 20% 23% 20% 25% 8/15/23 70 Aaser Abdelazim ---- Professor of Medical Biochemistry and Molecular Biology NOTE: The highest cholesterol concentration is present in LDL, highest triglycerides is present in chylomicrons, highest protein concentration is present in HDL, highest phospholipids concentration is present in HDL.
  • 71.
    8/15/23 71 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology [e]: lipoproteins metabolism
  • 72.
    8/15/23 72 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology [f]: LDL and its receptors
  • 73.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 73 [g]: clinical disorders of lipid metabolism (dyslipidemias) Genetic causes Secondary causes Disorder Genetic defect Fredrickson Risk (1) Lipoprotein lipase deficiency Reduced the activity of LPL I Pancreatitis (2) Apo C-II deficiency Inability to synthesis Apo C-II the cofactor for LPL I Pancreatitis (3) Familial hypercholesterolemia Reduced the number of functional LDL receptors IIa or IIb CHD (4) Familial hypertriglyceridemia Single gene defect IV or V (5) Familial combined hyperlipidemia Single gene defect IIa, IIb, IV or V CHD (6) A betalipoproteinemia Inability to synthesize ApoB Normal Deficiency of fat soluble vitamins and neurological defects (7) An alphalipoproteinemia (Tangier disease) Inability to synthesize ApoA Normal Storage of cholesteryl ester in abnormal places and neurological defects A. Genetic causes of dyslipidemias
  • 74.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 74 A. Secondary causes of dyslipidemias Disorder Dominant lipid that affected (1) Diabetes mellitus Triglyceride (2) Excess alcohol intake (3) Chronic renal failure (4) Drugs as (thiazide diuretics, nonselective B-blockers ) (5) Hypothyroidism Cholesterol (6) A betalipoproteinemia (7) Nephrotic syndrome
  • 75.
    8/15/23 75 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology [h]: Frederickson (WHO) classification of dyslipidemias NOTE: Fredrickson classification of dyslipidemias based on the appearance of fasting plasma samples after standing for 12 hrs at 4 ºC then determination of its cholesterol and triglycerides content.
  • 76.
    8/15/23 76 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Conversion factors 1. Cholesterol = x38.66 2. Glucose_____ x18.016 3. Triglycerides _____ x 87.5 4. BUN_____x2.808 5. Urea___-x6.006 6. Uric acid _____x 59.48 Case study 1
  • 77.
    8/15/23 77 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 1
  • 78.
    8/15/23 78 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology
  • 79.
    8/15/23 79 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Case study 2
  • 80.
    8/15/23 80 Aaser Abdelazim---- Professor of Medical Biochemistry and Molecular Biology Answer of Case study 2
  • 81.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 81 3
  • 82.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 82 Body fluid compartments: 1. An average person weighting 70 kg; contains 42 liters of water. 2. ECF can be classified into plasma fluid and interstitial fluids. 3. Inlet; oral or I/V injection fluids. 4. Outlet; through urine or respiration or evaporation from skin. Inlet Extracellular fluids Intracellular fluids Outlet Normal
  • 83.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 83 Fluid loss consequences Intracellular loss Extracellular loss Cellular dysfunctions, coma 1) Circulatory collapse 2) Renal failure 3) Shock Normal Normal Over hydration Dehydration
  • 84.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 84 Points Dehydration Over hydration Pulse Increase Normal BP Decrease Normal / increase Skin trugor Decrease Increase Eyeball Soft/sunken Normal Mucous membrane Dry Normal Urine output Decrease Normal/decrease Consciousness Decrease Decrease Clinical disorders of severe hydration disorders:
  • 85.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 85 Electrolytes: Na+ qNa is the main extracellular cation. qHighest solute concentration in plasma so it mainly used to determine plasma osmolality qConcentration of Na may be changed due to the change in Na conc. Itself or due to the change in water conc. K+ Proteins/ phosphates Cl-/ HCO3- Osmolality: Movement of water between body compartments keeps osmolality the same Osmol. qOsmolality of a solution = mmol of solutes/kg solvents (water). qNormal osmolality of serum and other body fluids except urine = 285 mmol/kg. qSerum osmolality (mmol/kg)= 2x serum conc. (mmol/l); this formula use only if the serum urea and glucose are within the reference range or the highest values should be added to correct the calculated osmolality. qOsmaolal gap: is the difference between calculated and measured osmolality. Osmol.
  • 86.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 86 Water and sodium balance: Unregulated Other ways of water loss are: qFistulae qDiarrhea qVomiting Regulated by AVP Water intake (0.5-5 liters/day) Depends on the daily habits Body distribution (42 liters)
  • 87.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 87 0.5 ml/min (decrease water excretion) AVP (ADH) (Arginine vasopressin) Posterior pituitary Hypothalamus 15 ml/min (increase water excretion) H2O Solute conc. Low (Low osmolality ) Solute conc. High (High osmolality ) Regulation of water balance by AVP:
  • 88.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 88 Sodium balance: Sodium intake 100-300 mmol/day In health total body level do not changed if the intake between 5-750 mmol/dy Body distribution (3700 mmol) for 70 kg man Na losses in diarrhea are usually fatal in infants
  • 89.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 89 Adrenal cortex Renin Angiotensinogen Angiotensin II Angiotensin I Aldosterone Angiotensin II Angiotensin I Angiotensinogen Renin Aldosterone Aldosterone reduces sodium loss at the expense of K&H in response to low blood pressure Sodium regulation by Aldosterone: Atrial natriuretic peptide increase Na loss by increase urinary sodium loss. Na retention in response of falling of BP Na loss in response to increase BP
  • 90.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 90 Regulation of volume: H2O Na/Cl Are mainly present in ECF They held water outside the cell qSo the amount of Na determine the volume of the compartment (ECF). qAldosterone and AVP mainly interacts to keep ECF. H2O Patients with loss of fluids due to vomiting or diarrhea in GIT infections without intake of Na or water become fluid depleted. So Aldosterone secretion is increase to retain any salts during fluid therapy in the same time AVP ensures water retain too. This rises ECF osmolality. ECF loss
  • 91.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 91 HYPERNATREMIA Definition: increase serum sodium above 135-145 mmol/l Before analyzing a patient sample for serum sodium many considerations should be taken: 1.Is this patient lost fluids? 2.Is the volume of ECF reduced? 3.If there is a fluids loss is this loss water or water with sodium? 4.Is the patient has given the appreciate fluid therapy or ingested sodium slats? When these questions have been answered the type of hypernatremia can be addressed and the treatment become easy.
  • 92.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 92 Assessing the cause of hypernatremia: A patient become hypernatremic because of: 1.Water depletion 2.Water and sodium depletion 3.Excess sodium intake or retention in ECF 4.Very rare in cases of renal failure when kidneys unable to secretes Na. [Na+] [Na+] (a) ECF and ICF are reduced (b) ECF slightly expanded and ICF is normal
  • 93.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 93 HYPERNATREMIA Na content normal& H2O decreased Na content decreased& H2O very decreased Na content increased& H2O normal Decrease H2O intake Renal water loss (diabetes insipidus) Excessive sweating or diarrhea in children Osmotic diuresis (diabetes mellitus) Conn’s syndrome Cushing’s syndrome Na+ administration Urine maximally concentrated & reduce urine volume Urine not be concentrated Normal or increased volume
  • 94.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 94 HYPONATREMIA DEFINITION: Is a significant fall in serum sodium concentration below the range 135-145 mmol/l. CAUSES: 1. Water retention: more water in the ECF lead to dilute Na. 2. Loss of Sodium: for ECF e.g. (vomiting, fistulae). [Na]
  • 95.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 95 HYPONATRAEMIA WITH WATER RETINTION Oedematous Non-oedematous Water excretion water intake e.g. Nephrotic syndrome e.g. Inappropriate I/V saline Water excretion water intake e.g. Renal failure, So-called syndrome of inappropriate antiduresis (SIAD) e.g. Compulsive water drinking
  • 96.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 96 4
  • 97.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 97 qDrug effect is assessed by observing patients clinical state. qTherapeutic drug monitoring (TDM) is : measurement of drug concentration in plasma, or saliva as a mean for calculation of drug dosage adequacy. qThe curve will give information about: 1) Half life of the drug. 2)Volume of drug distribution which estimate the correct dose once or several times doses. THERAPEUTIC DRUG MONITORING (TDM): Figure (1): Concentration of drug in plasma
  • 98.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 98 Sampling for TDM Before taking the samples for TDM important things should be taken in mind like: 1)Ask the patient about the compliance (is the prescribed drug accurate for the compliance ?). 2)Check for drug interaction. 3)Note the doses and time of last dose. 4)Take the sample at appropriate time (the best time to take the sample is just before the dose this known as trough concentration). INTERPERTATION OF DRUG LEVELS qHigher or lower levels than the expected depend on the compliance and changes occurring with other drug or in kidneys and liver. qCumulative reports are very useful for the comparison between levels. qEach drug has a population reference range with minimal toxicity and maximal therapeutic effect and the therapeutic dose for a patient may be toxic to the other.
  • 99.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 99 Drugs for which TDM is appropriate Although many drugs are prescribed in the specialists units only small groups of them need to be measured and need TDM most of them have a low therapeutic index means that toxic dose not far from therapeutic dose (table 1 show them) Drug Reason for TDM Notes Toxicity Interactions Compliance Phenytoin √ √ √ Has saturable kinetics Digoxin √ √ √ Highly depend on renal functions Theophylline √ √ √ Has low therapeutic index (common toxicity) Methotrexate √ If slowly excreted patients need folate Cyclosporin √ Nephrotoxic (need to measure Creatinine ) Carbamazapine √ √ √ Risk of a plastic anemia and fetal anomalies like Primidone √ Metabolized to phenobarbitone and both should be measured Phenobarbitone √ Can cause depression of CNS and PNS Gentamycin and other √ Both peak and trough concentration should be measured
  • 100.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 100 Drug Medical use Phenytoin Is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures, partial seizures, but not absence seizures. Digoxin Digoxin is occasionally used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication. Theophylline known as 1,3-dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. Methotrexate It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid via dihydrofolate reductase. Cyclosporin Is an immunosuppressant drug widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells. Carbamazapine used in the treatment of epilepsy and neuropathic pain. It may be used in schizophrenia along with other medications and as a second line agent in bipolar disorder. Primidone Is an anticonvulsant of the barbiturate class. Phenobarbitone is a medication recommended by the World Health Organization for the treatment of certain types of epilepsy. Gentamycin and other aminoglycosides It is an antibiotic used to treat several types of bacterial infections, This include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis.
  • 101.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 101 Common causes of sub-therapeutic or toxic levels Sub-therapeutic levels Toxic levels 1. Non compliance 2. Dose too low 3. Malabsorption 4. Rapid metabolism 1. Overdose 2. Dose too high 3. Dose too frequent 4. Impaired renal function 5. Reduced hepatic metabolism
  • 102.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 102 DRUG INTERACTIONS qInterference of one drug with the metabolism and excretion of the other; on the other hand addition of one drug will alter the plasma concentration of the another. qIn these circumstances it is useful to lower the dose or discontinue the drug for a time. EXAMPLE: Patients with chronic asthma controlled on THEOPHYLLINE usually develop a sever chest infection, the patients in this case were prescribed ERYTHROMYCIN which will interfere with theophylline inducing tachycardia and dizziness. So we enforced to stop theophylline for two days and once the infection was clear; the original dose of theophylline will restart. Absorption Distribution Metabolism Excretion Affected drug Interacting drug (s) Increase decrease Interacting drug (s) Increase plasma level of affected drug decrease plasma level of affected drug
  • 103.
    8/15/23 Aaser Abdelazim ----Professor of Medical Biochemistry and Molecular Biology 103 Answer of Case study 1 Case study 1