Clinical Chemistry 1 Carbohydrates (PDF)

Clinical Chemistry 1 Carbohydrates Part 1 Introduction ⚫ Organisms rely on the oxidation of complex organic compounds to obtain energy ⚫ Three general types of such compounds are: ⚫ Carbohydrates (CHO) ⚫ Amino acids ⚫ And lipids ⚫ CHO are the primary sou...

Clinical Chemistry 1 Carbohydrates Part 1 Introduction ⚫ Organisms rely on the oxidation of complex organic compounds to obtain energy ⚫ Three general types of such compounds are: ⚫ Carbohydrates (CHO) ⚫ Amino acids ⚫ And lipids ⚫ CHO are the primary source of energy for brain, erythrocytes and retinal cells ⚫ Stored primarily as liver & muscle glycogen M. Zaharna Clin. Chem. 2009 Carbohydrates: CHO ⚫ Compounds containing C, H, O ⚫ General formula (CH2O)n ⚫ All CHO contain C=O and –OH functional groups ⚫ There are some derivatives of this formula, carbohydrate derivatives can be formed addition of other chemical groups (phosphates, amines…) ⚫ Classification of CHO is based on four different properties: 1. The size of the base carbon chain 2. The location of the CO functional group 3. The number of sugar units 4. The stereochemistry of the compound M. Zaharna Clin. Chem. 2009 1- The size of the base carbon chain ⚫ Can be classified based on the number of carbons in the molecule ⚫ Trioses ( 3 Carbons) ⚫ Tetroses ⚫ Pentoses ⚫ And hexoses ⚫ The smallest CHO is glyceraldehyde (3 Carbon) M. Zaharna Clin. Chem. 2009 2. The location of the CO functional group ⚫ CHO are hydrates of aldehyde or ketone derivatives based on the location of the CO functional group ⚫ Aldose form – aldehyde as functional group ⚫ Ketose form – ketone as functional group M. Zaharna Clin. Chem. 2009  3- The number of sugar units ⚫ Classification based on the number of sugar units in the chain 1. Monosaccharide 2. Disaccharide (2 sugars linked together) 3. Oligosaccharide (2-10 linked sugars) 4. Polysaccharide (long sugar chains) M. Zaharna Clin. Chem. 2009 Monosaccharides ⚫ Simplest sugars; cannot be broken down into any simpler sugar ⚫ 3 carbons = triose, 4 carbons = tetraose, 5 carbons = pentose, & 6 carbons = hexose ⚫ Important pentose (5 carbon) sugars include ribose and 2-deoxyribose M. Zaharna Clin. Chem. 2009 Disaccharides ⚫ Formed from two monosaccharide with the production of water. ⚫ Most common form is sucrose (table sugar), which is glucose and fructose ⚫ Other forms include: ⚫ Lactose (glucose and galactose) ⚫ Maltose (glucose and glucose) M. Zaharna Clin. Chem. 2009 Common Disaccharides Glucose + Glucose Glucose + Galactose Glucose + Fructose Sucrose ( table sugar ) M. Zaharna Clin. Chem. 2009 Polysaccharides ⚫ Plants (cellulose) ⚫ not digested by humans. ⚫ Starch ⚫ principal CHO (polysaccharide) storage product of plants ⚫ Glycogen ⚫ principal CHO storage product in animal. ⚫ formed by the combination of monosaccharide. M. Zaharna Clin. Chem. 2009 4- Stereochemistry ⚫ Mirror image forms ⚫ D = right side OH, L = left side OH ⚫ D & L designations are based on the configuration about the single asymmetric C M. Zaharna Clin. Chem. 2009 Glucose Metabolism ⚫ Glucose is a primary source of energy. ⚫ Various tissues and muscles throughout the body depend on glucose from the surrounding extracellular fluid for energy. ⚫ Nervous tissue cannot concentrate or store CHO, critical to maintain steady supply ⚫ If glucose levels fall below certain levels the nervous tissue lose its primary energy source and is incapable of maintaining normal function. M. Zaharna Clin. Chem. 2009 Fate of Glucose ⚫ CHO is digested (starch and glycogen). ⚫ Amylase digest the nonabsorbable forms of CHO to dextrin and disaccharide which are hydrolyzed to monosaccharide. ⚫ Maltase is an enzyme released by intestinal mucosa that hydrolyzes maltose to two glucose units ⚫ Sucrase hydrolyze sucrose to glucose & fructose ⚫ Lactase: hydrolyze lactose to glucose & galactose. M. Zaharna Clin. Chem. 2009 Fate of Glucose ⚫ Disaccharides are converted into monosaccharide – absorbed by the gut transported to the liver by the hepatic portal venous blood supply. ⚫ Glucose is the only CHO to be directly used for energy or stored as glycogen. ⚫ Others (galactose & fructose) have to be converted to glucose before they can be used M. Zaharna Clin. Chem. 2009 Lactose Intolerance ⚫ Lactose intolerance: due to a deficiency of lactase enzyme on or in the intestinal lumens, which is needed to metabolize lactose. ⚫ Results in an accumulation of lactose in the intestine as waste lactic acid- causing the stomach upset and discomfort. M. Zaharna Clin. Chem. 2009 Fate of Glucose ⚫ After glucose enters the cell it can go into one of three metabolic pathways based on ⚫ availability of substrate and ⚫ nutritional status of cell. ⚫ Ultimate goal is to convert glucose to CO2 and H2O. ⚫ During this process the cell obtains the high- energy molecule (ATP) from (ADP). M. Zaharna Clin. Chem. 2009 Glucose Metabolism ⚫ 1st step in all pathways Glucose is converted to glucose -6 phosphate using ATP- catalyzed by hexokinase. ⚫ Glucose-6- phosphate enters the pathways: 1. Embden-Meyerhof pathway 2. Hexose Monophosphate shunt 3. Glucogenesis (storage of glucose as glycogen) M. Zaharna Clin. Chem. 2009 Glucose Metabolism 1. Embden-Meyerhof pathway ⚫ Glucose is broken down into two, three-carbon molecules of pyruvic acid that can enter the tricarboxylic acid cycle (TCA cycle) on conversion to acetyl-coenzyme A (acetyl-CoA). 2. Hexose Monophosphate shunt The principal functions of the pathway are the production of: o Deoxyribose and ribose sugars for nucleic-acid synthesis; o The generation of reducing power in the form of NADPH for fatty-acid and/or steroid synthesis; M. Zaharna Clin. Chem. 2009 Glucose Metabolism M. Zaharna Clin. Chem. 2009 Pathways in Glucose Metabolism Major energy pathways involved either directly or indirectly with glucose metabolism: 1. Glycolysis Breakdown of glucose for energy production 2. Glycogenesis Excess glucose is converted and stored as glycogen High concentrations of glycogen in liver and skeletal muscle Glycogen is a quickly accessible storage form of glucose 3. Glycogenolysis Breakdown of glycogen into glucose Glycogenolysis occurs when plasma glucose is decreased Occurs quickly if additional glucose is needed M. Zaharna Clin. Chem. 2009 Pathways in Glucose Metabolism 4. Gluconeogenesis ⚫ Conversion of non-carbohydrate carbon substrates to glucose ⚫ Gluconeogenesis takes place mainly in the liver 5. Lipogenesis ⚫ Conversion of carbohydrates into fatty acids ⚫ Fat is another energy storage form, but not as quickly accessible as glycogen 6. Lipolysis ⚫ Decomposition of fat M. Zaharna Clin. Chem. 2009 M. Zaharna Clin. Chem. 2009 Regulation of Carbohydrate Metabolism ⚫ The liver, pancreas, and other endocrine glands are all involved in controlling the blood glucose concentrations within a narrow range ⚫ During a brief fast, glucose is supplied to the ECF from the liver through glycogenolysis. ⚫ When the fasting period is longer than 1 day, glucose is synthesized from other sources through gluconeogenesis. ⚫ Control of blood glucose is under two major hormones: insulin and glucagon, both produced by the pancreas M. Zaharna Clin. Chem. 2009 Regulation of Carbohydrate Metabolism ⚫ Other hormones also exert some control over blood glucose concentrations ⚫ As needed hormones regulate release of glucose. ⚫ Hormones work together to meet 3 requirements: 1. Steady supply of glucose. 2. Store excess glucose 3. Use stored glucose as needed M. Zaharna Clin. Chem. 2009 Regulation of Carbohydrate Metabolism Organs / Systems involved in glucose regulation ○ Liver : Glucose Glycogen Glucose ○ Muscle : Skeletal and heart ○ Pancreas : Synthesizes hormones insulin and glucagon, somatostatin ○ Other endocrine glands Anterior pituitary gland ( growth hormone) Adrenal gland (epinephrine and cortisol) Thyroid gland (thyroxine) M. Zaharna Clin. Chem. 2009 Regulation of Carbohydrate Metabolism If plasma glucose is decreased : ○ Glycogenolysis The liver releases glucose into the plasma (quick response) ○ Gluconeogenesis and lipolysis If plasma glucose is increased : ○ Glycogenesis Liver stores glucose as glycogen ○ Lipogenesis Formation of lipids M. Zaharna Clin. Chem. 2009 Insulin ⚫ Primary hormone responsible for the entry of glucose into the cell. ⚫ Synthesized in the beta cells of islets of langerhans in the pancreas. ⚫ Insulin release cause increase movement of glucose into the cells and increase glucose metabolism ⚫ Is the only hormone that decreases glucose levels and is referred as a hypoglycemic agent. M. Zaharna Clin. Chem. 2009 Action / Effects of Insulin ⚫ Facilitates glucose entry into cells ⚫ Cell membranes need insulin to be present for glucose to enter ⚫ Promotes liver glycogenesis ⚫ Glucose to glycogen ⚫ Promotes glycolysis ⚫ Speeds up utilization of glucose in cells ⚫ Promotes synthesis of lipids from glucose ⚫ Such as the formation of Triglycerides ⚫ Promotes amino acid synthesis from glucose intermediates ⚫ Decreases / inhibits glycogenolysis and gluconeogenesis M. Zaharna Clin. Chem. 2009 Glucagon ⚫ Peptide hormone that is synthesized by the alpha cells of the Islets cells of the pancreas ⚫ Released during stress and fasting states. ⚫ Released in response to decreased body glucose. ⚫ Main function is to: ⚫ increase hepatic glycogenolysis, ⚫ increase gluconeogenesis. ⚫ Hyperglycemic agent M. Zaharna Clin. Chem. 2009 Action / Effects of Glucagon ⚫ Stimuli – decreased plasma glucose ⚫ Action ⚫ Increases glycogenolysis & gluconeogenesis ⚫ Promotes breakdown of fatty acids ⚫ Promotes breakdown of proteins to form amino acids ⚫ Increases plasma glucose concentration M. Zaharna Clin. Chem. 2009 M. Zaharna Clin. Chem. 2009 Epinephrine (adrenaline) ⚫ Hormone produced by the adrenal gland ⚫ Increases plasma glucose by: ⚫ inhibiting insulin secretion, ⚫ increasing glycogenolysis ⚫ and promotes lipolysis. ⚫ Release during times of stress M. Zaharna Clin. Chem. 2009 Glucocorticoids ⚫ Primarily cortisol is released when stimulated by adrenocorticotropic hormone (ACTH). ⚫ Cortisol increases plasma glucose by: ⚫ Increasing gluconeogenesis, ⚫ Inhibition of glucose uptake in muscle & adipose tissue ⚫ lipolysis ⚫ Insulin antagonist M. Zaharna Clin. Chem. 2009 Growth Hormones ⚫ Growth Hormone (GH) and Adrenocorticotropic Hormone (ACTH) ⚫ Origin – anterior pituitary gland ⚫ Effect – antagonistic to insulin ⚫ increases plasma glucose levels ⚫ inhibits insulin secretion ⚫ inhibits entry of glucose into muscle cells ⚫ inhibits glycolysis ⚫ inhibits formation of triglycerides from glucose ⚫ Stimuli ⚫ decreased glucose stimulates its release ⚫ increased glucose inhibits its release M. Zaharna Clin. Chem. 2009 Thyroxine ⚫ The thyroid gland releases thyroxine. ⚫ Increases glucose levels by: ⚫ increasing glycogenolysis ⚫ gluconeogenesis ⚫ intestinal absorption of glucose M. Zaharna Clin. Chem. 2009 Somatostatin ⚫ Produced by the delta cells of the lslets of Langerhans of the pancreas. ⚫ The inhibition of insulin, glucagon ⚫ Therefore, only minor overall effect M. Zaharna Clin. Chem. 2009 M. Zaharna Clin. Chem. 2009 Hyperglycemia ⚫ Increase in plasma glucose levels ⚫ In healthy persons during a hyperglycemia state, insulin is secreted by the beta cells of the pancreatic islets of Langerhans. ⚫ Insulin enhances membrane permeability to cells in the liver, muscle, and adipose tissue. ⚫ Hyperglycemia is caused by an imbalance of hormones. M. Zaharna Clin. Chem. 2009 Lab Findings in Hyperglycemia M. Zaharna Clin. Chem. 2009 Diabetes Mellitus ⚫ Metabolic diseases characterized by hyperglycemia resulting from defect in insulin secretion, insulin action or both. ⚫ Two major types: (in 1979) ⚫ Type I, (insulin dependent) and Type 2, (non insulin dependent) ⚫ 1995: further categories by WHO: ⚫ Type 1 diabetes, type 2 diabetes, other specific types and gestational diabetes mellitus. M. Zaharna Clin. Chem. 2009 Classification of Diabetes Mellitus M. Zaharna Clin. Chem. 2009 Classification of Diabetes Mellitus M. Zaharna Clin. Chem. 2009 Type 1 Diabetes Mellitus ⚫ Due to cellular-mediated autoimmune destruction of the β-cells of the pancreas, causing an absolute deficiency of insulin secretion ⚫ or idiopathic type 1 diabetes that has no known etiology ⚫ Commonly occurs in children (juvenile diabetes) ⚫ Constitutes only 10% to 20% of all cases of diabetes ⚫ Genetics play a minimal role, can be due to exposure to environmental substances or viruses. ⚫ Treatment: insulin M. Zaharna Clin. Chem. 2009 Characteristics of T1DM ⚫ Abrupt onset ⚫ Insulin dependence ⚫ Ketosis tendency ⚫ One or more of the following markers are found in 85% to 90% of individuals with fasting hyperglycemia: ⚫ Islet cell autoantibodies (ICA) ⚫ Insulin autoantibodies (IAA) ⚫ Glutamic acid decarboxylase autoantibodies (GAD-65) ⚫ IA-2A protein tyrosine phosphatase M. Zaharna Clin. Chem. 2009 Laboratory Findings in T1DM ⚫ Hyperglycemia - plasma levels >126 mg/dL ⚫ Glucosuria - plasma glucose >180 mg/dL ⚫ Decreased insulin ⚫ Increased glucagon ⚫ Stimulation causes ⚫ Gluconeogenesis ⚫ Lipolysis (breakdown of fat produces ketones) ⚫ Ketoacidosis ⚫ Decreased blood pH ( acidosis ) ⚫ ↓ Sodium… ↑ Potassium … ↓ CO2 M. Zaharna Clin. Chem. 2009 Type 2 Diabetes Mellitus ⚫ Due to insulin resistance and relative insulin deficiency. ⚫ Type 2 constitutes the majority of the diabetes cases ⚫ Most patients in this type are obese or have an increased percentage of body fat distribution in the abdominal region ⚫ Often goes undiagnosed for many years and is associated with a strong genetic predisposition M. Zaharna Clin. Chem. 2009 Characteristics of T2DM ⚫ Adult onset of the disease ⚫ Ketoacidosis seldom occurring. ⚫ These patients are more likely to go into a hyperosmolar coma and ⚫ Are at an increased risk of developing macrovascular and microvascular complications. ⚫ Contributory Factors ▪ Obesity ▪ Diet ▪ Drugs, such as diuretics, psychoactive drugs ▪ Increases in hormones that inhibit/antagonize insulin (GH & cortisol) M. Zaharna Clin. Chem. 2009 Laboratory Findings in T2DM ⚫ Hyperglycemia ⚫ Glucosuria ⚫ Insulin is present ⚫ Glucagon is NOT elevated ⚫ No lipolysis and no ketoacidosis ⚫ Excess glucose is converted to triglycerides ( ↑ plasma triglycerides) ⚫ Normal / Increased Na / K ⚫ Increased BUN & Creatinine (Decreased renal function) ⚫ Hyperosmolar plasma from hyperglycemia M. Zaharna Clin. Chem. 2009 Ketone Body Pathogenesis M. Zaharna Clin. Chem. 2009 Ketone Bodies Formation In A Diabetic Patient M. Zaharna Clin. Chem. 2009 DKA vs HHS M. Zaharna Clin. Chem. 2009 HHS vs DKA M. Zaharna Clin. Chem. 2009 Major Causes of DKA & HHS M. Zaharna Clin. Chem. 2009 M. Zaharna Clin. Chem. 2009 Other Specific Types ⚫ Secondary conditions, ⚫ genetic defect in beta cell function ⚫ or insulin action, ⚫ pancreatic disease, ⚫ disease of endocrine origin, ⚫ drug or chemical induced. ⚫ Characteristics of the disease depends on the primary disorder. M. Zaharna Clin. Chem. 2009 Gestational Diabetes Mellitus ⚫ Glucose intolerance that is induced by pregnancy ⚫ Caused by metabolic and hormonal changes related to the pregnancy. ⚫ Glucose tolerance usually returns to normal after delivery. ⚫ An increased risk for development of diabetes in later years M. Zaharna Clin. Chem. 2009 Gestational Diabetes M. Zaharna Clin. Chem. 2009 Diagnostic Criteria for DM M. Zaharna Clin. Chem. 2009 Categories for Fasting Plasma Glucose M. Zaharna Clin. Chem. 2009 Criteria for Testing for Prediabetes and Diabetes ⚫ ADA recommendations: ⚫ All adults beginning at the age of 45 years should be tested for diabetes every 3 years using: ⚫ hemoglobin A1c (HbA1c) ⚫ fasting plasma glucose ⚫ or a 2-hour 75 g oral glucose tolerance test (OGTT) ⚫ Testing should be carried out at an earlier age or more frequently in individuals who display ⚫ overweight tendencies, BMI greater than or equal to 25 kg/m2 (at-risk BMI may be lower in some ethnic groups, i.e., Asian Americans ≥23 kg/m2), M. Zaharna Clin. Chem. 2009 Criteria for Testing for Prediabetes and Diabetes ⚫ Habitually physically inactive ⚫ Family history of diabetes in a first-degree relative In a high-risk minority population (e.g., African American, Latino, Native American, Asian American, and Pacific Islander) ⚫ History of GDM or delivering a baby weighing more than 9 lb (4.1 kg) M. Zaharna Clin. Chem. 2009 Criteria for Testing for Prediabetes and Diabetes ⚫ Hypertension (BP ≥ 140/90 mm Hg) ⚫ Low high-density lipoprotein (HDL) cholesterol concentrations (250 mg/dL (2.82 mmol/L) ⚫ A1C ≥ 5.7% (33 mmol/mol), IGT, or IFG on previous testing ⚫ History of impaired fasting glucose /impaired glucose tolerance M. Zaharna Clin. Chem. 2009 Criteria for Testing for Prediabetes and Diabetes ⚫ Women with polycystic ovarian syndrome ⚫ Other clinical conditions associated with insulin resistance (e.g., severe obesity and acanthosis nigricans) ⚫ History of cardiovascular disease M. Zaharna Clin. Chem. 2009 Hypoglycemia Plasma glucose level falls below 60 mg/dL Glucagon is released when plasma glucose is < 70 mg / dL to inhibit insulin Epinephrine, cortisol, and growth hormone released from adrenal gland to increase glucose metabolism and inhibit insulin Treatment – Varies with cause. Generally, hypoglycemia is treated with small, frequent meals, (5-6 / day) low in carbohydrates, high in protein M. Zaharna Clin. Chem. 2009 Hypoglycemia Symptoms Lab Findings ⚫ Increased hunger ⚫ Decreased plasma glucose ⚫ Sweating ⚫ Nausea ⚫ Vomiting ⚫ Dizziness ⚫ Shaking ⚫ Blurring of speech and sight ⚫ Mental confusion M. Zaharna Clin. Chem. 2009 Hypoglycemia Causes of: – Reactive Insulin overdose in diabetics Ethanol ingestion – Fasting Insulin-producingtumors Hepatic dysfunction Sepsis M. Zaharna Clin. Chem. 2009 Inborn Errors of Metabolism Leading to Hypoglycemia ⚫ Galactosemia ⚫ Hereditary fructose intolerance ⚫ Glycogen storage disease ⚫ Disorders of gluconeogenesis ⚫ Organic acidemia ⚫ Maple syrup disease ⚫ Disorders of fatty acid oxidation M. Zaharna Clin. Chem. 2009 Galactosemia ⚫ Serious inborn error because of the deficiency of enzyme galactose 1 phosphate uridyl transferase. ⚫ Due to the blockage of this enzyme, galactose 1 phosphate accumulates in the liver. ⚫ This inhibits galactokinase and glycogen phosphorylase enzyme activity. ⚫ Resulting hypoglycemia M. Zaharna Clin. Chem. 2009 Galactosemia M. Zaharna Clin. Chem. 2009 Galactosemia M. Zaharna Clin. Chem. 2009 Hereditary Fructose Intolerance ⚫ An autosomal recessive inborn error of metabolism. ⚫ Defect is in enzyme aldolase B; hence fructose 1 phosphate can not be metabolized. ⚫ Accumulation of this product inhibits glycogen phosphorylase because allosterically inhibits liver phosphorylase and blocks glycogenolysis. ⚫ It leads to the accumulation of glycogen in liver and associated with hypoglycemia. M. Zaharna Clin. Chem. 2009 Hereditary Fructose Intolerance M. Zaharna Clin. Chem. 2009 Glycogen Storage Diseases M. Zaharna Clin. Chem. 2009 Disorders of Gluconeogenesis Pyruvate Carboxylase Deficiency – It is a defect in the first step of gluconeogenesis which is the production of oxaloacetate from pyruvate. Fasting results in hypoglycemia. Fructose-1,6-Bisphosphatase Deficiency – Impaired gluconeogenesis Accumulation of precursors of gluconeogenesis: lactate, pyruvate, alanine, ketones. The only glucose source is - dietary or via glycogenolysis. M. Zaharna Clin. Chem. 2009 END OF PART 1 M. Zaharna Clin. Chem. 2009