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دانلود کتاب Medical Biochemistry
دانلود کتاب بیوشیمی پزشکی
مشخصات کتاب
Medical Biochemistry
ویرایش: [5 ed.] نویسندگان: JOHN W. BAYNES, MAREK H. DOMINICZAK سری: ISBN (شابک) : 9780702072994 ناشر: Elsevier Inc. سال نشر: 2019 تعداد صفحات: [698] زبان: English فرمت فایل : PDF (درصورت درخواست کاربر به PDF، EPUB یا AZW3 تبدیل می شود) حجم فایل: 51 Mb
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Front Matter Resident Drawing Copyright Page List of Contributors Acknowledgments Dedication Preface Abbreviations 1 Introduction Abstract Keywords Biochemistry and clinical medicine: introduction and overview Biochemistry is constantly changing Biochemistry has fuzzy borders A textbook is a snapshot of rapidly changing knowledge Improvements in the fifth edition One studies biochemistry to understand the interplay of nutrition, metabolism, and genetics in health and disease: let’s start here with the shortest possible overview of the field Proteins, carbohydrates, and lipids are the major structural components of the body Oxygen is essential for energy production but can also be toxic Metabolism continuously cycles between fasting and posteating modes Tissues perform specialized functions The genome underpins it all Further reading Relevant websites Abbreviations 2 Amino Acids and Proteins Abstract Keywords Learning objectives Introduction Proteins are major structural and functional polymers in living systems Amino acids Stereochemistry: Configuration at the α-carbon and d- and l-isomers Classification of amino acids based on chemical structure of their side chains Aliphatic amino acids Aromatic amino acids Phenylalanine, tyrosine, and tryptophan have aromatic side chains Neutral polar amino acids Acidic amino acids Basic amino acids Sulfur-containing amino acids Proline, a cyclic imino acid Classification of amino acids based on the polarity of the amino acid side chains Ionization state of an amino acid Amino acids are amphoteric molecules - they have both basic and acidic groups Henderson–Hasselbalch equation and pKa The H-H equation describes the titration of an amino acid and can be used to predict the net charge and isoelectric point of a protein Buffers Amino acids and proteins are excellent buffers under physiological conditions Peptides and proteins Primary structure of proteins The primary structure of a protein is the linear sequence of its amino acids Amino acid side chains contribute both charge and hydrophobicity to proteins Secondary structure of proteins The secondary structure of a protein is determined by hydrogen bond interactions between backbone carbonyl and amide groups The α-helix The β-pleated sheet Tertiary structure of proteins The tertiary structure of a protein is determined by interactions between side chain functional groups, including disulfide bonds, hydrogen bonds, salt bridges, and hydrophobic interactions Quaternary structure of proteins The quaternary structure of multisubunit proteins is determined by covalent and noncovalent interactions between the subunit surfaces Purification and characterization of proteins Protein purification is a multistep process, based on protein size, charge, solubility, and ligand binding Protein purification-precipitation Protein purification is based on differences in a protein’s solubility, size, charge, and binding properties Dialysis and ultrafiltration Small molecules, such as salts, can be removed from protein solutions by dialysis or ultrafiltration Gel filtration (molecular sieving) Gel filtration chromatography separates proteins on the basis of size Ion-exchange chromatography Proteins bind to ion-exchange matrices based on charge–charge interactions Affinity chromatography Affinity chromatography purifies proteins based on ligand interactions Determination of purity and molecular weight of proteins Polyacrylamide gel electrophoresis in sodium dodecylsulfate can be used to separate proteins based on charge Isoelectric focusing (IEF) IEF resolves proteins based on their isoelectric point Analysis of protein structure Determination of the primary structure of proteins Historically, analysis of protein sequence was carried out by chemical methods; today, both sequence analysis and protein identification are performed by mass spectrometry Determination of the three-dimensional structure of proteins X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy are usually used for determination of the three-dimensional structure of proteins Summary Further reading Relevant websites Abbreviations 3 Carbohydrates and Lipids Abstract Keywords Learning objectives Introduction Carbohydrates and lipids are major sources of energy and are stored in the body as glycogen and triglycerides (fat) Carbohydrates Nomenclature and structure of simple sugars The classic definition of a carbohydrate is a polyhydroxy aldehyde, or ketone Cyclization of sugars Disaccharides, oligosaccharides, and polysaccharides Sugars are linked to one another by glycosidic bonds to form complex glycans Differences in linkage of sugars make a big difference in metabolism and nutrition Lipids Lipids are found primarily in three compartments in the body: plasma, adipose tissue, and biological membranes Fatty acids Fatty acids exist in free form and as components of more complex lipids Triacylglycerols (triglycerides) Triglycerides are the storage form of lipids in adipose tissue Phospholipids Phospholipids are the major lipids in biological membranes Structure of biomembranes Eukaryotic cells have a plasma membrane and intracellular membranes that define compartments with specialized functions The fluid mosaic model The fluid mosaic model portrays cell membranes as flexible lipid bilayers with embedded proteins Membranes maintain the structural integrity, cellular recognition processes, and transport functions of the cell Summary Further reading Relevant websites Carbohydrates: Lipids: Abbreviations 4 Membranes and Transport Abstract Keywords Learning objectives Introduction Biomembranes are not rigid or impermeable but highly mobile and dynamic structures Types of transport processes Simple diffusion through the phospholipid bilayer Some small, neutral molecules can traverse biomembranes by simple diffusion Transport mediated by membrane proteins Membrane proteins are required for transport of larger molecules across biomembranes Saturability and specificity are important characteristics of membrane transport systems Characteristics of glucose transporters (uniporters) Glucose transporters catalyze downhill transport of glucose into and out of cells Transport by channels and pores Membrane channels or pores are open, less selective conduits for transport of ions, metabolites, and even proteins across biomembranes Examples of pores important for cellular physiology Active transport Primary active transport systems use ATP directly to drive transport; secondary active transport uses an electrochemical gradient of Na+ or H+ ions, or a membrane potential produced by primary active transport processes Primary active transport systems use ATP to drive ion pumps (ion-transporting ATPases, or pump ATPases) Uniport, symport, and antiport are examples of secondary active transport Examples of transport systems and their coupling Ca2+ transport and mobilization in muscle Membrane depolarization opens up voltage-dependent ion channels at the neuromuscular junction Active transport of glucose into epithelial cells A Na+/K+-ATPase drives uptake of glucose into intestinal and renal epithelial cells Acidification of gastric juice by a proton pump in the stomach P-ATPase in gastric parietal cells maintains the low pH of the stomach Summary Further reading Relevant websites General reviews: Animations: Abbreviations 5 Oxygen Transport Abstract Keywords Learning objectives Introduction Vertebrates are aerobic organisms Properties of oxygen Most oxygen in the body is bound to a carrier protein containing heme Characteristics of mammalian globin proteins Globins constitute an ancient family of soluble metalloproteins Structure of the heme prosthetic group Heme, the O2-binding moiety common to Mb and Hb, is a porphyrin molecule to which an iron atom (Fe2+) is coordinated Myoglobin: An oxygen storage protein Mb binds O2 that has been released from Hb in tissue capillaries and subsequently diffused into tissues Hemoglobin: An oxygen transport protein Hb is the principal O2-transporting protein in human blood; it is localized exclusively in erythrocytes Interactions of hemoglobin with oxygen Hb binds oxygen cooperatively, with a Hill coefficient of ~2.7 Hb can bind up to four molecules of O2 in a cooperative manner Hemoglobin subunits may assume two different conformations that differ in O2 affinity Allosteric modulation of the oxygen affinity of hemoglobin Allosteric proteins and effectors Hb is an allosteric protein; its affinity for O2 is regulated by small molecules Bohr effect Acidic pH (protons) decreases the O2 affinity of Hb As Hb binds O2, protons dissociate from selected weak-acid functions; conversely, in acidic media, protonation of the conjugate bases inhibits O2 binding Effects of CO2 and temperature Like H+, CO2 is increased in venous capillaries and is a negative allosteric effector of the O2 affinity of Hb Effect of 2,3-bisphosphoglycerate 2-3-Bisphoglycerate (2,3-BPG), an intermediate in carbohydrate metabolism, is an important allosteric effector of Hb Selected topics Interaction of hemoglobin with nitric oxide Nitric oxide, a potent vasodilator, is stored on Hb as S-nitrosoHb (SNO-Hb) Neuroglobin and cytoglobin: Minor mammalian hemoglobins Two other globins have recently been identified in humans Hemoglobin variants Sickle cell disease: A common hemoglobinopathy In sickle cell disease (SCD), distortion of erythrocyte structure (sickling) limits capillary blood flow Other hemoglobinopathies More than 1000 mutations in the genes encoding the α- and β-globin polypeptides have been documented Summary Further reading Relevant websites Abbreviations 6 Catalytic Proteins - Enzymes Abstract Keywords Learning objectives Introduction Almost all biological functions are supported by chemical reactions catalyzed by biological catalysts called enzymes Enzymatic reactions Factors affecting enzymatic reactions Effect of temperature Enzymes have an optimum temperature at which they function most efficiently Effect of pH Every enzyme has a pH optimum because ionizable amino acids, such as histidine, glutamate, and cysteine, participate in the catalytic reactions Definition of enzyme activity One international unit (IU) of enzyme catalyzes conversion of 1 µmol of substrate to product per minute The specific activity of an enzyme is a measure of the number of IU/mg protein Reaction and substrate specificity Most enzymes are highly specific for both the type of reaction catalyzed and the nature of the substrate(s) Roles of coenzymes Helper molecules, referred to as coenzymes, play an essential part in many enzyme-catalyzed reactions Enzyme kinetics The Michaelis–Menten equation: A simple model of enzyme catalysis Enzyme reactions are multistep in nature and comprise several partial reactions Analysis of the previous equations indicates that the Michaelis constant, Km, is expressed in units of concentration and corresponds to the substrate concentration at which v is 50% of the maximum velocity - that is, and v = Vmax/2 (Fig. 6.4) Use of the Lineweaver–Burk and Eadie–Hofstee plots Alternative graphical analyses permit more accurate determination of the Km and Vmax of an enzyme Lineweaver–Burk plot Eadie–Hofstee plot Mechanism of enzyme action Enzymatic reactions involve functional groups on amino acid side chains, coenzymes, substrates, and products Enzyme inhibition Competitive inhibitors cause an apparent increase in Km without changing Vmax Uncompetitive inhibitors cause an apparent decrease in Vmax Noncompetitive inhibitors may bind to sites outside the active site and alter both the Km and the Vmax of the enzyme Many drugs and poisons irreversibly inhibit enzymes Regulation of enzyme activity There are multiple complementary mechanisms for regulation of enzyme activity Proteolytic activation of digestive enzymes Some enzymes are stored in subcellular organelles or compartments in an inactive precursor form Allosteric regulation of rate-limiting enzymes in metabolic pathways Allosteric enzymes display sigmoidal, rather than hyperbolic, plots of reaction rate versus substrate concentration Positive and negative cooperativity Enzymatic measurement of blood glucose The glucose oxidase/peroxidase assay In clinical laboratories, most compounds are measured by automated enzymatic methods Reagent strips and glucometers People with diabetes normally monitor their blood glucose several times a day using reagent strips or glucose meters Kinetic assays Kinetic assays are more rapid than endpoint assays Summary Further reading Relevant websites Abbreviations 7 Vitamins and Minerals Abstract Keywords Learning objectives Introduction Vitamins and trace elements are micronutrients essential for metabolism Fat-soluble and water-soluble vitamins Fat-soluble vitamins Fat-soluble vitamins are stored in tissues Vitamin A Vitamin A is stored in the liver and needs to be transported to its sites of action Vitamin A deficiency presents as night blindness Severe vitamin A deficiency leads to permanent blindness Vitamin A is toxic in excess Vitamin D Vitamin D is toxic in excess. Vitamin E Vitamin E is a membrane antioxidant Fat malabsorption reduces vitamin E absorption Vitamin K Vitamin K is necessary for blood clotting Vitamin K deficiency causes bleeding disorders Premature infants are at particular risk of deficiency and may develop hemorrhagic disease of the newborn Inhibitors of vitamin K action are valuable antithrombotic drugs Water-soluble vitamins Vitamin B and vitamin C are water soluble B-complex vitamins B-complex vitamins are essential for normal metabolism and serve as coenzymes in many reactions in carbohydrate, fat, and protein metabolism Vitamin B1 (thiamine) is essential for carbohydrate metabolism Beriberi was the first-discovered deficiency disease Thiamine deficiency is associated with alcoholism Vitamin B2 (riboflavin) is required for FMN and FAD synthesis Vitamin B3 (niacin) is required for NAD+ and NADP+ synthesis Severe niacin deficiency results in dermatitis, diarrhea, and dementia Vitamin B6 (pyridoxine) participates in carbohydrate and lipid metabolism and is particularly important for amino acid metabolism Pyridoxine requirements increase with high protein intake Pyridoxine deficiency causes neurologic symptoms and anemia Vitamin B7 (biotin) participates in carboxylation reactions in lipogenesis and gluconeogenesis and in the catabolism of the branched-chain amino acids Vitamin B9 (folic acid) derivatives are important in single-carbon-transfer reactions and are necessary for the synthesis of DNA Structural analogues of folate are used as antibiotics and anticancer drugs Folate deficiency is one of the commonest vitamin deficiencies Folate deficiency in adults causes megaloblastic anemia Adequate intake of folate around conception is essential Vitamin B12 forms part of the heme structure Vitamin B12 requires the intrinsic factor for its absorption Vitamin B12 is only present in animal products Vitamin B12 deficiency causes pernicious anemia The function of vitamin B12 needs to be considered together with folate Vitamin B12 must be supplemented during folate treatment Pantothenic acid Pantothenic acid is widely distributed in animals and plants Vitamin C Humans cannot synthesize ascorbic acid; therefore it is an essential nutrient Vitamin C deficiency causes scurvy and compromises immune function Dietary supplementation of vitamins The benefits of vitamin supplementation in cancer and cardiovascular disease are uncertain Vitamin supplementation can be harmful Fruit and vegetables are the best sources of vitamins Minerals Major minerals present in the human body are sodium, potassium, chloride, calcium, phosphate, and magnesium Iron metabolism Iron is important in the transfer of molecular oxygen Iron is transported in plasma bound to transferrin Erythrocyte content of iron affects its absorption from the intestine Iron deficiency causes anemia Zinc metabolism Zinc is a trace element contained in approximately 100 enzymes associated with carbohydrate and energy metabolism, protein synthesis and degradation, and nucleic acid synthesis Zinc shares transport mechanisms with copper and iron in the gut Zinc deficiency is common Zinc deficiency affects growth, skin integrity, and wound healing Zinc supplements are used in the treatment of diarrhea in children Copper metabolism Copper scavenges superoxide and other reactive oxygen species Pathways of copper metabolism are shared with other metals Rare copper deficiency leads to anemia; skin and hair may also be affected Copper excess causes liver cirrhosis Selenium Selenium is present in all cells as amino acids selenomethionine and selenocysteine Selenium status may influence the risk of many chronic conditions Other metals Summary Further reading Relevant websites More Clinical Cases Abbreviations 8 Bioenergetics and Oxidative Metabolism Abstract Keywords Learning objectives Introduction ATP is the central metabolic currency Oxidation as a source of energy Energy content of foods The basal metabolic rate (BMR) The BMR is a measure of the total daily energy expenditure by the body at rest Stages of fuel oxidation Free energy The direction of a reaction depends on the difference between the free energy of reactants and products The free energy of metabolic reactions is related to their equilibrium constants by the Gibbs’ equation Conservation of energy by coupling of reactions to hydrolysis of atp ATP is a product of catabolic reactions and a driver of biosynthetic reactions Mitochondrial synthesis of adenosine triphosphate from reduced coenzymes Oxidative phosphorylation is the mechanism by which energy derived from fuel oxidation is conserved in the form of ATP Transduction of energy from reduced coenzymes to high-energy phosphate NAD+, FAD, and FMN are the major redox coenzymes The mitochondrial electron transport system The mitochondrial electron transport chain transfers electrons in a defined multistep sequence from reduced nucleotides to oxygen Electrons are funneled into the electron transport chain by several flavoproteins Flavoproteins contain FAD or FMN prosthetic groups Transfer of electrons from NADH into mitochondria Electron shuttles Electron shuttles are required for mitochondrial oxidation of NADH produced in the cytoplasmic compartment Ubiquinone (coenzyme Q10) Ubiquinone transfers electrons from flavoproteins to complex III Complex III: cytochrome c reductase Complex III accepts electrons from ubiquinone and pumps four hydrogen ions across the inner mitochondrial membrane Cytochrome c Cytochrome c is a peripheral membrane protein, shuttling electrons from complex III to complex IV Complex IV Complex IV, at the end of the electron transport chain, transfers electrons to oxygen, producing water Synthesis of adenosine triphosphate: the chemiosmotic hypothesis The ATP synthase complex (complex V) is an example of rotary catalysis P : O ratios “Respiratory control” is the dependence of oxygen uptake by mitochondria on the availability of ADP Uncouplers Uncouplers and uncoupling proteins are thermogenic Uncoupling proteins (UCP) Inhibitors of oxidative metabolism Electron transport system inhibitors Rotenone inhibits complex I (NADH–Q reductase) Antimycin A inhibits complex III (QH2–cytochrome c reductase) Cyanide and carbon monoxide inhibit complex IV Oligomycin inhibits ATP synthase Inhibitors of the ADP–ATP translocase Regulation of oxidative phosphorylation Respiratory control and feedback regulation ADP is the key feedback regulator of oxidative phosphorylation Regulation by covalent modification and allosteric effectors (ATP–ADP) Regulation by thyroid hormones Mitochondrial permeability transition pore (MPTP) Summary Further reading Relevant websites Movies: Animations: Other resources: Abbreviations 9 Anaerobic Metabolism of Carbohydrates in the Red Blood Cell Abstract Keywords Learning objectives Introduction Glycolysis is the central pathway of glucose metabolism in all cells Pyruvate, a three-carbon carboxylic acid, is the end product of anaerobic glycolysis; 2 moles of pyruvate are formed per mole of glucose The erythrocyte The erythrocyte, or red blood cell, relies exclusively on blood glucose as a metabolic fuel Glycolysis Overview Pyruvate is the end product of anaerobic glycolysis The investment stage of glycolysis Glucose-6-phosphate Fructose-6-phosphate The splitting stage of glycolysis Fructose-1,6-BP is cleaved in the middle by a reverse aldol reaction The yield stage of glycolysis: Synthesis of ATP by substrate-level phosphorylation The yield stage of glycolysis produces 4 moles of ATP, yielding a net of 2 moles of ATP per mole of glucose converted into lactate Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) GAPDH catalyzes a redox reaction, forming a high-energy acyl phosphate compound Substrate-level phosphorylation Substrate-level phosphorylation produces ATP from another high-energy phosphate compound Phosphoglycerate kinase and pyruvate kinase catalyze substrate-level phosphorylation reactions Lactate dehydrogenase (LDH) LDH regenerates NAD+ consumed in the GAPDH reaction, producing lactate, the end product of anaerobic glycolysis Fermentation Fermentation is a general term for anaerobic metabolism of glucose, usually applied to unicellular organisms Regulation of glycolysis in erythrocytes Hexokinase Phosphofructokinase-1 (PFK-1) PFK-1 is the primary site of regulation of glycolysis Pyruvate kinase (PK) Characteristics of regulatory enzymes Regulatory enzymes are rate-limiting steps in metabolic pathways Synthesis of 2,3-bisphosphoglycerate (2,3-BPG) 2,3-BPG is a negative allosteric effector of the oxygen affinity of hemoglobin The pentose phosphate pathway Overview The pentose phosphate pathway is divided into an irreversible redox stage, which yields both NADPH and pentose phosphates, and a reversible interconversion stage, in which excess pentose phosphates are recycled into glycolytic intermediates NADPH is a major product of the pentose phosphate pathway in all cells The redox stage of the pentose phosphate pathway: Synthesis of NADPH NADPH is synthesized by two dehydrogenases in the first and third reactions of the pentose phosphate pathway The interconversion stage of the pentose phosphate pathway Excess pentose phosphates are converted to Fru-6-P and glyceraldehyde-3-P in the interconversion stage of the pentose phosphate pathway Antioxidant function of the pentose phosphate pathway The pentose phosphate pathway protects against oxidative damage in the red cell Summary Further reading Relevant websites Abbreviations 10 The Tricarboxylic Acid Cycle Abstract Keywords Learning objectives Introduction Functions of the tricarboxylic acid cycle Four oxidative steps provide free energy for ATP synthesis The TCA cycle provides a common ground for interconversion of fuels and metabolites Acetyl-CoA is a common product of many catabolic pathways The TCA cycle is located in the mitochondrial matrix Pyruvate carboxylase Pyruvate may be directly converted to four different metabolites The pyruvate dehydrogenase complex Enzymes and reactions of the tricarboxylic acid cycle The TCA cycle is a sequence of reactions for oxidation of acetyl-CoA to CO2 and reduced nucleotides Citrate synthase Aconitase Isocitrate dehydrogenase and α-ketoglutarate dehydrogenase Succinyl-CoA synthetase Succinate dehydrogenase Fumarase Malate dehydrogenase Energy yield from the tricarboxylic acid cycle Anaplerotic (“building up”) reactions Regulation of the tricarboxylic acid cycle Pyruvate dehydrogenase and isocitrate dehydrogenase regulate TCA cycle activity Deficiencies in tricarboxylic acid–cycle enzymes Summary Further reading Relevant websites TCA cycle animations: Abbreviations 11 Oxidative Metabolism of Lipids in Liver and Muscle Abstract Keywords Learning objectives Introduction Fats are normally the major source of energy in liver and muscle and in most other tissues, with two major exceptions: brain and red cells Activation of fatty acids for transport into the mitochondrion Fatty acids are activated by formation of a high-energy thioester bond with coenzyme A The length of the fatty acid dictates where it is activated to CoA The carnitine shuttle The carnitine shuttle bypasses the impermeability of the mitochondrial membrane to coenzyme A Oxidation of fatty acids Mitochondrial β-oxidation Oxidation of the β-carbon (C-3) facilitates sequential cleavage of acetyl units from the carboxyl end of fatty acids Peroxisomal catabolism of fatty acids Alternative pathways of oxidation of fatty acids Unsaturated fatty acids yield less FADH2 when they are oxidized Odd-chain fatty acids produce succinyl-CoA from propionyl-CoA α-Oxidation initiates oxidation of branched-chain fatty acids to acetyl-CoA and propionyl-CoA Ketogenesis, a metabolic pathway unique to liver Ketogenesis in fasting and starvation Ketogenesis is a pathway for regenerating CoA from excess acetyl-CoA What does the liver do with the excess acetyl-CoA that accumulates in fasting or starvation? Mobilization of lipids during gluconeogenesis Carbohydrate and lipid metabolism are coordinately regulated by hormone action during the feed–fast cycle Regulation of ketogenesis Ketogenesis is activated in concert with gluconeogenesis during fasting and starvation Summary Further reading Relevant websites Abbreviations 12 Biosynthesis and Storage of Carbohydrate in Liver and Muscle Abstract Keywords Learning objectives Introduction Hepatic glycogenolysis and gluconeogenesis are required for maintenance of normal blood glucose concentration Glycogen is stored in muscle for use in energy metabolism Structure of glycogen Glycogen, a highly branched glucan, is the storage form of glucose in tissues Pathway of glycogenesis from blood glucose in the liver Glycogenesis is activated in the liver and muscle after a meal Pathway of glycogenolysis in the liver Hepatic glycogen phosphorylase provides for rapid release of glucose into the blood during the postabsorptive state Hormonal regulation of hepatic glycogenolysis Three hormones (insulin, glucagon, and cortisol) counterregulate glycogenolysis and glycogenesis Mechanism of action of glucagon Glucagon activates glycogenolysis during the postabsorptive state Glycogenolysis and glycogenesis are counterregulated by protein kinase A, which activates phosphorylase and inhibits glycogen synthase Mobilization of hepatic glycogen by epinephrine Epinephrine activates glycogenolysis during stress, increasing blood glucose concentration Glycogenolysis in muscle Muscle lacks a glucagon receptor and glucose-6-phosphatase; it is not a source of blood sugar during hypoglycemia Regulation of glycogenesis Insulin opposes the action of glucagon and stimulates gluconeogenesis Gluconeogenesis Gluconeogenesis is required to maintain blood glucose during fasting and starvation Gluconeogenesis from lactate Gluconeogenesis uses lactate, amino acids, and glycerol as substrates for synthesis of glucose; fatty acids provide the energy Gluconeogenesis from amino acids and glycerol Glucose cannot be synthesized from fatty acids! Regulation of gluconeogenesis Fructose-2,6-bisphosphate allosterically counterregulates glycolysis and gluconeogenesis Conversion of fructose and galactose to glucose Summary Further reading Relevant websites Abbreviations 13 Biosynthesis and Storage of Fatty Acids Abstract Keywords Learning objectives Introduction Fatty acid synthesis Fatty acids are synthesized from acetyl-CoA The preparatory stage: Acetyl-CoA carboxylase Carboxylation of acetyl-CoA to malonyl-CoA is the committed step of fatty acid synthesis Acetyl-CoA carboxylase is subject to strict regulation Dietary carbohydrate and fat intake also controls acetyl-CoA carboxylase Synthesizing a fatty acid chain: Fatty acid synthase Fatty acid synthase builds the fatty acid molecule up to 16-carbon length Alteration in the amount of enzyme protein is affected by the nutritional state The malate shuttle Malate shuttle allows recruitment of two-carbon units from the mitochondrion to the cytoplasm Fatty acid elongation Elongation of a fatty acid chain beyond 16-carbon length requires another set of enzymes Desaturation of fatty acids Desaturation reactions require molecular oxygen Essential fatty acids The ω-3 and ω-6 fatty acids (or their precursors) must be supplied with diet Storage and transport of fatty acids: synthesis of triacylglycerols (Triglycerides) Fatty acids derived from endogenous synthesis or from the diet are stored and transported as triacylglycerols known also as triglycerides Triacylglycerols produced in the liver on the smooth endoplasmic reticulum can only be transiently stored Regulation of total body fat stores Adipose tissue is an active endocrine organ Summary Further reading Abbreviations 14 Biosynthesis of Cholesterol and Steroids Abstract Keywords Learning objectives Introduction Cholesterol is essential for cell structure and function Plasma cholesterol concentration depends on endogenous cholesterol synthesis and on its dietary intake Humans cannot metabolize the sterol structure The cholesterol molecule Cholesterol increases membrane fluidity Cholesterol is esterified within cells and in plasma Cholesterol is absorbed in the intestine by specific transporters Biosynthesis of cholesterol Cholesterol is synthesized from acetyl-coenzyme A The first committed step in the pathway of cholesterol synthesis is the formation of mevalonic acid The rate-limiting enzyme in the pathway is HMG-CoA reductase Farnesyl pyrophosphate is made up of three isoprene units Squalene is a linear molecule capable of a ring formation Squalene cyclizes to lanosterol Final stages of cholesterol biosynthesis occur on a carrier protein Oxidation of the cholesterol side chain yields oxysterols Plant sterols and cholesterol precursors are markers of cholesterol absorption and metabolism Regulation of cellular cholesterol content Cells acquire cholesterol from de novo synthesis and through external supply Synthesis of cholesterol de novo and delivery by lipoproteins are reciprocally related Sterol regulatory element-binding proteins (SREBP) are transcriptional regulators of cholesterol synthesis HMG-CoA reductase regulation by cholesterol involves enzyme degradation SREBPs have wide-ranging effects on the synthesis of cholesterol and fatty acids SREBP1c can be activated by liver X receptors in response to oxysterols SREBP1c regulates cholesterol efflux from cells SREBP1c regulates fatty acid synthesis Statins inhibit HMG-CoA reductase Cholesterol elimination: the bile acids Liver removes cholesterol either in a free form or as bile acids Primary bile acids are synthesized in the liver Liver X receptors participate in bile synthesis and secretion Secondary bile acids are synthesized in the intestine Bile acids assist the digestion of dietary fat Bile acids recirculate to the liver Cholesterol is excreted in the feces Cholestyramine is a bile acid–binding resin that has been used to lower plasma cholesterol Steroid hormones Cholesterol is the precursor of all steroid hormones Biosynthesis of the steroid hormones Synthesis of steroid hormones occurs in three organs: adrenal cortex, testis, and ovary Steroidogenesis is controlled by cytochrome P450 monooxygenases Corticosteroids In the adrenal glands, the zona fasciculata and zona reticularis are places of synthesis of cortisol and adrenal androgens; the outer layer (zona glomerulosa) synthesizes aldosterone Androgens Conversion of corticosteroids into androgens requires the C17–20 split and addition of 17α-hydroxyl group Estrogens Conversion of androgens into estrogens involves removal of the methyl group at C-19 Mechanism of action of steroid hormones Steroid hormones act via nuclear receptors Vitamin D Elimination of steroid hormones Summary Further reading Relevant websites More Clinical Cases Abbreviations 15 Biosynthesis and Degradation of Amino Acids Abstract Keywords Learning objectives Introduction Amino acids are a source of energy from the diet and during fasting Metabolism of dietary and endogenous proteins Relationship to central metabolism Muscle protein and adipose lipids are consumed to support gluconeogenesis during fasting and starvation Digestion and absorption of dietary protein Turnover of endogenous proteins Amino acid degradation Amino acids destined for energy metabolism must be deaminated to yield the carbon skeleton Nitrogen atoms are incorporated into urea from two sources: glutamate and aspartate The central role of glutamine Ammonia is detoxified by incorporation into glutamine, then eventually into urea The urea cycle and its relationship to central metabolism The urea cycle is a hepatic pathway for disposal of excess nitrogen The urea cycle is split between the mitochondrial matrix and the cytosol Regulation of the urea cycle N-acetylglutamate (and indirectly, arginine) is an essential allosteric regulator of the urea cycle The concept of nitrogen balance A careful balance is maintained between nitrogen ingestion and secretion Metabolism of the carbon skeletons of amino acids Metabolism of amino acids interfaces with carbohydrate and lipid metabolism Amino acids may be either glucogenic or ketogenic Metabolism of the carbon skeletons of selected amino acids The 20 amino acids are metabolized by complex pathways to various intermediates in carbohydrate and lipid metabolism Biosynthesis of amino acids Evolution has left our species without the ability to synthesize almost half the amino acids required for the synthesis of proteins and other biomolecules Amino acids are precursors of many essential compounds Inherited diseases of amino acid metabolism Phenylketonuria (PKU) Alkaptonuria (black urine disease) Maple syrup urine disease (MSUD) Summary Further reading Relevant websites Urea cycle disorders: Abbreviations 16 Biosynthesis and Degradation of Nucleotides Abstract Keywords Learning Objectives Introduction Purines and pyrimidines Nucleotides are formed from three components: a nitrogenous base, a five-carbon sugar, and phosphate Purine metabolism De novo synthesis of the purine ring: Synthesis of inosine monophosphate (IMP) Purines and pyrimidines are synthesized by both de novo and salvage pathways Synthesis of ATP and GTP from IMP Salvage pathways for purine nucleotide biosynthesis Purine and uric acid metabolism in humans Sources and disposal of uric acid Uric acid is the end product of purine catabolism in humans Endogenous formation of uric acid Hyperuricemia and gout Most persons with hyperuricemia remain asymptomatic throughout life, but there is no gout without hyperuricemia Pyrimidine metabolism De novo pathway Metabolic channeling by multienzymes improves efficiency Pyrimidine salvage pathways Formation of deoxynucleotides Ribonucleotide reductase Ribonucleotide reductase catalyzes reduction of ribose to deoxyribose in nucleotides for the synthesis of DNA A unique pathway to thymidine triphosphate Thymine is synthesized by a complex reaction pathway, providing many opportunities for chemotherapy De novo nucleotide metabolism is highly regulated Ribonucleotide reductase is the allosteric enzyme that coordinates a balanced supply of deoxynucleotides for synthesis of DNA Ribonucleotide reductase coordinates the biosynthesis of all four deoxynucleotides Catabolism of pyrimidine nucleotides Summary Further reading Relevant websites SCIDS: Abbreviations 17 Complex Carbohydrates Abstract Keywords Learning objectives Introduction Glycoconjugates include glycoproteins, proteoglycans, and glycolipids Structures and linkages Sugars are attached to specific amino acids in proteins N-glycans have either “high-mannose” or “complex” structures built on a common core General structures of glycoproteins Structure–function relationships in mucin glycoproteins Interconversions of dietary sugars Cells can use glucose to make all the other sugars they need Formation of galactose, mannose, and fucose from glucose Metabolism of galactose Metabolism of fructose Fructose accounts for about half the sugar in both sucrose (table sugar) and high-fructose corn syrup Other pathways of sugar nucleotide metabolism UDP-GlcUA GDP-Man and GDP-Fuc Amino sugars Fru-6-P is the precursor of amino sugars Sialic acid Biosynthesis of oligosaccharides N-glycan assembly begins in the endoplasmic reticulum Intermediate processing continues in the endoplasmic reticulum (ER) and Golgi apparatus O-glycans O-glycans are synthesized in the Golgi apparatus Functions of the oligosaccharide chains of glycoproteins N-glycans have an important role in protein folding Oligosaccharides containing Man-6-P target lysosomal enzymes to the lysosome The oligosaccharide chains of glycoproteins generally increase the solubility and stability of proteins Sugars are involved in chemical recognition interactions with lectins Summary Further reading Relevant websites Abbreviations 18 Complex Lipids Abstract Keywords Learning objectives Introduction Synthesis and turnover of glycerophospholipids Synthesis of glycerophospholipids De novo pathway Phospholipids are in a constant state of synthesis, turnover, and remodeling Remodeling pathway Turnover of phospholipids Sphingolipids Structure and biosynthesis of sphingosine Sphingomyelin Sphingomyelin is the only sphingolipid that contains phosphate and is the major phospholipid in the myelin sheath of nerves Glycolipids Structure and nomenclature of gangliosides Gangliosides are glycosphingolipids containing sialic (N-acetylneuraminic) acid Lysosomal storage diseases resulting from defects in glycolipid degradation ABO blood group antigens Summary Further reading Relevant websites Abbreviations 19 The Extracellular Matrix Abstract Keywords Learning Objectives Introduction Collagens Collagens are the major proteins in the ECM Triple-helical structure of collagens The left-handed triple-helical structure of collagen is unique among proteins Fibril-forming collagens Fibrillar collagens provide tensile strength to tendons, ligaments, and skin Nonfibrillar collagens Nonfibrillar, lattice-forming collagens are major structural components of basement membranes Synthesis and posttranslational modification of collagens Collagen synthesis begins in the rough endoplasmic reticulum (RER) Procollagen is finally modified to collagen in the Golgi apparatus Noncollagenous proteins in the extracellular matrix Elastin Weak hydrophobic interactions between valine residues permit the flexibility and extensibility of elastin Other major ECM glycoproteins Fibronectin and laminin have multiple binding sites for ECM proteins and proteoglycans Proteoglycans Structure of proteoglycans Glycosaminoglycans are the polysaccharide components of proteoglycans Synthesis and degradation of proteoglycans The structure of glycosaminoglycans is determined by the cell’s complement of glycosyl and sulfotransferases Defects of proteoglycan degradation lead to mucopolysaccharidoses Functions of the proteoglycans Communication of cells with the extracellular matrix Integrins are plasma membrane proteins that bind to and transmit mechanical signals between the ECM and intracellular proteins Summary Further reading Relevant websites Mucopolysaccharidoses: Abbreviations 20 Deoxyribonucleic Acid Abstract Keywords Learning objectives Introduction Structure of deoxyribonucleic acid DNA is an antiparallel dimer of nucleic acid strands Watson and Crick model of DNA Three-dimensional DNA Alternative forms of DNA may help to regulate gene expression Separated DNA strands can reassociate to form duplex DNA Complementary strands of DNA spontaneously hybridize to form helical structures The human genome Satellite DNA Mitochondrial DNA The mitochondrial genome is small in size, is circular, and encodes relatively few proteins DNA is compacted into chromosomes Chromosomes are compact, highly organized forms of DNA Chromatin contains DNA, RNA, and protein, plus inorganic and organic counterions Nucleosomes are the building blocks of chromatin Telomeres The cell cycle in eukaryotes DNA replication DNA is replicated by separating and copying the strands DNA replication DNA synthesis proceeds in opposite directions along the leading and lagging strands of the template DNA Eukaryotes stringently regulate DNA replication DNA repair There are typically more than 10,000 modifications of DNA per cell per day Multiple enzymatic pathways repair a wide range of chemical modifications of DNA UV light produces thymine dimers: nucleotide excision repair Deamination: Excision repair Depurination Strand breaks Mismatch repair 8-Oxo-2′-deoxyguanosine Recombinant DNA technology DNA sequencing, hybridization, and cloning are fundamental techniques of genetic engineering Principles of molecular hybridization Hybridization is based on the annealing properties of DNA For molecular hybridization, it is essential that the probe and target are initially single stranded Formation of probe–target heteroduplexes is key to the usefulness of molecular hybridization The stability of a nucleic acid duplex can be assessed by determining its melting temperature (Tm) Probes must have a label to be identified Southern blots are the prototype for methods that use specific hybridization probes to identify sequences in DNA or RNA Restriction enzymes: Use of restriction enzymes to analyze genomic DNA Restriction enzymes cleave DNA at specific nucleotide sequences DNA fragments, blotted onto a solid gel phase, are used as a template for exposure to a range of molecular probes Restriction-fragment-length polymorphisms (RFLP) and single-nucleotide polymorphisms (SNP) Analysis of restriction fragment length may be used to detect a mutation or polymorphism in a gene Cloning of DNA Cell-based cloning Bacterial plasmids are bioengineered to optimize their use as vectors Future directions Summary Further reading Relevant websites Abbreviations 21 Ribonucleic Acid Abstract Keywords Learning objectives Introduction Transcription is defined as the synthesis of a ribonucleic acid (RNA) molecule using deoxyribonucleic acid (DNA) as a template Molecular anatomy of ribonucleic acid molecules In contrast to DNA, RNAs are single stranded and contain uracil instead of thymine rRNAs: the ribosomal RNAs tRNA: the molecular cloverleaf mRNA: prokaryotic and eukaryotic mRNAs differ significantly in structure and processing Ribonucleic acid polymerases RNA polymerases transcribe defined segments of DNA into RNA with a high degree of selectivity and specificity Each eukaryotic polymerase specializes in transcription of one class of RNA Messenger ribonucleic acid: transcription Transcription is a dynamic process involving interaction of enzymes with DNA to produce RNA molecules Initiation Initiation begins with site-specific interaction of the RNA polymerase with DNA Elongation Elongation is the process by which single nucleotides are added to the growing RNA chain Termination Termination of transcription is catalyzed by multiple mechanisms in both prokaryotes and eukaryotes. Posttranscriptional processing of ribonucleic acids Pre-rRNA and pre-tRNA rRNAs and tRNAs are synthesized as larger precursors (pre-RNAs) that are processed to yield mature transcripts (Fig. 21.6) Ribozymes Pre-mRNA processing Eukaryotic mRNAs have longer half-lives than prokaryotic mRNAs because of protective modifications at their 5′ and 3′ ends The spliceosome joins exons from pre-mRNA to form a mature mRNA Alternative splicing produces multiple mRNAs from a single pre-mRNA transcript Editosomes modify the nucleotide sequence of mature mRNAs Selective degradation or inactivation of mRNA Micro-RNAs, siRNA, RNAi, and RISC miRNAs si-RNAs Interferon activates additional pathways that inhibit proliferation of RNA viruses Summary Further reading Relevant websites RNA polymerase: Spliceosome and alternative splicing: micro-RNA and RNAi: Macular degeneration: The RNA world: Abbreviations 22 Protein Synthesis and Turnover Abstract Keywords Learning objectives Introduction Translation is the process by which the information encoded in an mRNA is translated into the primary structure of a protein The genetic code The genetic code is degenerate and not quite universal The machinery of protein synthesis The ribosome is a multistep assembly line for protein synthesis Each amino acid has a specific synthetase that attaches it to all the tRNAs that encode it Some flexibility in base pairing occurs at the 3′ base of the mRNA codon How does the ribosome know where to begin protein synthesis? The process of protein synthesis Translation is a dynamic process that involves the interaction of mRNA, enzymes, tRNAs, translation factors, ribosomal proteins, and rRNAs Initiation Synthesis of a protein is initiated at the first AUG (methionine) codon in the mRNA Elongation Factors involved in the elongation stage of protein synthesis are targets of some antibiotics Termination Protein folding and endoplasmic reticulum (ER) stress ER stress, the result of errors in protein folding, develops in many chronic conditions, including obesity, diabetes, and cancer Protein targeting and posttranslational modifications Protein targeting Cellular fate of proteins is determined by their signal peptide sequences Posttranslational modification Most proteins require posttranslational modification before they become biologically active Proteasomes: Cellular machinery for protein turnover Unlike DNA, damaged proteins are not repaired but degraded The proteasome is a multicatalytic complex designed for degradation of cytosolic proteins Ubiquitin targets proteins to the proteasome for degradation Summary Further reading Relevant websites Abbreviations 23 Regulation of Gene Expression Abstract Keywords Learning objectives Introduction Despite identical DNA in all cells, gene expression varies significantly with time and place in the body as well as sex Basic mechanisms of gene expression Gene expression is regulated at several different steps Gene transcription depends on key cis-acting DNA sequences in the region of the gene A transcription unit encompasses more than just a gene Promoters Promoters are usually upstream of the transcription start point of a gene The efficiency and specificity of gene expression are conferred by promoter elements Alternative promoters permit tissue or developmental stage–specific gene expression Enhancers Enhancers modulate the strength of gene expression in a cell Insulators Insulators restrict the action of enhancers Response elements Response elements are binding sites for transcription factors and coordinately regulate expression of multiple genes (e.g., in response to hormonal or environmental stimuli) Transcription factors Transcription factors are DNA-binding proteins that regulate gene expression Transcription factors can affect transcription directly by controlling the function of RNA polymerase or indirectly by affecting the chromatin structure Initiation of transcription requires binding of general transcription factors to DNA Transcription factors have highly conserved DNA-binding sites Steroid receptors Steroid receptors possess many characteristics of transcription factors and provide a model for the role of zinc finger proteins in DNA binding The zinc finger motif A zinc finger motif in steroid receptors binds to the steroid-response element in DNA Organization of the steroid receptor Steroid receptors are products of a highly conserved gene family Alternative approaches to gene regulation in humans Promoter access Chromatin structure affects access of transcription factors to genes and thereby affects gene expression Nucleosomes are dynamically altered during gene expression through the action of enzymes that modify and remodel them Methylation of DNA regulates gene expression Methylation is one of several epigenetic modifications of DNA; patterns of DNA methylation at birth affect risk for a number of age-related diseases Alternative splicing of mRNA Alternative splicing yields many variants of a protein from a single pre-mRNA Editing of RNA at the posttranscriptional level The editosome modifies the internal nucleotide sequence of mature mRNAs RNA interference Preferential activation of one allele of a gene Human genes are biallelic, but sometimes only one allele of the gene is expressed Summary Further reading Relevant websites CRISPR: Abbreviations 24 Genomics, Proteomics, and Metabolomics Abstract Keywords Learning objectives Introduction Many of the complex biological functions are generated by interactions among genes rather than by individual genes Posttranslational modifications add further levels of complexity Studies of the genome, transcriptome, proteome, and metabolome pose different challenges Genomics Genome analysis provides a way to predict the probability of a condition, but it does not provide information on whether and when this probability will manifest itself Many diseases have an inheritable genetic component Karyotyping, comparative genome hybridization (CGH), chromosomal microarray analysis (CMA), and fluorescence in situ hybridization (FISH) Karyotyping assesses the general chromosomal architecture Comparative genome hybridization compares two genomes of interest In chromosomal microarray analysis, the labeled DNA is hybridized to an array of oligonucleotides Fluorescence in situ hybridization can be used when the gene in question is known Gene mutations can be studied by sequencing Four principles of DNA sequencing There are several NGS methods using different ways to read the DNA sequence Single-nucleotide polymorphisms (SNP) are useful in identification and assessment of disease risk Systematic SNP mapping has proved useful in studying genetic identity and inheritance and also in the identification and risk assessment of genetic diseases Genome-wide association studies (GWAS) try to link the frequency of SNPs to disease risks Epigenetic changes are heritable traits not reflected in the DNA sequence Although the genome as defined by its DNA sequence is commonly viewed as the hereditary material, there are also other heritable traits that are not reflected by changes in the DNA sequence Gene expression and transcriptomics Studying gene transcription by gene (micro)arrays and RNA sequencing ChIP-on-chip technique combines chromatin immunoprecipitation with microarray technology Mapping of the occupancy of transcription-factor-binding sites can reveal which genes are likely to be regulated by these factors Proteomics Proteomics is the study of the protein complement of a cell, the protein equivalent of the transcriptome or genome Proteomics poses several challenges There is no protein equivalent of PCR that would allow for the amplification of protein sequences, so we are limited to the amount of protein that can be isolated from the sample Proteomics in medicine Despite the challenges, proteomics has become a powerful tool for understanding fundamental biological processes Proteomics has been applied successfully to the study of basic biochemical changes in many different types of biological samples: cells, tissues, plasma, urine, cerebrospinal fluid, and even interstitial fluid collected by microdialysis Main methods used in proteomics Proteomics relies on the separation of complex mixtures of proteins or peptides, quantification of protein abundances, and identification of the proteins Protein separation techniques A classic protein-separation method is two-dimensional (2D) polyacrylamide gel electrophoresis (2DE, 2D-PAGE) The first 2D liquid chromatography (LC) method with direct coupling of the two dimensions is called multidimensional protein identification technology (MudPIT) Protein identification by mass spectrometry Mass spectrometry is a technique used to determine the molecular masses of molecules in a sample A tandem mass spectrometer is effectively two mass spectrometric analyzers joined together sequentially, with an area between them where molecules can be fragmented To enable the targeted identification of specific proteins, a technique was developed, called selected-reaction monitoring (SRM) or multiple-reaction monitoring (MRM) Quantitative mass spectrometry Affinity capture methods for molecular interactions Non-MS-based technologies The Human Protein Atlas aims to generate antibodies to every protein in the human proteome and use these to visualize proteins and their subcellular localization in healthy and diseased human tissues Metabolomics Metabolomics gives another level of information on a biological system Metabolomics can be broken down into a number of areas Biomarkers Biomarkers are markers that can be used in medicine for the early detection, diagnosis, staging, or prognosis of disease or for determination of the most effective therapy The most common methods for biomarker discovery have developed from those used in transcriptomics, proteomics, and metabolomics (i.e., gene arrays; mass spectrometry, often coupled with chromatography; and NMR spectroscopy) Some well-known examples of biomarkers are the measurement of blood glucose levels in diabetes, prostate-specific antigen for prostate cancer, and HER-2 or BRCA1/2 genes in breast cancer Data analysis and interpretation by bioinformatics and systems biology Summary Further reading Relevant websites Abbreviations 25 Membrane Receptors and Signal Transduction Abstract Keywords Learning objectives Introduction Cellular signals are processed by specific receptors, effector elements, and regulatory proteins Types of hormone and monoamine receptors Receptors for steroid hormones differ from those for polypeptide hormones and monoamines Steroid hormones traverse cell membranes Intracellular receptors for steroid and thyroid hormones and retinoids are transcription factors Polypeptide hormones act through membrane receptors Some low-molecular-mass signaling molecules traverse the cell membrane Receptor coupling to intracellular signal transduction Membrane receptors couple to signaling pathways utilizing diverse mechanisms Some receptors possess intrinsic protein kinase activity The example of insulin signaling Some membrane receptors are coupled to G-proteins G-proteins regulate a diverse range of biological processes G-proteins act as molecular switches Second messengers Cyclic AMP (cAMP) is a key molecule in signal transduction Glucagon and β-adrenergic receptors are coupled to cAMP Adenylyl cyclase is regulated by G-protein α-subunits Signals can activate different receptor subtypes, with different consequences Protein kinase A Protein kinase A binds cAMP and phosphorylates other enzymes Many other cellular responses can be mediated by the cAMP–PKA signaling cassette cAMP can stimulate cellular signaling independent of PKA Signal cascades amplify signals initiated by receptor binding Phosphodiesterases terminate the cAMP signal Phospholipase-derived second messengers Phospholipase C hydrolyzes the membrane phospholipid phosphatidylinositol 4,5-bisphosphate to generate two second messengers IP3 stimulates intracellular calcium mobilization Signal transduction by Ca2+ Many downstream signaling events mediated by Ca2+ are modulated by a Ca2+-sensing and binding protein, calmodulin Calmodulin has a wide range of target effectors Diacylglycerol activates protein kinase C Other phospholipases hydrolyze phosphatidylcholine or phosphatidylethanolamine, generating a range of lipid second messengers Arachidonic acid is a second messenger regulating phospholipases and protein kinases Arachidonic acid is the precursor of eicosanoids Summary Further reading Relevant websites Abbreviations 26 Neurotransmitters Abstract Keywords Learning objectives Introduction Neurotransmitters are molecules that act as chemical signals between nerve cells Several transmitters may be found in one nerve Neurotransmission Action potentials are caused by changes in ion flows across cell membranes A change in voltage that tends to drive the resting potential toward zero from the normal negative voltage is known as a depolarization, whereas a process that increases the negative potential is called hyperpolarization Neurotransmitters alter the activity of various ion channels to cause changes in the membrane potential Neurotransmitters act at synapses Receptors Neurotransmitters act by binding to specific receptors and opening or closing ion channels Ionotropic receptors (ion channels) Metabotropic receptors All known metabotropic receptors are coupled to G-proteins Regulation of neurotransmitters The action of transmitters must be halted by their removal from the synaptic cleft Concentrations of neurotransmitters may be manipulated Classes of neurotransmitters Amino acids Glutamate Glutamate is the most important excitatory transmitter in the CNS Glutamate and excitotoxicity Excess glutamate is toxic to nerve cells γ-Amino butyric acid (GABA) GABA is synthesized from glutamate by the enzyme glutamate decarboxylase Glycine Catecholamines Norepinephrine and epinephrine Norepinephrine (also known as noradrenaline) is a major transmitter in the sympathetic nervous system Epinephrine (also known as adrenaline) is produced by the adrenal medulla under the influence of ACh-containing nerves, analogous to the sympathetic preganglionic nerves Dopamine Dopamine is both an intermediate in the synthesis of norepinephrine and a neurotransmitter Serotonin (5-hydroxytryptamine) Serotonin, also called 5-hydroxytryptamine (5-HT), is derived from tryptophan Acetylcholine Acetylcholine (ACh) is the transmitter of the parasympathetic autonomic nervous system and of the sympathetic ganglia (Fig. 26.1) Nitric oxide gas In autonomic and enteric nerves, nitric oxide (NO) is produced from arginine by the tetrahydrobiopterin-dependent nitric oxide synthases NO is not stored in vesicles but released directly into the extracellular space Other small molecules ATP and other purine-containing molecules derived from it are now known to have transmitter functions The study of histamine in nerves is complicated by the large amounts that are present in mast cells Peptides Many peptides act as neurotransmitters Many neuropeptides belong to a multigene family Neuropeptides can act as neuromodulators Summary Further reading Relevant websites Abbreviations 27 Biochemical Endocrinology Abstract Keywords Learning objectives Introduction Hormones There are endocrine, paracrine, and autocrine hormones Classification of hormones Structurally, hormones may be modified amino acids, peptides, glycoproteins, or steroids Principles of hormone action Regulation of hormone production Hormone systems are typically controlled by feedback mechanisms Hormone degradation and clearance The inactivation of hormones is key to their function as controllers of homeostasis Laboratory assessment of hormone action Measurement of hormones in blood and fluids (e.g., urine and saliva) forms part of the assessment of hormone action and endocrine axes Hormone day profiles, stimulation tests, and suppression tests Isolated measurements of hormones that exhibit circadian rhythm, such as cortisol and growth hormone are of limited value Endocrine laboratory In the clinical laboratory, hormone levels in blood and urine are usually measured using immunoassay or mass spectrometry (MS) Causes of endocrine disease Autoimmunity and neoplasia Loss of functioning endocrine tissue may be the result of destruction due to autoimmunity or neoplasia Endocrine neoplastic disease may be benign or malignant Exogenous hormone administration Hormone therapy may result in clinical problems attributable to excess hormone administration, loss of physiologic pulsatility, or loss of diurnal rhythm The hypothalamus and the pituitary gland Structure Hypothalamic regulation of the pituitary Both the anterior and posterior pituitary are under the influence of the hypothalamus Anterior pituitary The hypothalamus secretes hormones that may stimulate or inhibit the release of hormones from the anterior pituitary Posterior pituitary Oxytocin and vasopressin are two peptide hormones synthesized in the cell bodies of the hypothalamic neurons that are subsequently secreted by the posterior pituitary Thyroid function: the hypothalamic–pituitary–thyroid axis Thyrotropin-releasing hormone (TRH) TRH (also known as thyreoliberin), a tripeptide synthesized in the peptidergic hypothalamic nuclei and transported to the anterior pituitary via the portal circulation, stimulates TSH synthesis and secretion. Thyroid-stimulating hormone (TSH) TSH is a glycoprotein heterodimer consisting of an α- and β-subunit and is about 15% carbohydrate by weight Thyroxine (T4) and triiodothyronine (T3) Actions of thyroid hormones Metabolic effects of thyroid hormones Thyroid hormones increase metabolic rate, with increased oxygen consumption and heat production Developmental effects of thyroid hormones The thyroid hormones have a critical effect on normal skeletal and central nervous system development Mechanism of action of thyroid hormones Thyroid hormones exert their effects via nuclear receptors. Disorders of thyroid function Hyperthyroidism Hyperthyroidism, also described as an “overactive thyroid,” is the excessive production and secretion of thyroid hormones and is caused by a number of conditions (Table 27.4) Hypothyroidism Hypothyroidism, also described as an “underactive thyroid,” is thyroid hormone deficiency Laboratory investigations of thyroid function Serum TSH is typically used as a first-line screen for thyroid disease; an fT4 may also be requested if there is a strong clinical suspicion of thyroid disease or if there is an indication to consider pituitary disease The hypothalamic–pituitary–adrenal axis Corticotropin-releasing hormone (CRH) Adrenocorticotropic hormone (ACTH) ACTH (also termed corticotropin) is a 39–amino acid polypeptide that is synthesized from a 241–amino acid precursor molecule, pro-opiomelanocortin (POMC) ACTH circulates unbound in plasma, and its half-life is approximately 10 min Anatomy and biochemistry of the adrenal gland Biosynthesis of cortisol Cortisol, a steroid hormone and the major glucocorticoid synthesized and secreted by the human adrenal cortex, is synthesized and released as required Actions of cortisol There are four broad areas of cortisol action: negative feedback to the hypothalamus and anterior pituitary, metabolic homeostasis, fluid/electrolyte homeostasis, and antiinflammatory/immunosuppressive effects Cortisol has multiple actions in adipose tissue, acting to induce lipogenic genes and adipose endocrine function Cortisol has a weak mineralocorticoid action, and the mineralocorticoid receptor binds aldosterone and cortisol with equal affinity Disorders of cortisol secretion Adrenal hypofunction Adrenocortical insufficiency may be due to primary adrenal pathology or secondary to anterior pituitary failure to produce ACTH Primary adrenal insufficiency The identification of cortisol deficiency can be clinically challenging, particularly in the early stages of the disease, because some common presenting features are nonspecific (Table 27.7) Adrenal insufficiency may result from genetic conditions caused by defects in steroid biosynthesis Secondary adrenal insufficiency Adrenal hyperfunction Hypercortisolism Diagnosis of Cushing syndrome Measurement of plasma ACTH in the presence of hypercortisolemia is used to determine whether cortisol production is ACTH-driven rather than autonomous Hyperaldosteronism The hypothalamo–pituitary–gonadal axis Gonadotropin-releasing hormone (GnRH) GnRH is essential for secretion of FSH and LH Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) The pituitary gland produces the gonadotropins FSH and LH, critical to gonadal reproductive function in both males and females Action of gonadotropins on the testes Androgens Biochemical actions of testosterone in the male Testosterone is an anabolic hormone and increases muscle mass by stimulating protein synthesis (Fig. 27.10) Testosterone deficiency in males Endocrine failure of the testes may be primary, due to trauma or inflammation of the testes, for example, or secondary, due to a failure of the hypothalamus or pituitary Gonadal dysgenesis in the male Klinefelter syndrome, which is most commonly caused by the acquisition of one extra copy of the X chromosome in each cell (karyotype 47, XXY), has a prevalence of 1 in 500–1000 of all phenotypic males Androgen excess in the male Hyperandrogenism due to testicular androgen excess may cause precocious puberty Actions of FSH and LH on the ovary In the mature female, there are cyclic changes in the hypothalamic–pituitary–gonadal axis orchestrated by the GnRH pulse generator Inhibin and the ovary Granulosa cells secrete inhibin, a heterodimeric glycoprotein composed of an α-subunit linked by a disulfide bridge to one of two homologous β-subunits Gonadotropins and pregnancy After successful implantation of a fertilized ovum, maintenance of the corpus luteum and progesterone production is vital to ensure progression of development Gonadotropins and menopause Ovarian follicles become depleted of oocytes after 30–40 years of ovulatory cycles, and normal pregnancy is no longer possible Estrogens and progesterone: Actions of steroid hormones in the female Aside from their role in the menstrual cycle, the female sex steroids have additional roles The growth hormone axis Growth hormone–releasing hormone (GHRH) GHRH is a 44–amino acid peptide synthesized in the arcuate and ventromedial hypothalamic nuclei of the hypothalamus Ghrelin is a 28–amino acid peptide hormone with a fatty acid chain that is also a potent inducer of GH secretion Somatostatin Somatostatin (sometimes referred to as growth hormone–inhibiting hormone [GHIH]) is synthesized in the paraventricular and ventromedial nuclei of the hypothalamus Somatostatin suppresses the release of the gastrointestinal hormones gastrin, cholecystokinin, vasoactive intestinal peptide (VIP), gastric inhibitory polypeptide, insulin, and glucagon Growth hormone (GH) GH release is episodic and under the influence of the hypothalamus, with approximately two-thirds of total 24-h GH secretion occurring at night GH is synthesized by the somatotropic cells of the anterior pituitary and stored within granules The overall action of GH is to promote growth of bone, cartilage, and soft tissue Insulin-like growth factor-1 (IGF-1) Measurement of IGF-1 has clinical utility as an indicator of integrated GH activity Clinical disorders of GH secretion Clinically significant GH excess or deficiency is relatively uncommon and can be difficult to diagnose Growth hormone deficiency Childhood GH deficiency is a possible cause for short stature Growth hormone excess Excess GH secretion is most commonly due to a pituitary tumor The prolactin axis Prolactin and dopamine Prolactin is a 198–amino acid polypeptide hormone secreted solely by lactotrope cells of the anterior pituitary Dopamine stimulates D2 receptors to inhibit adenylyl cyclase and thereby inhibit prolactin synthesis and secretion Disorders of prolactin secretion Pathologic hyperprolactinemia Extreme hyperprolactinemia is highly suggestive of a prolactinoma in patients not taking antidopaminergic drugs Macroprolactin is prolactin bound to antibody circulating as a complex and may be detected by some prolactin assays resulting in a high measured serum prolactin concentration Endocrine systems not considered in this chapter Summary Further reading Relevant websites More Clinical Cases Abbreviations 28 Cellular Homeostasis Abstract Keywords Learning objectives Introduction Development and survival of multicellular organisms such as human beings are reliant on the appropriate regulation of growth, differentiation, and death of individual cell types to maintain the integrity of the organism Research in transformed cancerous cells has highlighted important mechanisms that regulate cellular growth and cell division in normal cells Cell cycle Individual cells multiply by duplicating their contents and then dividing into two daughter cells In recent years, extensive research of the cell cycle has defined a number of key control points The G0 phase is a form of the resting state, or quiescence, in which cells reside until they receive appropriate signals - for example, from growth factors - stimulating them to re-enter and progress through the cell cycle Regulation of cell proliferation and growth: Growth factors Cells of a multicellular organism have to receive positive signals in order to grow and divide In most cell types, proliferation is controlled by signals generated from a specific combination of growth factors rather than stimulation by a single growth factor Growth factors bind to specific cell-surface receptors Growth factors selectively initiate signaling cascades Growth factors selectively initiate signaling cascades by binding to their receptors Epidermal growth factor receptor (EGFR) signaling Upon ligand binding, the EGFR activates signals through Ras/Raf/MAPK- and PI3K/Akt/mTor-mediated signaling cascades Signaling cascade involving Ras GTPase is important in regulating cell division mTORC-1 and mTORC-2 complexes integrate mitogen and nutrient signals Although the signaling pathways just described are linear, a significant amount of cross-talk occurs among these cascade elements Cytokine receptor signaling Cytokines are growth factors that mainly coordinate the development of hematopoietic cells and the immune response, although they also have multiple effects on non-hematopoietic cell types Janus kinases (JAK) link the hematopoietic receptors with the downstream signaling and gene transcription Regulation of the cell cycle Cyclin-dependent kinase (CDK) family and cyclins regulate cell-cycle transition points Mitogenesis Mitogenic signals activated by growth factors exert their effects between the onset of the G1 phase and a point late in the G1 phase, called the restriction point Monitoring for DNA damage Molecular checkpoints that mediate appropriate progression through the cell cycle sense problems that may occur during DNA synthesis and chromosome segregation In the case of damage occurring, the DNA damage checkpoints sense alterations and activate signaling pathways that mediate DNA repair The tumor-suppressor protein p53 is predominantly a DNA-damage-sensing protein that monitors DNA damage throughout the cell cycle A p53-independent pathway involving the INK4 family of proteins can also induce cell-cycle arrest in the G1 phase in response to DNA damage Cell death Cell death is a fundamentally important part of a cell’s life cycle, and appropriate regulation of this process is critical to maintaining the homeostatic regulation of a multicellular organism Apoptosis Apoptosis is initiated and executed through either perturbation of intracellular homeostasis by intrinsic (mitochondrial) or extrinsic (e.g., Fas, TNFR) pathways Caspases Caspases are cysteine proteases with aspartate substrate specificity IAP gene family: its main function is to inhibit apoptosis The Bcl-2 gene family is composed of structurally related proteins that form homo- or heterodimers and act as positive or negative regulators of apoptosis There are alternative routes to apoptosis Autophagy Autophagy is a process that degrades cellular components, in which a part of cytoplasm is engulfed by a specific membrane and the contents are degraded by lysosomal enzymes Autophagy is induced by a variety of stress stimuli, including nutrient and energy stress as well as hypoxia, oxidative stress, infections, ER stress, and mitochondrial damage Cancer Cells that develop mutations affecting normal regulation of the cell cycle are able to undergo unchecked proliferation, resulting in a loss of homeostatic regulation and the development of a tumor or neoplasm In the majority of cases, a single mutation is not sufficient to convert a healthy cell to a cancer cell; several rare mutations have to occur together Mutations need to occur in the appropriate cells to enable the neoplasm to develop, indicating that cell context has an important bearing on the type of cancer that subsequently develops Mutations that lead to the expression of established oncogenes do not necessarily lead to the development of cancer if they occur in nonsusceptible cells Tumor promoters: Oncogenes Oncogenes were first identified as viral genes that infect normal cells and transform them into tumor cells The key to understanding cell transformation lies in the mutation of a normal cellular gene that controls cell growth Most human tumors are nonviral in origin and arise from spontaneous or induced mutations Whole-exome/genome sequencing of individual patients, utilized to determine the specific mutational landscape within cancer subtypes, has enabled links to be established between seemingly diverse cancers that result from similar genetic mutations Tumor-suppressor genes: Subversion of the cell cycle p53: Guardian of the genome Phosphatase and Tensin homologue (PTEN) The tumor suppressor PTEN is one of the most commonly inactivated proteins in sporadic cancer Summary Further reading Relevant websites Abbreviations 29 Aging Abstract Keywords Learning objectives Introduction Aging may be defined as the time-dependent deterioration in function of an organism Aging of complex systems The Hayflick limit: Replicative senescence The replicative capacity of cells decreases with age Mathematical models of aging In poikilotherms, the rate of aging is correlated with temperature, physical activity, and metabolic rate Theories of aging Theories of aging can be divided into two general categories: Biological and chemical The free-radical theory of aging The free-radical theory of aging is the most widely accepted theory of aging Mitochondrial theories of aging Mitochondrial DNA is particularly susceptible to oxidative damage Genetic models of increased lifespan The effect of genetics on longevity is readily apparent in animal models Antiaging interventions: what works and what doesn’t Antioxidant supplements Antioxidant supplements may improve health but do not increase lifespan Calorie restriction Caloric restriction is the only regimen known to increase lifespan in animals Caloric restriction delays the onset of age-related diseases, including cancer Summary Further reading Relevant websites Aging resources and links: Abbreviations 30 Digestion and Absorption of Nutrients Abstract Keywords Learning objectives Introduction Water and electrolyte handling in the gastrointestinal tract Handling of electrolytes and water by the GI tract is one of its main functions A large volume of fluid is secreted and reabsorbed by the GI tract Electrolytes are secreted by the salivary glands, stomach, and pancreas Impaired intestinal function leads to potentially serious disorders of fluid–electrolyte and acid–base balance Mechanisms of water and electrolyte transport in the intestine Sodium-potassium ATPase is the driving force for transport processes in the enterocytes Sodium cotransporters are a common mode of intestinal transport Other modes of sodium transport include electroneutral and electrogenic transport Chloride transport: Cystic fibrosis transmembrane conductance regulator (CFTR) Potassium absorption and potassium secretion in the colon are aided by different potassium channels Reabsorption of short-chain fatty acids occurs together with bicarbonate secretion Aquaporins control colonic water reabsorption Intestinal secretions differ in their pH Components of digestion Digestion is a sequential series of processes There is considerable functional reserve in all aspects of digestion and absorption Digestive enzymes and zymogens Most digestive enzymes are secreted as inactive precursors All digestive enzymes are hydrolases Digestion and absorption of carbohydrates Dietary carbohydrates enter the GI tract as mono-, di-, and polysaccharides Disaccharides and polysaccharides require hydrolytic cleavage into monosaccharides before absorption Disaccharidases are inducible, with the exception of lactase Active and passive transport systems transfer monosaccharides across the brush-border membrane Glucose, fructose, and galactose are the primary monosaccharides generated by digestion of dietary carbohydrates There are at least two carrier-mediated transport mechanisms for monosaccharides Digestion and absorption of lipids Fats need to be emulsified before digestion Bile salts and pancreatic enzymes act on the lipid emulsion in the duodenum Bile salts are essential for solubilizing lipids during the digestive process The fate of fatty acids depends on their chain length Triacylglycerol synthesis requires activation of fatty acids Digestion and absorption of proteins Proteins are hydrolyzed by peptidases Protein digestion begins in the stomach Proteolytic enzymes are released from the pancreas as inactive zymogens Pancreatic proteases cleave peptide bonds in different locations in a protein Final digestion of peptides depends on peptidases present in small intestine Summary Further reading Relevant websites Abbreviations 31 Glucose Homeostasis and Fuel Metabolism Abstract Keywords Learning objectives Introduction The most important energy substrates are glucose and fatty acids Metabolism is geared toward safeguarding continuous glucose supply; glucose is being stored as glycogen and can also be synthesized from non-carbohydrate compounds Fatty acids are the primary energy source during prolonged fasting and prolonged exercise; large amounts of fatty acids are stored as triacylglycerols Amino acids become a fuel after conversion to glucose Organs and tissues differ in their handling of fuels Glucose homeostasis Insulin and the counterregulatory hormones control fuel metabolism Insulin Insulin secretion is controlled by glucose metabolism in the β-cell Insulin acts through a membrane receptor that triggers multiple intracellular signaling pathways; intracellular insulin signaling occurs through complex cascades of phosphorylation reactions The IRS-PI3K-Akt signaling pathway controls the metabolic effects of insulin The GRB2-SOS-Ras-MAPK signaling pathway has mitogenic effects The PI3K-independent pathway stimulates glucose transport Metabolic effects of insulin Insulin stimulates glucose transport across the cell membrane Insulin resistance: A key concept in glucose homeostasis The most important cause of insulin resistance is defective insulin signaling (Table 31.2) Glucagon and other antiinsulin hormones Glucagon and other antiinsulin (counterregulatory) hormones increase plasma glucose concentration by stimulating glycogenolysis and gluconeogenesis Epinephrine acts on liver and muscle Incretin hormones Incretin hormones are secreted by the gut and potentiate insulin secretion The feed–fast cycle Human metabolism oscillates between the fed state and the fasting state; the molar ratio of insulin to glucagon in plasma depends on which pattern of metabolism is present Insulin and glucagon switch genes on and off during feed–fast cycle Metabolism in the fed state Metabolism in fed state is geared toward energy production and storage Metabolism in the fasting state Liver switches from a glucose-utilizing to a glucose-producing organ The three key substrates for gluconeogenesis are lactate, alanine, and glycerol Prolonged fasting (starvation) Metabolic response to stress The metabolic response to stress mobilizes energy substrates from all available sources; during stress, metabolism is driven by the antiinsulin hormones The stress response includes insulin resistance Diabetes mellitus Diabetes is a disorder of fuel metabolism characterized by hyperglycemia and (later) by vascular damage Type 1 diabetes is an autoimmune disease Susceptibility to type 1 diabetes is inherited Type 2 diabetes develops when β cells fail to compensate for existing insulin resistance Genetic predisposition and obesity are the most important risk factors for type 2 diabetes Heritability of type 2 diabetes is greater than 50% In type 2 diabetes, ketoacidosis is rare Metabolism in diabetes In poorly controlled diabetes, metabolic decompensation leads to ketoacidosis Key features of diabetic ketoacidosis are hyperglycemia, ketonuria, dehydration, and metabolic acidosis Diabetes, obesity, and hypertension are linked with cardiovascular disease Late vascular complications of diabetes mellitus Oxidative stress, advanced glycation (glycoxidation) end products, and activity of the polyol pathway contribute to the development of complications Increased activity of the polyol pathway is associated with diabetic neuropathy and ocular cataracts Hypoglycemia Hypoglycemia is the most common acute complication of diabetes Laboratory assessment of fuel metabolism Diagnosis and monitoring of patients with diabetes mellitus The key diagnostic tests for diabetes are measurements of plasma glucose and glycated hemoglobin concentration A continuum exists between normal, prediabetic, and diabetic states Oral glucose tolerance test (OGTT) assesses blood glucose response to a carbohydrate load The glycated hemoglobin (HbA1c) concentration reflects average concentration of plasma glucose HbA1c is used to diagnose diabetes and to monitor glycemic control Urine glucose is not a diagnostic test for diabetes Ketone bodies in the urine of a diabetic person signify metabolic decompensation Urinary albumin excretion is important in the assessment of diabetic nephropathy Increased plasma lactate indicates inadequate tissue oxygenation Treating diabetes Keeping glycemia close to normal prevents development of diabetic complications Lifestyle modification is the mainstay of diabetes prevention and treatment Patients with type 1 diabetes are treated with insulin Standard insulin treatment protocols involve daily subcutaneous injections throughout life Emergency treatment of diabetic ketoacidosis includes intravenous insulin, rehydration, and potassium supplementation Patients with type 2 diabetes are treated with oral hypoglycemic drugs, but some may also require insulin Antidiabetic drugs Biguanides and thiazolidinediones sensitize the peripheral tissues to insulin Sulfonylureas, meglitinides, and drugs affecting the incretin system stimulate insulin secretion GLP-1 receptor agonists and DPP-4 inhibitors affect the incretin system Acarbose decreases the availability of glucose Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease glucose reabsorption in the kidney Bariatric surgery is used as an option for diabetes treatment in severely obese people Summary Further reading Relevant websites Abbreviations 32 Nutrients and Diets Abstract Keywords Learning objectives Introduction Nutritional status is determined by biological, psychologic, and social factors Basic definitions Main classes of nutrients Carbohydrates The glycemic index and glycemic load provide quantitative and qualitative insight into the handling of carbohydrate-containing foods Proteins Fats Fats are divided into saturated and unsaturated (the latter being either mono- or polyunsaturated) Oleic acid (ω-9) is the only significant dietary monounsaturated fatty acid Polyunsaturated fatty acids include ω-3 and ω-6 acids Essential nutrients Essential (limiting) nutrients are these that cannot be synthesized in the human body Some plant proteins are relatively deficient in essential amino acids, whereas animal proteins usually contain a balanced mixture Essential fatty acids (EFA) are linoleic acid and α-linolenic acid Vitamins and trace metals are important for the catalysis of chemical reactions Healthy eating Current dietary recommendations for general population focus on a balanced diet Regulation of food intake Food intake is controlled by hunger (a desire to eat) and appetite (a desire for a particular food) The hypothalamus and brainstem translate the information about energy balance into eating behavior Energy balance Adipose tissue is an active endocrine organ Leptin regulates adipose tissue mass and responds to the energy status Adiponectin increases insulin sensitivity; its lack leads to insulin resistance Adipose tissue also secretes proinflammatory cytokines AMP-stimulated kinase (AMPK) is a cellular energy sensor AMPK stimulates energy-producing (catabolic) pathways and suppresses energy-utilizing (anabolic) ones. Energy expenditure Basal metabolic rate is the energy expenditure required to maintain body function at complete rest In health, physical activity is the most important changeable component of energy expenditure Nutrigenomics Genotype influences plasma concentrations of nutrients Nutrition, life cycle, and metabolic adaptation Pregnancy is an example of metabolic adaptation termed expansive adaptation Nutrient intake changes during the life cycle assessing nutrition Dietary intake is not easy to assess Assessing the nutritional status of an individual Dietary history should include more than the details of food intake Simplified assessment of nutritional status Body weight and the body mass index Biochemical markers of nutritional status Urinary nitrogen excretion helps assess nitrogen balance Specific plasma proteins are used as markers of nutritional status Full assessment involves measurements of vitamins and trace metals Other laboratory tests provide information complementing nutritional assessment Obesity Obesity has emerged as a major health problem worldwide Genetic regulation of food intake and energy expenditure Obesity is associated with an increased risk of medical and surgical problems Attempting weight loss to reverse the consequences of obesity To lose weight, one needs to change the balance between energy intake and expenditure - that is, between food intake and physical activity Malnutrition Malnutrition is a gradual decline in nutritional status, which leads to a decrease in functional capacity and to other complications Markers of malnutrition risk There are two types of protein–calorie malnutrition: marasmus and kwashiorkor Refeeding syndrome develops as a consequence of inappropriate feeding of a malnourished person Syndromes related to malnutrition Frailty is a multisystem deterioration associated with age Cachexia is weight loss predominantly related to disease Nutritional support Enteral nutrition entails feeding a person through special tubes placed in the stomach or jejunum Total parenteral nutrition is appropriate when the gastrointestinal tract does not function because of, for instance, intestinal obstruction or when large parts of it have been surgically removed The effectiveness of nutritional support using TPN depends on the cause of weight loss Summary Further reading Relevant websites Abbreviations 33 Lipoprotein Metabolism and Atherogenesis Abstract Keywords Learning objectives Introduction Lipoproteins distribute triacylglycerols and cholesterol between the intestine and liver, on the one hand, and peripheral tissues, on the other Nature of lipoproteins Lipoproteins are clusters of hydrophilic, hydrophobic, and amphipathic molecules Lipoproteins differ in size and density Apolipoproteins Apolipoproteins are proteins present in lipoprotein particles; they fulfill structural and metabolic functions Lipoprotein receptors The LDL receptor is regulated by the intracellular cholesterol concentration Scavenger receptors are nonspecific and nonregulated Enzymes and lipid transfer proteins Pathways of lipoprotein metabolism Lipoproteins fulfill a dual function: distribution of triacylglycerols and cholesterol delivery to cells Lipoprotein metabolism: The fuel distribution stage In the fed state, triglycerides are delivered from the intestine to the periphery by chylomicrons; chylomicron remnants form after triacylglycerols are removed Triglycerides synthesized in the liver are transported to the periphery by the VLDL; this happens in both fed and fasting states Lipoprotein metabolism: The cholesterol delivery stage Cholesterol present in the remnant particles and in the LDL is transported to the liver Plasma lipoprotein cholesterol forms an extracellular pool available to cells Reverse cholesterol transport HDL particles remove cholesterol from cells HDL take cholesterol out of cells Transfer of cholesterol from HDL to triglyceride-rich particles is the principal route of cholesterol transport in humans The concept of cardiovascular risk Cardiovascular risk means the probability of an ASCVD event Overall CVD risk is calculated using risk calculators Atherosclerosis Atherogenesis: The role of vascular endothelium Normal endothelium has anticoagulant and antiadhesion properties Endothelium controls vasodilatation by secreting nitric oxide Atherogenesis is initiated by endothelial damage Atherogenesis: Contribution of retained lipoproteins Dysfunctional endothelium facilitates entry and retention of lipoproteins in the intima Cellular basis of atherogenesis Cells enter vascular intima Monocytes transform into resident macrophages Oxidized lipoproteins are taken up by macrophages Migration of vascular smooth muscle cells changes the structure of the vascular wall Inflammatory activity destabilizes the plaque, making it prone to rupture Atherogenesis: The role of thrombosis Platelets stimulate thrombotic phenomena in the plaques Dyslipidemias Conditions associated with low HDL concentration Conditions associated with high plasma HDL concentration Principles of treatment of dyslipidemias Management of dyslipidemias combines lifestyle measures and drug treatment Statins inhibit HMG-CoA reductase Fibrates act through PPARα transcription factor Inhibitors of intestinal absorption bind bile acids and inhibit cholesterol transporter Omega-3 fatty acids lower plasma triglyceride concentration PCSK9 inhibitors are the newest class of cholesterol-lowering drugs Summary Further reading Relevant websites More clinical cases Abbreviations 34 Role of the Liver in Metabolism Abstract Keywords Learning objectives Introduction The liver is the largest organ in the body and has a substantial reserve metabolic capacity Structure of the liver Structure of the liver facilitates exchange of metabolites between hepatocytes and plasma Liver and carbohydrate metabolism The liver plays a central role in glucose metabolism, specifically in maintaining the circulating concentration of glucose Depending on metabolic conditions, the liver can either take up or produce glucose Liver and protein metabolism Most plasma proteins are synthesized in the liver A better index of hepatocyte synthetic function is the production of the coagulation factors II, VII, IX, and X Response to an acute insult is associated with wide-ranging changes in liver protein synthesis Protein degradation by the ubiquitin–proteasome system Ubiquitin marks intracellular proteins for proteasomal degradation Removal of nitrogen The urea cycle is essential for the removal of nitrogen generated by amino acid metabolism Impaired clearance of ammonia causes brain damage Heme synthesis Heme is a constituent of hemoglobin, myoglobin, and cytochromes Bilirubin metabolism Excess bilirubin causes jaundice Bilirubin is metabolized by the hepatocytes and excreted in bile Bile acids and cholesterol metabolism Bile acids are key elements in fat metabolism Drug metabolism The low substrate specificity of some hepatic enzymes produces a wide-ranging capability for drug metabolism Drug metabolism proceeds in two phases Three of the 18 cytochrome P-450 gene families share the responsibility for drug metabolism Induction and competitive inhibition of cytochrome P-450 enzymes underpin mechanisms of drug interactions Cytochrome P-450 gene polymorphisms determine the response to many drugs Drug hepatotoxicity Drugs that exert their toxic effects on the liver may do so through the hepatic production of a toxic metabolite The commonly used drug acetaminophen (paracetamol) is hepatotoxic in excess Alcohol Alcohol excess is a major cause of liver disease Ethanol oxidation alters the redox potential of the hepatocyte Symptoms of alcohol intolerance are exploited to reinforce abstinence Pharmacogenomics The response to any particular drug is influenced by the drug’s kinetic properties (pharmacokinetics) and its effects (pharmacodynamics) Pharmacogenomics studies the effects of genetic heterogeneity on drug responsiveness Biochemical tests of liver function Transaminases Prothrombin time Alkaline phosphatase Classification of liver disorders Hepatocellular disease Cholestatic disease Jaundice Jaundice can be pre-, post, or intrahepatic Prehepatic hyperbilirubinemia results from excess production of bilirubin caused by hemolysis or a genetic abnormality in the hepatic uptake of unconjugated bilirubin Intrahepatic jaundice reflects a generalized hepatocyte dysfunction Posthepatic jaundice is caused by obstruction of the biliary tree Genomics of liver disease Hereditary hemochromatosis is a genetically determined disorder of iron metabolism Wilson’s disease is a condition associated with liver and CNS damage; it results from abnormal tissue copper disposition Deficiency of α1-antitrypsin presents in infancy as liver disease or in adulthood as lung disease Liver cancer is associated with particularly high plasma concentrations of α-fetoprotein There are a number of genetic disorders that impair bilirubin conjugation or secretion Summary Further reading Relevant websites More clinical cases Abbreviations 35 Water and Electrolytes Homeostasis Abstract Keywords Learning objectives Introduction Water and electrolytes are constantly exchanged with the environment Body water compartments The body exchanges water with the environment The capillary vessel wall separates plasma and the interstitial fluid The plasma membrane separates the intracellular and extracellular fluid Ion movements and transport systems Water diffuses freely across most cell membranes, but the movement of ions and neutral molecules is restricted; Na+/K+-ATPase maintains the sodium and potassium gradients across the cell membrane The Na+/K+-ATPase is subject to regulation by a number of hormones, including aldosterone The electrochemical gradient drives the passive movement of electrolytes through ion channels Cells protect themselves against changes in volume The role of osmotic pressure in fluid shifts between ECF and ICF Osmolality depends on the concentration of molecules in water Differences in osmolality drive movement of water between ICF and ECF Balance between the oncotic and hydrostatic pressures is fundamental for the circulation of substrates and nutrients Role of the kidneys in water and electrolyte balance Sodium transport systems in the renal tubules Regulation of water and electrolyte balance Renin, angiotensin, and aldosterone The Renin–angiotensin system controls blood pressure and the vascular tone Angiotensin receptors are important in the pathogenesis of cardiovascular disease Aldosterone regulates sodium and potassium homeostasis The natriuretic peptides Natriuretic peptides promote sodium excretion and decrease the blood pressure. They are important markers of heart failure Vasopressin and aquaporins Vasopressin regulates water reabsorption by the kidneys Aquaporins are membrane channel proteins which transport water Defects in vasopressin secretion and defective aquaporins cause diabetes insipidus Integration of water and sodium homeostasis Handling of sodium and water is subject to integrated control by aldosterone and vasopressin Water deficit (dehydration) decreases plasma volume, renal blood flow, and GFR Water excess increases plasma volume, renal blood flow, and GFR Plasma sodium concentration Disorders of plasma sodium concentration are closely linked to dehydration and overhydration Clinical abnormalities that develop after excessive fluid loss depend on the ionic composition of the lost fluid Hypernatremia is most commonly associated with dehydration Both severe hypernatremia and hyponatremia cause neurologic symptoms Plasma potassium concentration Disorders of plasma potassium concentration carry the risk of cardiac arrhythmias Monitoring plasma potassium concentration is fundamentally important Assessment of water and electrolyte status in clinical practice Summary Further reading Relevant websites More Clinical Cases Abbreviations 36 The Lung and the Regulation of Hydrogen Ion Concentration (Acid–Base Balance) Abstract Keywords Learning objectives Introduction Metabolism generates acids Maintaining the acid–base balance involves the lungs, erythrocytes, and the kidneys Clinical relevance Body buffer systems: respiratory and metabolic components of the acid–base balance Blood and tissues contain buffer systems that minimize changes in hydrogen ion concentration Bicarbonate buffer remains at equilibrium with atmospheric air Bicarbonate is generated in erythrocytes and renal tubules Respiratory and metabolic components of the acid–base balance are interlinked Intracellular buffering Inside cells, hydrogen ion is buffered by proteins and phosphates Lungs: the gas exchange The lungs supply oxygen necessary for tissue metabolism and remove the generated CO2 The respiratory center in the brainstem controls respiration rate Ventilation and lung perfusion together determine gas exchange Different combinations of disturbed ventilation and perfusion may occur Handling of carbon dioxide by erythrocytes Erythrocytes transport CO2 to the lungs in a “fixed” form - as bicarbonate Bicarbonate handling by the kidneys Distal tubules generate new bicarbonate and excrete hydrogen Ammonia generated by glutaminase reaction participates in the excretion of hydrogen ion Disorders of the acid–base balance Classification of the acid–base disorders There are four main disorders of acid–base balance The lungs and kidneys work in a concerted way to minimize changes in plasma pH Acidosis Respiratory acidosis occurs most often in lung disease and results from decreased ventilation Metabolic acidosis results from excessive production or inefficient metabolism or excretion, of nonvolatile acids Rare renal tubular acidoses are characterized by impaired bicarbonate reabsorption and hydrogen ion secretion Alkalosis Alkalosis is rarer than acidosis Mixed acid–base disorders Summary Further reading Relevant websites Abbreviations 37 Muscle Abstract Keywords Learning objectives Introduction There are three types of muscle: skeletal, cardiac, and smooth muscle - each with a unique physiologic role Muscle structure The sarcomere: The functional contractile unit of muscle The thick and thin filaments Actin and myosin account for more than 75% of muscle protein Sarcomere proteins Myosin Interaction between actin and myosin during muscle contraction is dependent on cytoplasmic Ca++ concentration Actin Tropomyosin and troponins Troponins modulate the interaction between actin and myosin Titin Titin modulates the passive tension of muscle The contractile process The sliding-filament model of muscle contraction The sliding-filament model describes how a series of chemical and structural changes in the actomyosin complex can induce sarcomere shortening Excitation–contraction coupling: Muscle membrane depolarization T tubules transmit electrochemical signals for efficient muscle contraction Excitation–contraction coupling: The calcium trigger Muscle energy metabolism Energy resources in the muscle cell ATP is used for muscle contraction Short-duration, high-power output contractions Creatine phosphate is a high-energy phosphate buffer used for rapid regeneration of ATP in muscle Low-intensity, long-duration contractions Fatty acids are the major source of energy in muscle during prolonged exercise Long-term muscle performance (stamina) depends on levels of muscle glycogen Fats burn in the flame of carbohydrates; glycogen is required for efficient metabolism of lipids in muscle Muscle consists of two types of striated muscle cells: Fast-glycolytic and slow-oxidative fibers Tissue engineering and replacement of muscle Effect of exercise Strength or resistance training increases muscle mass Endurance, or aerobic, training increases the oxidative metabolic capacity of muscle Summary Further reading Relevant websites Muscular dystrophies: Animations: More Clinical Cases Abbreviations 38 Bone Metabolism and Calcium Homeostasis Abstract Keywords Learning objectives Introduction Cellular role of calcium Entry of calcium into cytoplasm is an important biological signal Bone structure and bone remodeling Bone is a specialized connective tissue that, along with cartilage, forms the skeletal system Bone growth Several signaling pathways are relevant to bone growth Bone remodeling Bone constantly changes its structure through remodeling Osteoblasts are bone-forming cells Osteoclasts are bone-resorbing cells RANK prepares the osteoclast to resorb bone Local factors and PTH contribute to osteoclast activation Bone markers Calcium homeostasis Calcium in plasma Calcium is present in the circulation in three forms Parathyroid hormone (PTH) PTH is the main regulator of calcium homeostasis PTH binds to a specific receptor and acts through cyclic adenosine monophosphate (cAMP) Calcitonin Calcitonin inhibits bone resorption Vitamin D Vitamin D is synthesized in the skin by ultraviolet (UV) radiation Calcidiol is the storage form of vitamin D Calcitriol is the most potent form of vitamin D Calcitriol increases the absorption of calcium and phosphate from the gut Intestinal absorption and renal excretion of calcium Calcium is absorbed in the small intestine and is excreted in urine and feces Calcium is excreted through the kidney Several other hormones affect bone metabolism and calcium homeostasis Disorders of calcium metabolism Hypercalcemia Hypercalcemia is most commonly caused by primary hyperparathyroidism or by malignancy Primary hyperparathyroidism is common Hypercalcemia occurs in advanced malignant disease and is usually a poor prognostic sign Hypercalcemia can also be caused by overtreatment with vitamin D Hypocalcemia Hypocalcemia is common in clinical practice Hypocalcemia may result from abnormal vitamin D metabolism Rickets Rickets can also develop as a result of phosphate deficiency Enhanced phosphate reabsorption may result in ectopic calcification Osteoporosis Osteoporosis is a common age-related disease of bone Paget’s disease of bone is characterized by areas of accelerated bone turnover Summary Further reading Abbreviations 39 Neurochemistry Abstract Keywords Learning objectives Introduction Brain and peripheral nerve The blood–brain barrier The term blood–brain barrier (BBB) is a slight misnomer in that the “barrier” is not absolute but relative: its permeability depends on the size of the molecule in question There are six sources of the CSF Cells of the nervous system Neurons The significant features of neurons are their length, their many interconnections, and the fact that they do not divide postpartum Because of their great length, neurons depend on an efficient system of axonal transport Neurotransmission is an energy-demanding process Neuroglial structures Astrocytes and oligodendrocytes comprise the neuroglial structures Synaptic transmission One of the unique chemical characteristics of the brain is the massively high density of synapses between different neurons Synaptic transmission involves the recycling of membrane components Types of synapse Cholinergic transmission The best-studied neurotransmitter is acetylcholine Catecholamine transmission Glutamate: Glutamatergic transmission Depending on the brain region, 50–80% of the neuronal population is glutamatergic γ-Aminobutyric acid (GABA): GABA-ergic transmission GABA is the chief inhibitory neurotransmitter in the brain Ion channels Even at rest, the neuron is working to pump ions along ionic gradients Calcium ions have an important role in the synchronization of neuronal activity Mechanism of vision The mechanism by which the human eye can detect a single photon of light provides a fascinating example of the chemical processes underlying neuronal function Summary Further reading Abbreviations 40 Blood and Plasma Proteins Abstract Keywords Learning objectives Introduction Plasma is an important “window” on metabolism Chemical measurements require serum or plasma Clinical laboratories perform a large number of biochemical analyses on body fluids to provide answers to specific clinical questions Hospital laboratories rely on automation, robotics, and information technology Formed elements of blood Hematopoiesis Erythrocytes do not possess nuclei and intracellular organelles Leukocytes protect the body from infection Thrombocytes are fragments derived from megakaryocytes Plasma proteins Albumin serves as an osmotic regulator and is a major transport protein Albumin transports fatty acids, bilirubin, and drugs Proteins that transport metal ions Transferrin transports iron Ferritin is the major iron storage protein found in almost all cells of the body Ceruloplasmin is the major transport protein for copper Immunoglobulins Immunoglobulins are proteins produced in response to foreign substances (antigens) Immunoglobulins share a common Y-shaped structure of two heavy and two light chains Major classes of immunoglobulins IgG, the most abundant immunoglobulin, protects tissue spaces and freely crosses the placenta IgA is found in secretions and presents an antiseptic barrier that protects mucosal surfaces IgM is confined to the intravascular space and helps eliminate circulating antigens and microorganisms Minor classes of immunoglobulins IgD is the surface receptor in B lymphocytes IgE binds antigens and promotes release of vasoactive amines from mast cells Monoclonal immunoglobulin synthesis is a result of benign or malignant transformation of B cells The acute-phase response The acute-phase response is a nonspecific response to tissue injury or infection C-reactive protein (CRP) is a major component of the acute-phase response and a marker of bacterial infection High-sensitivity CRP assay is used in the assessment of cardiovascular risk Biomarkers A biomarker is a substance or a characteristic that is measured as an indicator of normal or pathologic processes Metabolomics explores patterns of small molecules Summary Further reading Relevant websites Abbreviations 41 Hemostasis and Thrombosis Abstract Keywords Learning objectives Introduction Hemostasis Hemostasis means “the arrest of bleeding” Hemostasis requires the coordinated function of blood vessels, platelets, coagulation factors, and the fibrinolytic system The lysis of fibrin is as important to health as its formation The vessel wall Vascular injury plays a key role in initiating local formation of the platelet–fibrin plug and in its subsequent removal by the fibrinolytic system Normal endothelium has an antithrombotic surface Endothelial damage exposes blood to tissue factor and to collagen Exposure of flowing blood to collagen as a result of endothelial damage also stimulates platelet activation Collagen plays a key role in the structure and hemostatic function of small blood vessels Platelets and platelet-related bleeding disorders Blood platelets form the initial hemostatic plug in small vessels and the initial thrombus in arteries and veins Congenital defects in platelet adhesion/aggregation can cause lifelong excessive bleeding Acquired disorders may be caused by defective formation and excessive destruction or consumption of platelets Antiplatelet drugs are used in the prevention or treatment of arterial thrombosis Coagulation Blood coagulation factors interact to form the secondary, fibrin-rich hemostatic plug in small vessels and the secondary fibrin thrombus in arteries and veins The coagulation cascade The status of the intrinsic, extrinsic, and final common pathway is assessed by specific laboratory tests Congenital deficiencies of coagulation factors (I–XIII) result in excessive bleeding Activated partial thromboplastin time (APTT) assesses the intrinsic pathway Prothrombin time assesses the extrinsic pathway Thrombin clotting time assesses the final common pathway The term “final common pathway” refers to the conversion of prothrombin to thrombin via Xa, with Va acting as a cofactor Several assays assess platelet function Thrombin Thrombin converts circulating fibrinogen to fibrin and activates factor XIII, which crosslinks the fibrin, forming a clot Thrombin has a central role in hemostasis Thrombin inhibitors have been developed as anticoagulant drugs Coagulation inhibitors are essential to prevent excessive thrombin formation and thrombosis Fibrinolysis The fibrinolytic system acts to limit excessive formation of fibrin through plasmin-mediated fibrinolysis Plasmin inhibitors prevent excessive fibrinolytic activity Summary Further reading Relevant websites Abbreviations 42 Oxidative Stress and Inflammation Abstract Keywords Learning objectives Introduction At body temperature, oxygen is a relatively sluggish oxidant The inertness of oxygen Oxygen is activated by transition metal ions, such as iron or copper, in the active site of metalloenzymes Reactive oxygen species and oxidative stress ROS are reactive, strongly oxidizing forms of oxygen Reactive nitrogen species (RNS) and nitrosative stress Peroxynitrite is a strongly oxidizing reactive nitrogen species The nature of oxygen radical damage The hydroxyl radical is the most reactive and damaging ROS Antioxidant defenses There are several levels of protection against oxidative damage Our first line of defense against oxidative damage is sequestration or chelation of redox-active metal ions Vitamin C is the outstanding antioxidant in biological systems Glutathionylation of proteins - protection against ROS under stress The beneficial effects of reactive oxygen species ROS are essential for many metabolic and signaling pathways Summary Further reading Relevant websites Abbreviations 43 The Immune Response Abstract Keywords Learning objectives Introduction Three layers of immune protection The first line of defense is the anatomical and physiologic barriers of the body The second line of defense is innate immunity The third level of defense is the adaptive immune response The innate immune response When activated, the innate response can present as an inflammatory response Cells of the innate response Neutrophils and monocytes are recruited to sites of infection Monocytes transform into macrophages, which are the “trash can” of the immune response Neutrophils and macrophages use their receptors to recognize attacking microbes There are several main categories of pattern recognition receptors, classified according to location and function PRRs are used by innate immune cells to trigger many of their functions NOD-like receptors are located in the cytoplasm Inflammatory mediators contribute to the immune response Cytokines Cytokines are soluble mediators of inflammatory and immune responses Cytokines in the innate immune response The complement system Activated complement proteins contribute to pathogen killing Adhesion molecules Adhesion molecules mediate adhesion between cells Dendritic cells link the innate and adaptive immune responses Antigen-presenting cells (APC) are specialized cells that display microbial antigens on their surface to initiate the adaptive immune response through activation of T cells Adaptive immune response Specificity of the response is achieved through unique receptors that recognize antigen T and B lymphocytes have distinct cell-surface markers that can assist in assigning their identification B and T lymphocytes are activated by recognition of antigen and through costimulatory molecules Molecules involved in antigen recognition Antigen is recognized by specific receptors on T and B cells Another group of surface receptors on T and B cells binds to the costimulatory molecules on APCs The T-cell antigen receptor The T-cell antigen receptor is termed the T-cell receptor (TCR), and it is complexed with CD3 Major histocompatibility complex The MHC proteins are the display units that present antigen in a way that T cells can recognize against a background of self The MHC complex of genes is grouped into three regions, termed class I, II, and III MHC class I genes are organized into several loci, the most important of which are termed HLA-A, HLA-B, and HLA-C MHC class II genes are HLA-DR, HLA-DQ, HLA-DM, and HLA-DP The B-cell antigen receptor The B-cell antigen receptor (BCR) is a membrane form of the immunoglobulin molecules found circulating in serum There is an almost infinite range of possibilities for antibody specificities Thymic education and self-tolerance help distinguish between self and non-self The adaptive immune response needs time to develop and remembers what it sees The adaptive response is an integrated response Atypical lymphocytes Lymphoid tissues Primary (central) lymphoid tissues Maturation of most B cells occurs within the bone marrow T-lymphocyte progenitors travel to the thymus, where they develop into T lymphocytes Secondary lymphoid tissues Within the lymph node, the T-cell area is the paracortex, and the B-cell areas are the follicular areas of the medulla The spleen contains nonlymphoid tissue (the red pulp) as well as lymphoid areas, the white pulp MALT comprises the lymphoid elements adjacent to the mucosal surfaces Elimination of pathogens by the adaptive immune response On binding to the antigen, lymphocytes differentiate into progeny with either an effector or a memory function Clonal selection creates clones of identical cells with unique antigen specificity Immunologic memory distinguishes the adaptive immune response from the innate response Effector T cells T helper cell subsets: TH1/TH2, TH17, TFH, and T regulatory (Treg) TH1/TH2 cells TH17 cells T follicular helper (TFH) T regulatory cells (Treg) CD8+ cytotoxic T cells (CTL) kill infected cells The adaptive humoral immune response Humoral immune responses are characterized by the release of antibodies from fully matured plasma cells B-cell subsets are involved in the humoral immune response Antibodies illustrate the capability of the immune system for diversity The terms antibody, gamma globulin, and immunoglobulin are synonymous Antibodies are good examples of how function is intimately related to structure Activation of the complement system is one of the most important antibody functions Vaccination Vaccination has probably been the single most beneficial application developed to harness the immune response Failure of the immune response Autoimmunity is normally prevented by thymic education; a breakdown in the processes may lead to autoimmune disease When there is too much of a good thing: hypersensitivity When the response doesn’t develop correctly: immunodeficiency Harnessing the power of antibodies for immunotherapy Summary Further reading Abbreviations Appendix 1 Selected Clinical Laboratory Reference Ranges Reference ranges Reference ranges are values of a given substance (analyte) obtained in a reference population (usually a group of healthy individuals) Distribution of values within the reference population When data from a large cohort of healthy subjects fit a Gaussian distribution, the reference limits are defined as two standard deviations above and below the mean Interpretation of laboratory results in individual persons The interpretation of results of laboratory tests is based on comparison with reference values Clinical decision limits In some cases, instead of reference values, clinical decision limits are the basis for interpretation Significant change in serial results Final notes and cautions when using reference intervals Abbreviations Further reading Relevant websites Appendix 2 More Clinical Cases Chapter 7 Vitamins and minerals Joint pain and abnormal liver function tests: Hereditary hemochromatosis Chapter 14 Biosynthesis of cholesterol and steroids Hirsutism and irregular periods: Nonclassical congenital adrenal hyperplasia A 72-year-old woman with hypersecretion of androgens: Leydig cell tumor A 30-year-old man with gynecomastia: Klinefelter’s syndrome Chapter 27 Biochemical endocrinology A 71-year-old woman with hypothyroidism and seizure: Myxoedema coma A 28-year-old woman with headache and blurred vision: Acromegaly A 32-year-woman with an elevated prolactin: Macroprolactin Pituitary hCG production can result in a positive pregnancy test in postmenopausal women Primary hypothyroidism can cause an increased prolactin Incidental finding of a prolactin-secreting tumor Chapter 33 Lipoprotein metabolism and atherogenesis Recurrent pancreatitis and severe mixed hyperlipidemia: Lipoprotein lipase deficiency Chapter 34 Role of the liver in metabolism Glandular fever can cause abnormal liver function tests Chapter 35 Water and electrolyte homeostasis A case of lithium-induced diabetes insipidus A 42-year-old man with a long history of hypertension: Primary aldosteronism Chapter 37 Muscle: energy metabolism and contraction exercise Rhabdomyolysis as a consequence of muscle ischemia Copyright Title Page Dedication Contents Chapter 1: ‘I’m thinking’ – Oh, but are you? Chapter 2: Renegade perception Chapter 3: The Pushbacker sting Chapter 4: ‘Covid’: The calculated catastrophe Chapter 5: There is no ‘virus’ Chapter 6: Sequence of deceit Chapter 7: War on your mind Chapter 8: ‘Reframing’ insanity Chapter 9: We must have it? So what is it? Chapter 10: Human 2.0 Chapter 11: Who controls the Cult? Chapter 12: Escaping Wetiko Postscript Appendix: Cowan-Kaufman-Morell Statement on Virus Isolation Bibliography Index
