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(BQ) Part 2 book Textbook of biochemistry has contents: Heme synthesis and breakdown, clinical enzymology and biomarkers, liver and gastric function tests, kidney function tests, plasma proteins, electrolyte and water balance, metabolic diseases, free radicals and antioxidants,... and other contents.
CHAPTER 29 Acid-Base Balance and pH Chapter at a Glance The reader will be able to answer questions on the following topics: ¾¾Acids and bases ¾¾pH ¾¾Buffers ¾¾Acid base balance in the body ¾¾Bicarbonate buffer system ¾¾Respiratory regulation of pH Hydrogen ions (H+) are present in all body compartments Maintenance of appropriate concentration of hydrogen ion (H+) is critical to normal cellular function The acid-base balance or pH of the body fluids is maintained by a closely regulated mechanism This involves the body buffers, the respiratory system and the kidney Some common definitions are given in Box 29.1 Functions of hydrogen ions include: The gradient of H+ concentration between inner and outer mitochondrial membrane acts as the driving force for oxidative phosphorylation The surface charge and physical configuration of proteins are affected by changes in hydrogen ion concentration Hydrogen ion concentration decides the ionization of weak acids and thus affects their physiological functions ¾¾Renal regulation of pH ¾¾Relation of pH and potassium ¾¾Respiratory acidosis ¾¾Metabolic acidosis ¾¾Respiratory alkalosis ¾¾Metabolic alkalosis ACIDS AND BASES Definition The electrolyte theory of dissociation was proposed by Arrhenius (Nobel prize, 1903) According to the definition proposed by Bronsted, acids are substances that are SPL Sorensen 1868–1939 Svante Arrhenius NP 1903 1859–1927 Johannes N Bronsted 1879–1947 Chapter 29: Acid-Base Balance and pH capable of donating protons and bases are those that accept protons Acids are proton donors and bases are proton acceptors A few examples are shown below: Acids Bases HA H + A NH3 + H+ HCl H+ + Cl – HCO3– +H+ + H2CO3 – NH4+ H2CO3 H+ + HCO3– Weak and Strong Acids i The extent of dissociation decides whether they are strong acids or weak acids Strong acids dissociate completely in solution, while weak acids ionize incompletely, for example, HCl H+ + Cl– (Complete) H2CO3 H+ + HCO3– (Partial) ii In a solution of HCl, almost all the molecules dissociate and exist as H+ and Cl– ions Hence the concentration of H+ is very high and it is a strong acid iii But in the case of a weak acid (e.g acetic acid), it will ionize only partially So, the number of acid molecules existing in the ionized state is much less, may be only 50% Dissociation Constant i Since the dissociation of an acid is a freely reversible reaction, at equilibrium the ratio between dissociated and undissociated particle is a constant The dissociation constant (Ka) of an acid is given by the formula, Ka = [H + ] [A − ] [HA] Box 29.1: Terms explained Term pH Acids Bases Strong acids Weak acids pK value Alkali reserve Buffers Definition and explanations Negative logarithm of hydrogen ion concentration Normal value 7.4 (range 7.38–7.42) Proton donors; pH Acids which ionize completely; e.g HCl Acids which ionize incompletely, e.g H2CO3 pH at which the acid is half ionised; Salt : Acid =1:1 Bicarbonate available to neutralise acids; Normal 24 mmol/L (range 22–26 mmol/L) Solutions minimize changes in pH 391 Where [H+] is the concentration of hydrogen ions, [A–] = the concentration of anions or conjugate base, and [HA] is the concentration of undissociated molecules ii The pH at which the acid is half ionized is called pKa of an acid which is constant at a particular temperature and pressure iii Strong acids will have a low pKa and weak acids have a higher pKa Acidity of a Solution and pH i The acidity of a solution is measured by noting the hydrogen ion concentration in the solution and obtained by the equation [H+] = Ka [acid] [HA] or [base] A− where Ka is the dissociation constant ii To make it easier, Sorensen expressed the H+ concentration as the negative of the logarithm (logarithm to the base 10) of hydrogen ion concentration, and is designated as the pH Therefore, pH = –log [H+] = log [H + ] Lawrence J Henderson 1878–1942 KA Hasselbalch 1874–1962 iii Thus the pH value is inversely proportional to the acidity Lower the pH, higher the acidity or hydrogen ion concentration while higher the pH, the acidity is lower (Table 29.1) iv At a pH of 1, the hydrogen ion concentration is 10 times that of a solution with a pH and 100 times that of a solution with a pH of and so on The pH indicates the neutral pH, when the hydrogen ion TABLE 29.1: Relation between hydrogen ions, hydroxyl ions and pH of aqueous solutions Ionic product of water = [H+][OH–] = 10–14 [OH–] mols/liter [H+] mols/liter log [H+] –log[H+] =pH pOH Inference × 1013 × 101 –1 13 Strong acid × 1010 × 10–4 –4 10 Acid × 107 × 10–7 –7 7 Neutral × 104 × 1010 –10 10 Alkali × 10 × 10 –13 13 Strong alkali 13 392 Textbook of Biochemistry concentration is 100 nanomoles/liter The pH meter is described in Chapter 35 The Effect of Salt Upon the Dissociation i The relationship between pH, pKa, concentration of acid and conjugate base (or salt) is expressed by the Henderson-Hasselbalch equation, pH = pKa + log [base] [salt] or pH = pKa + log [acid] [acid] When [base] = [acid]; then pH = pKa ii Therefore, when the concentration of base and acid are the same, then pH is equal to pKa Thus, when the acid is half ionized, pH and pKa have the same values BUFFERS Definition Buffers are solutions which can resist changes in pH when acid or alkali is added Composition of a Buffer Buffers are of two types: a Mixtures of weak acids with their salt with a strong base or b Mixtures of weak bases with their salt with a strong acid A few examples are given below: i H2CO3/NaHCO3 (Bicarbonate buffer) (carbonic acid and sodium bicarbonate) ii CH3COOH/CH3COO Na (Acetate buffer) (acetic acid and sodium acetate) iii Na2HPO4/NaH2PO4 (Phosphate buffer) Factors Affecting pH of a Buffer The pH of a buffer solution is determined by two factors: a The value of pK: The lower the value of pK, the lower is the pH of the solution b The ratio of salt to acid concentrations: Actual concentrations of salt and acid in a buffer solution may be varying widely, with no change in pH, so long as the ratio of the concentrations remains the same Factors Affecting Buffer Capacity i On the other hand, the buffer capacity is determined by the actual concentrations of salt and acid present, as well as by their ratio ii Buffering capacity is the number of grams of strong acid or alkali which is necessary for a change in pH of one unit of one litre of buffer solution iii The buffering capacity of a buffer is defined as the ability of the buffer to resist changes in pH when an acid or base is added How Buffers Act? i Buffer solutions consist of mixtures of a weak acid or base and its salt ii To take an example, when hydrochloric acid is added to the acetate buffer, the salt reacts with the acid forming the weak acid, acetic acid and its salt Similarly when a base is added, the acid reacts with it forming salt and water Thus changes in the pH are minimized CH3–COOH + NaOH → CH3–COONa + H2O CH3–COONa + HCl → CH3–COOH + NaCl iii The buffer capacity is determined by the absolute concentration of the salt and acid But the pH of the buffer is dependent on the relative proportion of the salt and acid (see the Henderson-Hasselbalch’s equation) iv When the ratio between salt and acid is 10:1, the pH will be unit higher than the pKa When the ratio between salt and acid is 1:10, the pH will be unit lower than the pKa Application of the Equation i The pH of a buffer on addition of a known quantity of acid and alkali can therefore be predicted by the equation ii Moreover, the concentration of salt or acid can be found out by measuring the pH iii The Henderson-Hasselbalch’s equation, therefore has great practical application in clinical practice in assessing the acid-base status, and predicting the limits of the compensation of body buffers Chapter 29: Acid-Base Balance and pH Effective Range of a Buffer A buffer is most effective when the concentrations of salt and acid are equal or when pH = pKa The effective range of a buffer is pH unit higher or lower than pKa Since the pKa values of most of the acids produced in the body are well below the physiological pH, they immediately ionize and add H+ to the medium This would necessitate effective buffering Phosphate buffer is effective at a wide range, because it has pKa values ACID-BASE BALANCE Normal pH The pH of plasma is 7.4 (average hydrogen ion concentration of 40 nmol/L) In normal life, the variation of plasma pH is very small The pH of plasma is maintained within a narrow range of 7.38 to 7.42 The pH of the interstitial fluid is generally 0.5 units below that of the plasma Acidosis If the pH is below 7.38, it is called acidosis Life is threatened when the pH is lowered below 7.25 Acidosis leads to CNS depression and coma Death occurs when pH is below 7.0 Alkalosis When the pH is more than 7.42, it is alkalosis It is very dangerous if pH is increased above 7.55 Alkalosis induces neuromuscular hyperexcitability and tetany Death occurs when the pH is above 7.6 Volatile and Fixed Acids i During the normal metabolism, the acids produced may be volatile acids like carbonic acid or nonvolatile (fixed) acids like lactate, keto acids, sulfuric acid and phosphoric acid ii The metabolism produces nearly 20,000 milli equivalents (mEq) of carbonic acid and 60–80 mEq of fixed acids per day iii The lactate and keto acids are produced in relatively fixed amounts by normal metabolic activity, e.g mol of glucose produces mols of lactic acid 393 iv The dietary protein content decides the amount of sulfuric and phosphoric acids The sulfoproteins yield sulfuric acid and phosphoproteins and nucleoproteins produce phosphoric acid On an average about g of phosphoric acid and about g sulfuric acid are produced per day v The carbonic acid, being volatile, is eliminated as CO2 by the lungs The fixed acids are buffered and later on the H+ are excreted by the kidney Mechanisms of Regulation of pH These mechanisms are interrelated See Box 29.2 BUFFERS OF THE BODY FLUIDS Buffers are the first line of defense against acid load These buffer systems are enumerated in Table 29.2 The buffers are effective as long as the acid load is not excessive, and the alkali reserve is not exhausted Once the base is utilized in this reaction, it is to be replenished to meet further challenge Bicarbonate Buffer System i The most important buffer system in the plasma is the bicarbonate-carbonic acid system (NaHCO3/H2CO3) It accounts for 65% of buffering capacity in plasma and 40% of buffering action in the whole body Box 29.2: Mechanisms of regulation of pH First line of defense Second line of defense Third line of defense : Blood buffers : Respiratory regulation : Renal regulation TABLE 29.2: Buffer systems of the body Extracellular fluid Intracellular fluid Erythrocyte fluid NaHCO3 H2 CO3 K2HPO4 KH2PO4 (bicarbonate) (phosphate) K+Hb H+Hb (hemoglobin) Na2HPO4 NaH2PO4 K+Protein H+Protein K2HPO4 KH2PO4 (phosphate) (protein buffer) (phosphate) Na+Albumin H+Albumin KHCO3 H2CO3 KHCO3 H2CO3 394 Textbook of Biochemistry ii The base constituent, bicarbonate (HCO3–), is regulated by the kidney (metabolic component) iii While the acid part, carbonic acid (H2CO3), is under respiratory regulation (respiratory component) iv The normal bicarbonate level of plasma is 24 mmol/L The normal pCO2 of arterial blood is 40 mm of Hg The normal carbonic acid concentration in blood is 1.2 mmol/L The pKa for carbonic acid is 6.1 Substituting these values in the HendersonHasselbalch’s equation, pH = pKa + log 7.4 = 6.1 + log − [HCO ] [H CO3 ] 24 1.2 = 6.1 + log 20 = 6.1 + 1.3 v Hence, the ratio of HCO3– to H2CO3 at pH 7.4 is 20 under normal conditions This is much higher than the theoretical value of which ensures maximum effectiveness vi The bicarbonate carbonic acid buffer system is the most important for the following reasons: a Presence of bicarbonate in relatively high concentrations b The components are under physiological control, CO2 by lungs and bicarbonate by kidneys Alkali Reserve Bicarbonate represents the alkali reserve and it has to be sufficiently high to meet the acid load If it was too low to give a ratio of 1, all the HCO3– would have been exhausted within a very short time; and buffering will not be effective So, under physiological circumstances, the ratio of 20 (a high alkali reserve) ensures high buffering efficiency against acids Antilog of 0.6 = 4; hence the ratio is This is found to be true under physiological condition The phosphate buffer system is found to be effective at a wide pH range, because it has more than one ionizable group and the pKa values are different for both = 1.96 H+ + H2PO4– H3PO4 pKa → H2PO4– pKa = 6.8 H++ HPO4= (Na2HPO4 /NaH2PO4) → HPO4= pKa = 12.4 H+ + PO4º → In the body, Na2HPO4/NaH2PO4 is an effective buffer system, because its pKa value is nearest to physiological pH Protein Buffer System Buffering capacity of protein depends on the pKa value of ionizable side chains The most effective group is histidine imidazole group with a pKa value of 6.1.The role of the hemoglobin buffer is considered along with the respiratory regulation of pH Relative Capacity of Buffer Systems In the body, 52% buffer activity is in tissue cells and 6% in RBCs Rest 43% is by extracellular buffers In plasma and extracellular space, about 40% buffering action is by bicarbonate system; 1% by proteins and 1% by phosphate buffer system (Fig 29.1) Buffers Act Quickly, But Not Permanently Buffers can respond immediately to addition of acid or base, but they not serve to eliminate the acid from the body They are also unable to replenish the alkali reserve of the body For the final elimination of acids, the respiratory and renal regulations are very essential Phosphate Buffer System It is mainly an intracellular buffer Its concentration in plasma is very low The pKa value is 6.8 So applying the equation, pH (7.4)= pKa (6.8) + log or 0.6 = log [salt] [acid] [salt] [acid] Fig 29.1: Intracellular buffers play a significant role to combat acid load of the body Chapter 29: Acid-Base Balance and pH RESPIRATORY REGULATION OF pH The Second Line of Defense i This is achieved by changing the pCO2 (or carbonic acid, the denominator in the equation) The CO2 diffuses from the cells into the extracellular fluid and reaches the lungs through the blood ii The rate of respiration (rate of elimination of CO2) is controlled by the chemoreceptors in the respiratory center which are sensitive to changes in the pH of blood iii When there is a fall in pH of plasma (acidosis), the respiratory rate is stimulated resulting in hyperventilation This would eliminate more CO2, thus lowering the H2CO3 level (Box 29.3) iv However, this can not continue for long The respiratory system responds to any change in pH immediately, but it cannot proceed to completion Action of Hemoglobin i The hemoglobin serves to transport the CO2 formed in the tissues, with minimum change in pH (see isohydric transport, Chapter 22) ii Side by side, it serves to generate bicarbonate or alkali reserve by the activity of the carbonic anhydrase system (see Chapter 22) Carbonic anhydrase CO2 + H2O H2CO3 H2CO HCO3 + H+ + - H + Hb HHb iii The reverse occurs in the lungs during oxygenation and elimination of CO2 When the blood reaches the lungs, the bicarbonate re-enters the erythrocytes by reversal of chloride shift It combines with H+ liberated on oxygenation of hemoglobin to form carbonic acid which dissociates into CO2 and H2O CO2 is thus eliminated by the lungs HHb + O2 HbO2 + H+ + – HCO3 + H H2CO3 H2CO3 H2O + CO2 iv The activity of the carbonic anhydrase (also called carbonate dehydratase) increases in acidosis and decreases with decrease in H+ concentration 395 pH is lower than that of extracellular fluid (pH = 7.4) This is called acidification of urine The pH of the urine may vary from as low as 4.5 to as high as 9.8, depending on the amount of acid excreted The major renal mechanisms for regulation of pH are: A Excretion of H+ (Fig 29.2) B Reabsorption of bicarbonate (recovery of bicarbonate) (Fig 29.3) C Excretion of titratable acid (net acid excretion) (Fig 29.4) D Excretion of NH4+ (ammonium ions) (Fig.29.5) Excretion of H+; Generation of Bicarbonate i This process occurs in the proximal convoluted tubules (Fig 29.2) ii The CO2 combines with water to form carbonic acid, with the help of carbonic anhydrase The H2CO3 then ionizes to H+ and bicarbonate iii The hydrogen ions are secreted into the tubular lumen; in exchange for Na+ reabsorbed These Na+ ions along with HCO3– will be reabsorbed into the blood iv There is net excretion of hydrogen ions, and net generation of bicarbonate So this mechanism serves to increase the alkali reserve Reabsorption of Bicarbonate i This is mainly a mechanism to conserve base There is no net excretion of H+ (Fig 29.3) ii The cells of the PCT have a sodium hydrogen exchanger When Na+ enters the cell, hydrogen ions from the cell are secreted into the luminal fluid The hydrogen ions are generated within the cell by the action of carbonic anhydrase RENAL REGULATION OF pH An important function of the kidney is to regulate the pH of the extracellular fluid Normal urine has a pH around 6; this Fig 29.2: Excretion of hydrogen ions in the proximal tubules; CA = Carbonic anhydrase 396 Textbook of Biochemistry iii The hydrogen ions secreted into the luminal fluid is required for the reabsorption of filtered bicarbonate iv Bicarbonate is filtered by the glomerulus This is completely reabsorbed by the proximal convoluted tubule, so that the urine is normally bicarbonate free v The bicarbonate combines with H+ in tubular fluid to form carbonic acid It dissociates into water and CO2 The CO2 diffuses into the cell, which again combines with water to form carbonic acid vi In the cell, it again ionizes to H+ that is secreted into lumen in exchange for Na+ The HCO3– is reabsorbed into plasma along with Na+ vii Here, there is no net excretion of H+ or generation of new bicarbonate The net effect of these processes is the reabsorption of filtered bicarbonate which is Box 29.3: Summary of buffering against acid load Stages Features Buffer components Normal Normal raio = 20:1 HCO3– (N) Normal pH = 7.4 First line of defense Acidosis; H enters Plasma buffer system blood, bicarbonate is used up Second line defense Hyperventilation Respiratory H2CO3 →H2O + compensation CO2↑ + H2CO3 (N) HCO3– (↓↓) H2CO3 (↓) Partially compen- sated acidosis Bicarbonate ↓; HCO3– (↓↓) pH ↓¯ H2CO3 (↓↓) Third line of defense kidney mechanism Excretion of H+; HCO3– (↓↓) Reabsorption of H2CO3 (↓↓) bicarbonate; Ratio and pH tend to restore Fig 29.3: Reabsorption of bicarbonate from the tubular fluid; CA = Carbonic anhydrase mediated by the Sodium-Hydrogen exchanger But this mechanism prevents the loss of bicarbonate through urine + Excretion of H as Titratable Acid i In the distal convoluted tubules net acid excretion occurs Hydrogen ions are secreted by the distal tubules and collecting ducts by hydrogen ion-ATPase located in the apical cell membrane The hydrogen ions are generated in the tubular cell by a reaction catalyzed by carbonic anhydrase The bicarbonate generated within the cell passes into plasma ii The term titratable acidity of urine refers to the number of milliliters of N/10 NaOH required to titrate liter of urine to pH 7.4 This is a measure of net acid excretion by the kidney iii The major titratable acid present in the urine is sodium acid phosphate As the tubular fluid passes down the renal tubules more and more H+ are secreted into the luminal fluid so that its pH steadily falls The process starts in the proximal tubules, but continues up to the distal tubules iv Due to the Na+ to H+ exchange occurring at the renal tubular cell boarder, the Na2HPO4 (basic phosphate) is converted to NaH2PO4 (acid phosphate) (Fig 29.4) As a result, the pH of tubular fluid falls v The acid and basic phosphate pair is considered as the urinary buffer The maximum limit of acidification is pH 4.5 This process is inhibited by carbonic anhydrase inhibitors like acetazolamide Fig 29.4: Phosphate mechanism in tubules Chapter 29: Acid-Base Balance and pH Excretion of Ammonium Ions i This predominantly occurs at the distal convoluted tubules This would help to excrete H+ and reabsorb HCO3– (Fig 29.5) ii This mechanism also helps to trap hydrogen ions in the urine, so that large quantity of acid could be excreted with minor changes in pH The excretion of ammonia helps in the elimination of hydrogen ions without appreciable change in the pH of the urine iii The Glutaminase present in the tubular cells can hydrolyze glutamine to ammonia and glutamic acid The NH3 (ammonia) diffuses into the luminal fluid and combines with H+ to form NH4+(ammonium ion) The glutaminase activity is increased in acidosis So large quantity of H+ ions are excreted as NH4+ in acidosis iv Since it is a positively charged ion, it can accompany negatively charged acid anions; so Na+ and K+ are conserved (Fig 29.5) v Normally, about 70 mEq/L of acid is excreted daily; but in condition of acidosis, this can rise to 400 mEq/ day vi The enhanced activity of glutaminase and increased excretion of NH4+ take about 3–4 days to set in under conditions of acidosis But once established, it has high capacity to eliminate acid vii Ammonia is estimated in urine, after addition of formaldehyde The titratable acidity plus the ammonia content will be a measure of acid excreted from 397 the body Maximum urine acidity reached is 4.4 A summary of buffering of acid load in the body is shown in Table 29.3 CELLULAR BUFFERS Cytoplasmic pH varies from 6.8 to 7.3 Intracellular pH modulates a variety of cell functions: The activity of several enzymes is sensitive to changes in pH Reduction in pH reduces the contractility of actin and myosin in muscles The electrical properties of excitable cells are also affected by changes in pH Intracellular buffers are depicted in Figure 29.1 The major tissues involved in cellular buffering are bone and skeletal muscle The buffering of acid is achieved by the exchange of H+ that enters into the cells for Na+ or K+ ions Relationship of pH with K+ Ion Balance i When there is increase in H+ in extracellular fluid (ECF), there may be exchange of H+ with K+ from within the cells Net effect is an apparent increase in ECF potassium level (hyperkalemia) ii In general, acute acidosis is associated with hyperkalemia and acute alkalosis with hypokalemia iii However, in renal tubular acidosis, due to failure to excrete hydrogen ions, potassium is lost in urine; then hypokalemia results iv Sudden hypokalemia may develop during the correction of acidosis K+ may go back into the cells, suddenly lowering the plasma K+ Hence it is important to maintain the K+ balance during correction of alkalosis Factors affecting Renal Acid Excretion Increased filtered load of bicarbonate Decrease in ECF volume Decrease in plasma pH Increase in pCO2 of blood Hypokalemia Aldosterone secretion DISTURBANCES IN ACID-BASE BALANCE Fig 29.5: Ammonia mechanism Acidosis is the clinical state, where acids accumulate or bases are lost A loss of acid or accumulation of base leads to alkalosis The body cells can tolerate only a narrow range of pH The extreme ranges of pH are between 7.0 and 398 Textbook of Biochemistry 7.6, beyond which life is not possible Box 29.4 shows the conditions in which acid-base parameters are to be checked Box 29.5 shows the steps to the clinical assessment of acid base status Box 29.6 summarizes the abnormal findings Classification of Acid-Base Disturbances Acidosis (fall in pH) a Respiratory acidosis: Primary excess of carbonic acid b Metabolic acidosis: Primary deficit of bicarbonate (Box 29.6) Alkalosis (rise in pH) a Respiratory alkalosis: Primary deficit of carbonic acid b Metabolic alkalosis: Primary excess of bicarbonate (Box 29.6) Compensatory Responses Each of the above disturbance will be followed by a secondary compensatory change in the counteracting variable, e.g a primary change in bicarbonate involves an alteration in pCO2 Depending on the extent of the compensatory change there are different stages (Table 29.3) In actual clinical states, patients will have different states of compensation (Box 29.7) The compensatory (adaptive) responses are: a A primary change in bicarbonate involves an alteration in pCO2 The direction of the change is the same as the primary change and there is an attempt at restoring the ratio to 20 and pH to 7.4 b Adaptive response is always in the same direction as the primary disturbance Primary decrease in arterial bicarbonate involves a reduction in arterial blood pCO2 by alveolar hyperventilation Box 29.4: Acid-base parameters are to be checked in patents with Box 29.6 Acid-base disturbances 2 3 4 5 6 pCO2 pCO2 HCO3 HCO3 H+ H+ Any serious illness Multi organ failure Respiratory failure Cardiac failure Uncontrolled diabetes mellitus Poisoning by barbiturates and ethylene glycol Box 29.5: Steps to the clinical assessment of acid-base disturbances > 45 mm Hg = < 35 mm Hg = > 33 mmol/L = < 22 mmol/L = > 45 nmol/L = < 35 nmol/L = Respiratory acidosis Respiratory alkalosis Metabolic alkalosis Metabolic acidosis Acidosis Alkalosis Box 29.7 Acid base disturbances Expected renal and respiratory compensations Assess pH (normal 7.4); pH 7.45 is alkalemia Serum bicarbonate level: See Box 29.6 Assess arterial pCO2: See Box 29.6 Check compensatory response: Compensation never overcompensates the pH If pH is 7.4, alkalosis is primary Assess anion gap Assess the change in serum anion gap/change in bicarbonate Assess if there is any underlying cause Metabolic acidosis: Expect pCO2 to be reduced by mm Hg for every mmol/L drop in bicarbonate Metabolic alkalosis: Expect pCO2 to be increased by 0.6 mm Hg for every mmol/L rise in bicarbonate Acute respiratory acidosis: Expect mmol/L increase in bicarbonate per 10 mm Hg rise in pCO2 Chronic respiratory acidosis: Expect 3.5 mmol/L increase in bicarbonate per 10 mm Hg rise in pCO2 Acute respiratory alkalosis: Expect mmol/L decrease in bicarbonate per 10 mm Hg fall in pCO2 Chronic respiratory alkalosis: Expect mmol/L decrease in bicarbonate per 10 mm Hg fall in pCO2 TABLE 29.3: Types of acid-base disturbances Disturbance pH Primary change Ratio Secondary change Metabolic acidosis Decreased Deficit of bicarbonate 20 Increase in PaCO2 Respiratory acidosis Decreased Excess of carbonic acid 20 Decrease in bicarbonate Chapter 29: Acid-Base Balance and pH c Similarly, a primary increase in arterial pCO2 involves an increase in arterial bicarbonate by an increase in bicarbonate reabsorption by the kidney d The compensatory change will try to restore the pH to normal However, the compensatory change cannot fully correct a disturbance e Clinically, acid-base disturbance states may be divided into: i Uncompensated ii Partially compensated iii Fully compensated (Table 29.4) Mixed Responses i If the disturbance is pure, it is not difficult to accurately assess the nature of the disturbance (Box 29.7) In mixed disturbances, both HCO3– and H2CO3 levels are altered (Fig 29.6) ii The adaptive response always involves a change in the counteracting variable; e.g a primary change in bicarbonate involves an alteration in pCO2 iii Adaptive response is always in the same direction as the primary disturbance iv Depending on the extent of the compensatory change there are different stages Looking at the parameters, the stage of the compensation can be identified (Table 29.4) Chemical Pathology of Acid-Base Disturbances Metabolic Acidosis i It is due to a primary deficit in the bicarbonate This may result from an accumulation of acid or depletion of bicarbonate ii When there is excess acid production, the bicarbonate is used up for buffering Depending on the cause, the anion gap is altered Anion Gap i The sum of cations and anions in ECF is always equal, so as to maintain the electrical neutrality Sodium and potassium together account for 95% of the cations whereas chloride and bicarbonate account for only 86% of the anions (Fig 29.7) Only these electrolytes are commonly measured ii Hence, there is always a difference between the measured cations and the anions The unmeasured anions constitute the anion gap This is due to the presence of protein anions, sulphate, phosphate and organic acids iii The anion gap is calculated as the difference between (Na+ + K+) and (HCO3– + Cl–) Normally this is about 12 mmol/L TABLE 29.4: Stages of compensation Stage pH HCO3 PaCO2 Ratio Metabolic acidosis Low Low N 20 Fully compensated N High High 20 Respiratory acidosis Low N High 20 Fully compensated N Low Low 20 399 Fig 29.6: Bicarbonate diagram 778 Textbook of Biochemistry Infarction 335 Infliximab 696 Infusion of fluids 411 Ingram’s technique 40 Inheritance of HBS-C disease 293f pattern of hemophilia 388f Inherited disorders 155 Inhibition of cell division 730 Inhibitors of ATP synthesis 265 DNA replication 586 oxidative phosphorylation 265 protein synthesis 605 in mammals 605 RNA synthesis 593, 593t TCA cycle 254 Inhibits gluconeogenesis 313 plasminogen activation 179f Initial number of cells 737 Initiation of protein synthesis 600 transcription 590 Inorganic acidosis 401 ions 59 mercury 552 pyrophosphate 258 Inositol triphosphate 495, 655f Insulin 113, 165, 318, 323 biosynthesis 318f deficiency 323, 416 dependent diabetes mellitus 323 injections 330 like growth factor receptor 742 resistance syndrome 325, 333 signaling pathway 656 therapy 512 Insulinoma 331 Integral membrane proteins 16 Integration of major metabolic pathways 251 Interconversion of amino acids 201 one-carbon groups 207 vitamin A molecules 464f Intermediate density lipoprotein 173, 176 filaments 726 Internal hemorrhage 498 Interorgan transport of amino acids 200, 200f Interpretation of blood urea value 370 creatinine clearance 368 gastric juice analysis 357 glycohemoglobin values 329 urea clearance value 370 Interrelations of amino sugars 142f Interstitial fluid 408 implantation for treating cancer 735 Intestinal digestion of proteins 198 malabsorption 508 system 228 villous cells 470 Intracellular fluid 408, 409 protein degradation 199 Intrahepatic cholestasis 305, 349, 351 Intralysosomal accumulation 145 Intravenous GTT 316 Inulin 79 clearance 371 Iodine 521, 735 metabolism 672 number 88 Ion channels 18 exchange chromatography 451, 451f Ionic bond 5, 5f in protein interactions 5f forms of amino acids 27f Ionization of aspartic acid 28f Ionized calcium 505 Ionophores 19 Iron absorption 517 containing proteins 514t deficiency 518 anemia 518, 519f produces free radicals 435f sulfur complexes 514 toxicity 520 vessels 520 Ischemia modified albumin 305 Ischemic heart disease 342 Isocitrate dehydrogenase 248, 253, 257 Isoelectric focusing 448 precipitation 41 Isoenzymes of alkaline phosphatase 306 CK 302 Isohydric transport of carbon dioxide 287 Isoleucine 26, 27, 223, 230, 450, 451 Isomaltose 77, 78f Isoniazid 482 Isonicotinic acid hydrazide 60 Isopentenyl pyrophosphate 171f Isosthenuria 373 Isotonic contraction 410 expansion 411 fluids 413 Isotope dilution technique 735 Isovaleric aciduria 208, 230, 430 J Jaffe’s test 367 Jaundice 278, 346f, 348 Jejunal mucosa 149 K Kartagener’s syndrome 724 Karyorrhexis 163 Kaschinbeck disease 523 Keratan sulfate 80, 143, 145 Keratomalacia 467, 468f Keshan disease 523 Ketogenesis 141, 163, 165, 322, 323, 326 Ketogenic amino acids 245, 252 Ketone bodies 100, 101, 103, 364, 365 Ketonemia 165, 326 Index Ketonuria 165, 326 Ketosis 165, 166, 326, 327, 400 Kidney 470 distal tubular cells 470 function tests 329, 361 scanning 736 Kill bacteria 185 Kimmelsteil-Wilson syndrome 316, 328 Kinase phosphorylates enzymes 652 Kjeldahl’s procedure 44 Klenow enzyme 643 fragment 580 Klinefelter syndrome 324 Klotho protein 505 Kornberg’s enzyme 580 Koshland’s induced fit theory 54f Krabbe’s disease 428 leukodystrophy 193 Krebs citric acid cycle 251f cycle 247, 249f, 254 Kussmaul’s respiration 166, 402 Kwashiorkor 535 L Lactalbumin 420 Lactate 77 dehydrogenase 67, 111, 303 production 100 Lactic acid cycle 114 acidemias 429 acidosis 117, 128, 140, 328, 400, 404, 428, 430, 478 Lactose 77, 77f free diet 140 intolerance 144, 430 synthesis 138, 420 Lactosuria 317 Lactosyl ceramidoses 193 Lambert’s law 455 L-amino acid oxidase 202f Large offspring syndrome 623 L-asparaginase 717 Late protein synthesis 621f Latent jaundice 278 Lathyrus sativus 555 Lead poisoning 276, 518, 519, 551 Leber’s hereditary 631 neuropathy 606 optic neuropathy 268 optic neuropathy 611 Lecithin 90 cholesterol acyl transferase 180f lysolecithin acyl transferase 192 Left ventricular hypertrophy 336 Leigh’s syndrome 606 Lens of eye 133 proteins 727 Lepore hemoglobin 611 Leprosy 375, 508 Lesch-Nyhan syndrome 430, 568 Lethal infantile mitochondrial ophthalmoplegia 268 mutations 614 Leuconostoc mesenteroides 66 Leucine 26, 27, 223, 230, 450, 451 aminopeptidase 198 Leukemia 641, 469 Leukocyte adhesion deficiency 144 alkaline phosphatase 306 esterase 364 migration 726 Leukoderma 234 Leukopenia 490 Leukotriene 188, 190, 191f Levels of organizations of proteins 37f Levy Jening’s chart 444 Liddle’s disease 20 Ligand binding domain 657 Limiting amino acid 534 Limits of compensation 405, 405t Lineweaver-Burk equation 58 plot 57, 57f 779 Linkage analysis 628 of heme with globin 284f Linoleic acid 186, 187, 187f Lipid accumulating 193, 347 peroxidation 186, 437 storage diseases 92, 193t, 194, 194f Lipogenesis 321 Lipolysis 165, 323 Lipolytic enzymes in intestines 148 Lipoprotein 173 cascade pathway 176 glomerulopathy 175 lipase 161, 176 metabolism 180f, 335f Liposomes 90 Lipoxin 190, 191f Lithium 524 Liver 101 adipose tissue axis 162 and gastric function tests 346 cells 307 cirrhosis 384 diseases 305, 353 function tests 346, 348, 349, 355t glycogen 123 metastases 354 mitochondria 163 regeneration 355 Lobry de Bruyn-van Ekenstein transformation 73f Location in human chromosome 710 of gout attack 567f Lohmann’s reaction 211, 212f, 222 Long chain fatty acids 184, 185 saturated fatty acids 339, 341 QT syndrome 20, 415 Lovastatin 61 Low blood sugar causes glucagon secretion 322f carbohydrate ketogenic diet 330 density lipoproteins 173, 177, 436 780 Textbook of Biochemistry HDL cholesterol 336 phenylalanine 237 Lower blood glucose 313 surface tension 147 Lowering of activation energy 51, 51f Lowry’s method 44 L-phosphatidic acid 89f Luminiscence 455 Lundh test 359 Lung maturity 423 surfactants 91 Lymph node enlargement in porta hepatis 349 Lymphoma 281, 375 Lynch syndrome 585 Lynen’s spiral 156 Lysine 26, 27, 29, 216, 223, 226, 451 vasopressin 659 Lysinuric protein intolerance 199 Lysolecithin 90 Lysosome 11, 12, 14, 199 M Macroamylasemia 358 Macrocytic anemia 490 Macrophage 687 colony stimulating factor 696 inflammatory proteins 696 migration inhibition factor 696 Maillard reaction 328 Main functions of kidney tubules 362t Maintaining blood sugar 311 Maintenance of nitrogen balance 533 Major catabolic pathway of tryptophan 240 Malabsorption 359, 512 Malaria 307 Malate aspartate shuttle 117, 118, 118f, 226, 260 dehydrogenase 118f, 248, 257 shuttle 260 Malic enzyme 159 Malignant hypertension 370 hyperthermia 121, 726 melanoma 234 transformation 711 Maltose 77, 77f Mammalian DNA polymerases 580 RNA polymerases 589 system 590 Mammary glands 132 Management of diabetes mellitus 330 hypercalcemia 508 ketoacidosis 166 ketosis 327 metabolic syndrome 325 sickle cell disease 292 Mancini’s technique 45 Manifestations of deficiency 475 liver dysfunction 348 mutations 614 Maple syrup urine disease 208, 230, 431 Marasmus 535 Marfan syndrome 222 Markers of bone diseases 510 formation 511 resorption 510 glomerular filtration rate 366 permeability 371 hepatic dysfunction 349 myocardial infarction 302t obstructive liver disease 353 Mass spectrometry 458, 458f Massive blood transfusions 512 Master lipid regulator in liver 160 Maternal serum alpha fetoprotein 425 Matrix assisted laser desorption ionization 458 metalloproteinases 742 McArdle’s disease 144 Measurement of alpha fetoprotein 423 bilirubin 349 glomerular filtration rate 366 osmolality 373 pancreatic enzymes 358 Mechanism of absorption of calcium 503 action of hormones and signaling molecules 649 insulin 319 nitric oxide 228 PTH 506 steroid hormones 667 thyroid hormone 674 HCl secretion 356 insulin secretion 319f regulation of pH 393 Medium chain fatty acids 184 Medullary carcinoma of thyroid 508 thyroid carcinoma 716 Megadose of vitamin C 499 Megaloblastic anemia 494 Meister cycle 199f Melanin synthesis pathway 234f Melanocyte stimulating hormone 234 Melatonin 239, 241, 242 Melting of DNA 576 Membranes of organelle 16 Memory aid for essential amino acids 27 Menke’s disease 355, 521 kinky hair syndrome 521 Mental retardation 139, 143, 145, 221, 244, 245 Mercury poisoning 552 Meselson-Stahl experiment 579f Messenger RNA 587, 588 Metabolic acidosis 166, 398, 399, 402, 416 alkalosis 398, 402, 403, 403t, 405 alterations in brain 100f cancer cells 712 Index derangements in diabetes mellitus 327f fate 228 of amino acids 245f of pyruvate 115 functions of cysteine 217 serine 214 junction point 117f pathways of carbohydrates 137 profile of organs 99 syndrome 324, 325, 333, 536 traffic circle 252 Metabolism of adipose tissue 161 alcohol 140 amino acids 197f, 200 sugars 142 arginine and ornithine 227f ascorbic acid 496 aspartic acid 225f catecholamines 235f chylomicrons 176f histamine 243f histidine 243f ketone bodies 163 sulfur 219 thyroid hormones 673f tryptophan 239f vitamin E 473 Metachromatic leukodystrophy 193 Metallo-enzymes 50 Metallopeptidase inhibitor 745 Metastatic breast cancer 641 carcinoma of bone 508 and hyperparathyroidism 354 Met-hemoglobin 218, 289 reductase system 289f Met-hemoglobinemias 134, 289 Methionine 24, 26, 27, 210, 216, 450, 451 adenosyl transferase 216, 229f Methotrexate 60, 61, 571, 620, 716 Methyl cobalamin 492 Folate trap 493 malonic acid 494 aciduria 155, 431, 493 malonyl CoA isomerase 493 mercury 552 transfer 216 reactions 217 transferase 489f Methylenetetrahydrofolate reductase 498 Methylmalonic aciduria 208, 429 Metyrapone test 667 Micellar formation 89 Michaelis constant 57 Menten theory 53, 67 Microalbuminuria 372 Microarray technique 635 Microcytic hypochromic anemia 519 normochromic anemia 521 Microsomal cytochrome 12, 258 ethanol oxidizing system 140 heme oxygenase system 277 system 186 Microsome 11, 155 Microtubules 726 Microvilli 16 Miester cycle 198 Migraine 236 Milk alkali syndrome 404, 512 Millon’s test 31 Minamata disease 552 Mineral content of milk 421t Mineralization of bone 509 Minor pathways of deamination 202 purine bases 560 Mitochondria 11, 13, 13f, 14, 248 Mitochondrial cytochrome 258 DNA and RNA 605 encephalopathy lactic acidosis 606 membrane permeabilization 268 permeability transition pore 268, 616 781 system 268 transport systems 267 Mitogen activated protein kinase 743 Mitomycin C 717 Mixed micelle formation 149 triglycerides 87 Mode of action of enzymes 51 Modifications of amino acids 603 Molecular structure of antigens 693 Molecule of polyunsaturated fatty acid 180 Molybdenum 51, 523, 565 Mono sodium glutamate 556 Monoamine oxidase 236, 241 Monoamino dicarboxylic acids 24 monocarboxylic acids 24 Monoclonal antibody 717 band 690 Mono-oxygenase 232, 258 Monosaccharides 69 Monounsaturated fatty acids 86, 185, 532 Movement of sperms 726 Mucopolysaccharidoses 80, 82, 145 Mucoproteins 81 Mucosal block theory 515 Multidrug resistance protein 278 Multienzyme complex 66, 210, 248, 570 Multifactorial disorders 611 Multiple endocrine neoplasia 245, 357, 711 myeloma 375, 382, 401, 508, 690, 715 sclerosis 16, 194, 422 Multispecific organic anion transporter 278 Multistep progression 707 Muscle 504 cramps 508 diseases 308 lacks glucose-6-phosphatase 125 proteins 724 weakness 511 782 Textbook of Biochemistry Muscular dystrophies 212, 303, 324 Mutagens 614, 705 Mutation detection techniques 641 Mutual supplementation 534 of cereals and pulses 539 of proteins 534 Myasthenia gravis 495 Mycobacterium tuberculosis 629 Myelin sheath 16, 495 Myeloperoxidase 133f, 304, 434 Myocardial infarction 169, 179, 202, 212, 302-305, 308, 335, 354, 436, 483 Myoclonic epilepsy 268, 606 Myoglobin 294, 304 chain 294f in urine and blood 295 Myoglobinuria 295 Myosin 724 kinase 504 Myotonic dystrophy 324 N N-acetyl glucosamine 82 glutamate 205 muramic acid 82 neuraminic acid 194f, 712 Naphthoquinone 474 Natural amino acids 29 course of disease 700 Needle shaped crystals 74 Negative acute phase proteins 385 Neonatal hypoglycemia 138 mortality 315 tyrosinemia 239 Neostigmine 61 Nephelometry 45 Nephron loss proteinuria 372 Nephrosis 370, 518, 519 Nephrotic syndrome 336, 344, 372, 412, 508 Nerve cell 632f conduction 504 Neural tube defects 352 Neurotoxins 551 Neutral amino acids 198 fats 87, 531 sulfur 514 Nezelof’s syndrome 692 Niacin 477, 480, 486 deficiency 240, 241, 481, 481f, 482 Nickel ions 306 Nicotinamide 50, 216 adenine dinucleotide phosphate 480 deficiency 240 Nicotinic acid 240, 340 pathway of tryptophan 240 Niemann-Pick disease 192, 193, 428, 430 Night blindness 467 Ninhydrin test 430 Nitric acid 279 oxide 223, 224, 227, 290, 434 synthase 227, 270, 434 Nitrogen balance 533 Nitrogenous substances 218 N-methyl D-aspartate 228 transferase 235 Nocturia 373 Node of Ranvier 16 Nomenclature of carbon atoms 87 Non-alcoholic fatty liver disease 163 steatohepatitis 163, 305, 325, 351, 353, 354 Non-carbohydrate reducing compounds 317 Non-competitive inhibition 61f Non-esterified fatty acids 181, 538 Non-HDL cholesterol 338 Non-Hodgkin’s lymphoma 641 Non-insulin dependent diabetes mellitus 324, 333 Non-isotopic immunoassays 453 Non-ketotic hyperglycinemia 208, 213, 245 Non-oxidative deaminations 202 Non-phosphorylated lipids 92 Non-protein nitrogen 365 Non-steroidal anti-inflammatory drugs 189, 195 Norepinephrine 216, 235 Normal anion gap 404 metabolic acidosis 400, 401 composition of amniotic fluid 422t constituents of cells 709 hydrochloric acid secretion 357t iron kinetics 515f oxygen atom 433f pH 393 RBCs 291f serum electrolyte 404, 405 level of magnesium 512 Normoglycemia 313 Normotonic hyponatremia 413 Nuclear receptors 657 Nucleated RBC 294f Nucleic acid 559, 560 of virus 708 research 735 testing 701 Nucleoside 560-562 diphosphate 562 monophosphate 562 triphosphate 562, 562t Nucleotide 561 excision repair 583, 584, 584f phosphatase 305, 306, 308, 354 Number of hydrogen atoms 279 Numbering of amino acids in proteins 35 Nutritional deficiency of iron 518 importance of lipids 531 Nyctalopia 467 Nystagmus 238 O Oasthouse syndrome 199, 220 Obermeyer test 242 Obesity 163, 336, 339, 536 index 536 Index Obstruction of bile duct 150 urinary tract 416 Obstructive jaundice 280, 281, 336, 350, 354 liver disease 354 stage of viral hepatitis 281 Oculocerebrorenal syndrome 729 Oculocutaneous tyrosinemia 239 Okazaki fragments 581 Oligomycin 264, 265 Oligosaccharides 69 Omega fatty acids 163, 339 oxidation 155 Oncogenes 709, 710 Oncogenic viruses 351, 707, 713f Optic neuritis 553 neuropathy 631 Oral cavity 498 contraceptives 412, 484 glucose tolerance test 314, 315f, 333 rehydration fluid 106 Organ perfusion 97 slices 97 Organic acid 208 disorders 208 acidosis 400 acidurias 154, 400, 428 mercury 552 Organization of electron transport chain 260 proteins 34 Organophosphorus 553 compounds 553 insecticides 307 Ornithine 31, 227, 450 decarboxylase 62, 229f transcarbamoylase 204, 209 Orotic aciduria 430, 570 Osazone formation 74 Oseltamiver 61, 621 Osmolal gap 401 Osmolality of extracellular fluid 408 plasma 408, 408t Osmotic diuresis 166, 373 Osteitis deformans 354 Osteoblastoma 354 Osteoblasts 305, 505 Osteocalcin 475, 509, 511, 743 Osteoclasts 506 Osteoid 498, 509 Osteomalacia 354, 471, 472, 510 Osteonectin 743 Osteopetrosis 510 Osteopontin 743 Osteoporosis 510 Osteoprotegerin 743 Ovarian cancers 714 hormones 669 Oxalic acid 515 Oxaloacetate 248 junction point 249 Oxidation 285 of acetyl CoA 165 of fat carbohydrate 252f of fatty acids 87 of homogentisic acid 237f of iodine 672 of odd chain fatty acids 154 of sugars 74 products of glucose 74f Oxidative deamination of glutamate 202 decarboxylation 248 phosphorylation 111, 256, 263 Oxidized fatty acids 336 Oxoprolinuria 199 Oxygen dissociation curve 284, 285 P Paget’s disease 508, 510 Palmitic acid 15, 85, 153, 156 Pancreatic digestion of proteins 197 elastase 358 enzymes 358 function tests 358, 359t lipase 148 Pancreozymin 197 Pantothenic acid 477, 484, 486 Paper chromatography 449, 449f Para amino benzoic acid 477, 488 Paracetamol 189 Paradoxic acidosis 402 Paralysis of respiratory 404 Paraproteinemia 401, 690 Parathyroid function tests 508 hormone 505, 509 Paraventricular nucleus 660 Parenchymal diseases 353 Parent cell 579f Paresthesia 508 Parkinson’s disease 245, 552, 606 Paroxysmal nocturnal hemoglobinuria 16, 144 Partial gastrectomy 357 hydrolysis 40 reversal of glycolysis 118 Pathogenesis of ascites 347f Prion diseases 728 Pathology of maple syrup urine disease 231f Pathways of glucose 105, 123 Pauly’s test 32 Pellagra 242, 481, 483 Penicillin 61 Pentagastrin stimulation test 357 Pentose phosphate 130 pathway 129, 159 sugar 559 Pentosuria 317 Penultimate carbon atom 70f Pepsin 197, 308, 357 Peptide bond formation 31, 31f, 34f, 601 partial double bond 34f Peptidyl transferase 592, 601, 602 783 784 Textbook of Biochemistry Peripheral blood picture 490 smear 519 neuritis 483 neuropathy 495 proteins 15 smear 494 Pernicious anemia 357 Peroxidase 13, 258, 435f Peroxidation of polyunsaturated fatty acids 438f Peroxisomal biogenesis disorders 185 defects 430 deficiency diseases 13 oxidation 185 Peroxisomes 13 Peroxy nitrite 228, 434 Pertussis toxin 653 Phagocytosis 22, 497 Phagosomes 22 Phenylalanine 26, 27, 29, 31, 232, 233, 245, 450, 451 catabolism 232f hydroxylase 232, 232f, 236, 258 load test 237 Phenylketonuria 236, 246, 431 carrier state 237 Philadelphia chromosome 708 Phosphate 19f, 142 buffer system 394 infusion 508 mechanism in tubules 396f Phosphatidates 89 Phosphatidic acid 89 Phosphatidyl ethanolamine 191f inositol 495 bisphosphate 655f serine 191f Phosphatidylcholine 90 Phosphatidylethanolamine 91, 91f Phosphatidylglycerol 91 Phosphatidylinositol 91, 91f Phosphodiester bonds 574 Phosphoenolpyruvate 258 carboxykinase 118, 118f, 320 Phosphofructokinase 63, 109, 113, 121, 320 Phosphoglucomutase 124, 124f Phosphogluconate oxidative pathway 129 Phosphoglyceromutase 111 Phospholipase 90, 189 Phospholipid 89, 495 synthesis 495 Phosphoproteins 214 Phosphoribosyl pyrophosphate 240f, 563, 563f Phosphoric acid 89, 92, 561 Phosphorus 507, 511, 551, 735 Phosphorylase enzyme 483 kinase 127, 504 Phosphorylation 603, 652 Phosphosphingosides 91, 92 Photoelectric colorimeter 455, 455f Photophobia 238 Phytanic acid 155 Phytic acid 515 Pineal gland 242 Pinocytosis 21 Pituitary adenoma 668 Plasma ACTH 667, 668 ammonium 428 bicarbonate 405 bile acids 355 bilirubin 278 cells 686 cortisol 668 lactate 428 lipids 173 membrane 14 osmolality 373 proteins 378 TSH 675, 676 Plasmacytoma 690 Plasmalogens 91, 192 Plasmid liposome complex 631 Plasminogen 179 Plasmodium falciparum 145 infection 134 Platelet aggregation 190 Plummer-Wilson syndrome 519 Pneumocystis carinii 704 Pneumonia 404 Polarity of DNA molecule 575 Polyacrylamide gel electrophoresis 447, 447f Polyamine synthesis 229f Polycystic ovarian syndrome 680 Polycythemia vera 737 Polydypsia 326 Polymerase chain reaction 638, 638f, 645 Polyneuritis 478 Polynucleotide 575f Polyol pathway of glucose 135, 135f Polypeptide 693 Polyphagia 326 Polyphenols 435 Polyribosomes 602, 603f Polysaccharides 70, 78 Polyunsaturated fatty acids 13, 85, 86f, 180, 186, 339, 437, 531, 532 Polyuria 326 Pompe disease 129, 144, 428, 429 Porphobilinogen synthase deficiency 275 Porphyria 274 cutanea tarda 275f Porphyrin ring 271f Portal hypertension 348 lymphadenopathy 351 vein thrombosis 348 Porter-Silber reaction 666 Positron emission tomography scan 736 Post-hepatic jaundice 350 Post-prandial blood sugar 313 hypoglycemia 331 Index Poststreptococcal glomerulonephritis 375 Post-translational processing of collagen 722 Potassium 363, 413 chromate 550 excretion 414 ion 19f Powerhouse of cell 13 Prader-Willi syndrome 324 Pre-eclampsia of pregnancy 221 Pre-hepatic jaundice 350 Preparation of specific human gene 626 Preventable blindness 468 Prevention of atherosclerosis 339 met-hemoglobinemia 133 Primary biliary cirrhosis 351 deficit of carbonic acid 403 excess of bicarbonate 402 carbonic acid 403 familial hypercholesterolemia 342 hemosiderosis 520 hepatoma 281 hyperoxaluria 213 hyperthyroidism 676 hypothyroidism 676 structure of human insulin 35f insulin 35 Principles of anti-sense therapy 593f heredity 608 radioimmunoassay 452, 452f thermodynamics Processing of rRNA 598 tRNA 597 Production of bilirubin diglucuronide 278f genomic library 630f homogentisic acid 233 hybridoma 640 niacin 483 Progression of atherosclerosis 335 Prokaryotes 570 Prokaryotic cell Prolactin stimulation test 663 Proline amino peptidase 198 Prolonged in liver disease 355 Promoters of cancer 706 Promotes glycogenolysis 313 glycolysis 313 Properties of amino acids 27 fatty acids 86 Propionic aciduria 208, 429 Propionyl CoA carboxylase deficiency 155 Prostacyclin 188, 190, 190t Prostaglandins 188 Prostate cancer 306, 308 Protease inhibitors 52, 554 Protein 422, 534 biosynthesis 596 bound calcium 381, 505 buffer system 394 calorie malnutrition 163 catabolism 674 deficiency 533 energy malnutrition 534 kinase 653, 653t, 655f misfolding diseases 729 phosphatase 127 phosphorylation 64 selectivity index 372 targeting 603 truncation test 642 Proteinuria 371 Proteoglycan 81, 142, 143 Proteolytic digestion of myosin 725f Prothrombin 385, 475, 476 time 352, 385 Proton motive force 264 pump 263 Proto-oncogenes are regulatory genes 709 785 Protoporphyria 351 Proximal convoluted tubule 361, 362, 395 histidine 283 Pseudocholinesterase 307 Pseudohyperkalemia 413, 415, 416 Pseudohypoparathyroidism 508, 509 Pseudouridine arm of tRNA 597 Pteroic acid 488 Pulmonary hypertension 228 Pulsed field gel electrophoresis 448 Purine nucleoside phosphorylase 566f synthesis 563t, 564f Puromycin 605 Purulent meningitis 422 Putrefaction of tryptophan 242 Pyranose ring 72f Pyridoxal phosphate 50, 124, 201, 215, 224, 271, 482 Pyridoxamine 482 Pyridoxine 477, 482, 486 Pyrimethamine 61, 491 Pyrimidine 477 ring 226 synthesis 571 Pyrrole ring 271f Pyrrolidine 26 Pyrrolysine 31 Pyruvate carboxylase 63, 120, 428, 486, 504 deficiency 121 reaction 117 dehydrogenase 115, 117, 247, 257, 320, 477, 504 complex 115 kinase 111, 113, 117, 256, 320, 504 transporter 115 Q Quantitation of proteinuria 372 Quantitative PCR 639 preparation of biomolecules 624 real-time PCR 639 786 Textbook of Biochemistry Quarter staggered arrangement 721 Quinolinate phosphoribosyl transferase 240, 240f R Radial immunodiffusion 45, 45f Radiation protection 738 Radioactive iodine 453, 675 Radioimmunoassay 452, 735 Radium needles 737 Rancidity of fat 88 Random blood sugar 313 Rapaport Leubering cycle 115 Raynaud’s disease 375 Reabsorption of bicarbonate 395 calcium 506 solutes in tubules 362 water 363 Reaction in liver 465f lungs 288f amide group 30 amino acids 29 CoA derivatives 485f cycle preparatory steps 247 glycogen phosphorylase 124f lactate dehydrogenase 50f monosaccharides 73 oxaloacetate 250f Receptor mediated endocytosis 21 Reciprocal regulation of glycogenolysis 126f Recommended daily allowance of thiamine 479 Red depicts blood 465f Reduce dietary cholesterol 339 Reduced DNA synthesis 490 excretion rate 567 Reflectance spectrophotometry 457 Refsum’s disease 155 Regeneration of glucose-6-phosphate 131 oxaloacetate 248 Regulation of acid secretion 357 ATP synthesis 265 beta oxidation 154 blood glucose 311 sugar 313f calcitriol formation 471 cholesterol synthesis 172f citric acid cycle 253 color of skin 234 deoxyribonucleotide formation 569t fatty acid synthesis 159 gene expression 616 gluconeogenesis 120 glycogen metabolism 126 glycolysis 112 glycosis 113f heme synthesis 273 HMG CoA reductase 172f HMP shunt pathway 131 ovarian hormones 669 purine synthesis 565 pyrimidine synthesis 570 secretion of HCl 356f sodium and water balance 409 synthesis 189 urea cycle 204 Relative capacity of buffer systems 394 Renal acid excretion 397 artery stenosis 415 blood flow 362 disease 370, 512 failure 400, 404, 508, 511 function tests 361 glucosuria 316, 317 impairment 417, 512 insufficiency 220 osteodystrophy 510 plasma flow 371 regulation of pH 395 rickets 472 tubular acidosis 401, 404, 412, 415, 417, 508, 511, 512 Renin angiotensin aldosterone 410f system 409 Reperfusion injury 436, 436f Replication bubble 580, 581f of DNA 578 of HIV 701 Requirement of biotin 486 iron 514 pantothenic acid 485 vitamin B12 494 C 498 D 473 zinc 522 Residual renal function 371 Respiratory acidosis 398, 403, 405 alkalosis 398, 403, 405, 512 burst 22, 434 chain 255, 479 diseases 436 distress syndrome 91, 436 tract 190 Restriction endonucleases 309, 586, 625 fragment length polymorphism 637 map 625 sites 625 Retention jaundice 350 Reticulocytosis 490 Retina 20 Retinal degeneration 244 isomerase 466 Retinitis pigmentosa 185 Retinoblastoma oncosuppressor protein 615 protein 744 Retinoic acid receptors 467 Retinol binding protein 372, 464 palmitate 464 Retrolental fibroplasia 436 Index Retroviruses 629, 630 Reverse transcriptase PCR 639 Reversible oxidation-reduction 496 Rheumatoid arthritis 144, 375, 436, 641 Rhodopsin 465 RIA and ELISA tests 45 Ribavirin 621 Riboflavin 477, 479, 486 deficiency 479 structure 479f Ribonucleic acid 559, 587 Ribonucleoside 561 phosphates 562 Ribonucleotide 561 reductase 571f complex 571 Ribosomal RNA 587, 598 Ribozymes 65, 592 Rickets 471, 354, 510 Right handed double helix 575 Rituximab 717, 718 RNA synthesis 621f viruses 629 Role of amylase 309 antioxidants 438 carnitine 151 cyclic GMP 655 liver in fat metabolism 162 Romberg’s sign 494 Rosenheim reaction 32 Rothera’s test 166, 326, 365, 429 Rotor syndrome 280 S S-adenosyl methionine 216, 217, 222, 229f, 235, 258, 548 Sakaguchi’s test 32 Salicylate 318, 400 Salivary alpha-amylase 105 Salvaging of iodine 674 Sandhoff’s disease 193 Saponification 88f Sarcoidosis 508 Sarcoplasmic reticulum 725 Saturated and transfatty acids 188 fatty acid 85, 86, 532 Schilling test 359, 494 Schlesinger’s reaction 279 test 279, 365 Schwann’s cells 16 Scleroderma 375 Scurvy 497 Second law of thermodynamics Secondary hyperthyroidism 676 hyperuricemia 567 hypothyroidism 676 immunodeficiency 692 structure of proteins 36 Secretin cholecystokinin test 358 Secretion of adrenal hormones 665 hormones 504 insulin 318 Segment of nephron 362 Selective serotonin reuptake inhibitors 240 Selenocysteine 31, 32, 214, 599 Self-monitoring of blood glucose 458 Seliwanoff’s test 317 Sensitive gel electrophoresis 642f Sephadex chromatography 451f Sequelae of protein calorie malnutrition 536 Sequence of amino acids in proteins 34 Serine 26, 29, 207, 210, 216, 450 metabolism 215f proteases 52 Serotonin 239, 240 and melatonin synthesis 241f Sertoli cells 670 Serum bilirubin 355 electrophoresis 352 ferroxidase 520 globulins 352 787 glutamate dehydrogenase 141 oxaloacetate transaminase 305 pyruvate transaminase 305 proteins 507 triglyceride 338 Severe hepatocellular disease 355 Sex hormone binding globulin 669 linked recessive inheritance 610, 610f steroids 509 Sheehan’s syndrome 676 Short chain fatty acids 195 hairpin RNA 594 Shunt bilirubin 274, 274f Sickle cell 291f anemia 636 disease 291 hemoglobin 291 trait 291, 292, 292f syndromes 291 Sickling test 292 Sideroblastic anemia 275 Signal molecule 653, 740 Significance of cholesterol 334 gluconeogenesis 118 glycolysis pathway 108 heat coagulation 42 HMP shunt pathway 131 isoelectric pH 41 lactate production 112 PUFA 86, 186 transamination 201 Sildenafil citrate 228, 656 Simple amino acids 25f Single nucleotide polymorphism 4, 637 strand conformation polymorphism 641 Site directed mutagenesis 614 Sjögren’s syndrome 12, 375 Skeletal muscle 100, 101, 107, 176 ollinger 788 Textbook of Biochemistry Skin diseases 436 Small and medium chain fatty acids 185 chain fatty acids 184 nuclear RNAs 592 RNA 588 Smell of acetone 166 Sodium channels 20 cyclamate 81 dodecyl sulfate 447 fluoride 442 hydroxide 550 ion 19f potassium pump 19f pump 20, 21, 23, 106, 411 restriction 412 Softening of cornea 467 Soluble matrix 259 Somatic mutation 584 recombination of DNA 693 Sorensen’s formal titration 29 Sources of biotin 486 C and N atoms of pyrimidine 569f calcium 502 carbohydrates 530t folic acid 490 iron 514 lead poison 551 pantothenic acid 485 PUFA 532t vitamin D 473 E 474 K 476 Southern blot technique 634, 634f Spectrophotometer 456, 456f Spermidine synthase 229f Spermine synthase 229f Sphingolipidoses 193, 194 Sphingolipids 91 Sphingomyelin 92, 92f, 192 Sphingosine 91, 91f Spiranolactone 363 Split gene 693 Spontaneous decarboxylation 164 mutations 610, 713f Stages of compensation 399t oxidation of foodstuffs 255 Standard deviation index 445 urea clearance 370 Staphylococcus aureus 692 Starch tolerance test 359 Starling hypothesis 381f Starvation 163, 165 ketosis 332 Stearic acid 85 Stem cells 631, 632f Stereoisomers 70, 70f Steroid hormone 169, 664, 669t enters nucleus 656f Stimulation test 667 Storage of iron 517 vitamin B12 492f Streptococcus thermophilus 66 Streptomycin 605 Structure of ADH and oxytocin 659f alpha helix 37f ATP 51f beta-pleated sheet 37f biotin 485, 485f cholesterol 170f chylomicrons 175f co-enzyme 484f collagen 720 DNA 574 folic acid 488f heme 270, 271f hemoglobin 283 HIV 701f immunoglobulins 687 insulin 318 lipoic acid 115f mitochondrion 259 niacin 480f pantothenic acid 484f primary bile acids 181f proteins 34 purines 560f riboflavin 479 starch 78 sucrose 76f T-cell receptor 694f thiamine 477 pyrophosphate 478f tRNA molecule 596 vitamin A 464f B12 491f Subacute combined degeneration 494 Subarachnoid hemorrhage 422 Subcellular movements 726 organelle 10, 11 Subclassification of metabolic alkalosis 402 Subluxation of lens 221 Substrate concentration 56, 56f level phosphorylation 110, 111, 248, 256 saturation curve 56f strain 52 Succinate dehydrogenase 248, 254, 257 Q-reductase 261 thiokinase 248, 256 Succinylcholine 307, 495 Sucrose 77, 530 Sugars of nucleic acids 76f Suicide inhibition 62, 568 Sulfate conjugation 547 Sulfonamide 60, 61, 491 Sulfur containing amino acids 24, 25f, 220t, 483 Sulfuric acid 550 Superoxide dismutase 13, 133f, 434, 435, 435f Index Surgical removal of gallbladder 360 Synthesis of catecholamines 234 ceramide 192, 192f cerebrosides 192, 193f cholecalciferol 469f CoA 484f collagen 721 compound lipids 191 deoxythymine nucleotides 571 ferritin and transferrin receptor 516 gangliosides 193, 193f glutathione 212 glycerophosphatides 191 glycosphingolipids 192 heme 212 leukotrienes 191f melanin 233 mineralocorticoids 665f nitric oxide 227 non-essential amino acids 30, 201 phosphatidylcholine 191, 191f phosphatidylinositol 191 pregnenolone 664f purines 212 pyrimidine nucleotides 570f secretory proteins 605f sex hormones 666f sphingolipids 192 sphingomyelin 192 steroid hormones 664 structural and functional proteins 196 sulfatides 193 thymidylic acid 208f thyroid hormones 236 triacylglycerols 160 triphosphates 569 Systemic lupus erythomatosus 375 T Tamoxifen 670 Tandem mass spectrometry 458, 458f Tangier disease 342 Tartaric acid 306 Tartrate resistant acid phosphatase 510 Tarui’s disease 144 Tata-binding protein 590 Tau protein 728, 729, 745 Tay-Sach’s disease 193, 194, 430 Tendinous xanthomata 342 Testicular hormones 670 Testosterone 669, 670 Tetracycline 412, 605 resistance gene 627 Tetrahydrobiopterine 227f, 232 Tetrahydrofolic acid 207f, 501, 572f Thalassemia 290, 293, 294f, 518 syndromes 294 Therapeutic potential of arginine 227 use of enzymes 308t niacin 482 vitamin A 469 vitamin C 499 Thermogenesis 162, 674 Thiamine 115, 230, 477, 486, 560 deficiency 134 pyrophosphate 50, 115, 130, 477 Thiazide 363 Thin layer chromatography 449, 450f Thioredoxin reductase 214, 571f Threonine 26, 27, 210, 450, 451 Thrombin 385 Thrombopoietin 745 Thrombosis 221, 335 Thromboxane 188, 190, 190t Thymine 477, 560 Thyroid cancer 716, 737 function tests 674 hormones 528, 672, 674 scanning 736 stimulating hormone 662 Thyrotoxicosis 508, 512 Thyroxine synthesis 673f Tissue of origin 303, 669 polypeptide antigen 715 Titration curve of glycine 28f Total iron binding capacity 516, 519, 524, 525 parenteral nutrition 541 Toxic exposure 354 hepatitis 349 Toxicity of folic acid 491 niacin 482 vitamin B6 484 C 499 Trait of disease 609 Transamination 30, 201, 483 of alanine 119f reaction 29f Transfatty acids 15, 86, 341, 532 Transfer RNA 588, 596 carrying serine 597f general structure 597f Transferrin receptor protein 525 Transformation of cells in tissue culture 712f Transforming growth factor 745 Transient glucosuria 317 Transketolase reaction 130 Transmembrane proteins 16 Transmethylation 30 reactions 489f Transmissible spongiform encephalopathies 728 Transport chain 255 of amino acids 219 of carbon dioxide 287 of cholesterol 335f of glucose 320 of thyroid hormones 674 proteins 39, 382 Transportation of ammonia 203 Trapping of ammonia 203 Treatment of adenocarcinoma of colon and breast 716 hemosiderosis 520 789 790 Textbook of Biochemistry hyocalcemia 509 hyperkalemia 416 hypokalemia 415 iron deficiency 519 lead poisoning 552 metabolic acidosis 402 obesity 536 protein-energy malnutrition 535 Triacylglycerol synthesis 160 Tricarboxylic acid cycle 249f Triglyceride 87f Tripeptidases 198 Triple stranded collagen fiber 721f stranded helix 721 Tropical splenomegaly syndrome 375 Trousseau’s sign 508, 509, 524 Tryptophan 26, 27, 29, 207, 232, 239, 450, 451 hydroxylase 240, 258 metabolism 497 pyrrolase 64, 240, 258, 270 Tubeless gastric analysis 357 Tuberculosis 326, 508, 700 Tuberculous meningitis 422 Tuberous xanthomata 342 Tubular dysfunction 374 maximum 362, 374 proteinuria 372 reabsorption of phosphate test 508 Tubules handle substances differently 366f Tumor cell destruction 686 index substances 713 marker 306, 308, 506, 713, 715 metastasis 722 necrosis factor 695 alpha 696 beta 696 receptor 746 of bile duct 349 of bladder 370 Turner syndrome 324 Types of acid-base disturbances 398t bilirubin 349 bond 547 calcium channels 503f jaundice 349 lactic acidosis 400 metabolic pathways 99 radiation 734 rickets 472 transport mechanisms 21t systems 21f tumor produced 708 Tyrosinase 234, 238 Tyrosine 26, 29, 232, 233, 450, 451 hydroxylase 234, 258 Tyrosinemia 239 U Unconjugated bilirubin 139, 280, 350 Uncouplers of oxidative phosphorylation 265 Uniport system 21, 106 Units of chondroitin sulfate 80f Unsaturated fatty acids 85 Upper part of jejunum 488 Urea clearance test 369 cycle 196, 203, 226 disorders 206t, 428 enzyme 571 Uremic syndrome 370 Uric acid 363, 565, 566, 567 Uridine diphosphate 142 Urinary acidification 373 bilirubin 349 buffer 396 calculi 468 excretion 366 of porphyrins 276t free cortisol 668 hydroxyproline excretion 510 osmolality 373 steroids 666, 667 urobilinogen 350 Urine appearance 364t bile salts 350 collection 442 excretion 366 of alkaptonuria 238f Urobilinogen 349, 350, 365 Urocanic aciduria 244 Urogenic proteinuria 372 Uronic acid 74 Use of radioisotope tracers 98 Utilization of glucose 210, 321 V Valinomycin 19, 23, 265 Van Den Bergh direct test 350 indirect test 350 reaction 349 test 279 Van Der Waals forces Vanillyl Mandelic acid 236, 246 Vascular cell adhesion molecule 746 diseases 328 endothelial growth factor 746 occlusion in sickle cell anemia 291f Ventromedial nucleus 660 Verner-Morrison syndrome 681 Very long chain fatty acids 184, 186 low density lipoproteins 173, 176 Vibrio cholerae 653 Vinyl phenols 553 Index Viral hepatitis 349, 351 infection 422 Virus 144, 620, 708 carrying gene 710 Visualization of chromatography 449 protein bands 447 Vitamin A 464, 465f, 507, 707, 758 deficiency 468 B12 217, 488, 491 B6 deficiency 240 C 317, 438, 495, 497, 509, 519, 707 deficiency 244 D 469, 505, 507 and absorption of calcium 471, 505 and bone 505 and innate immunity 472 and metabolic syndrome 473 and renal tubules 505 deficiency 471, 472, 512 resistant rickets 21 E 163, 438, 340, 473, 707 K 474, 474f cycle 475f deficiency 352 dependent carboxylase 475 reductase 475f Volatile acids 393 Voltage dependent anion channel 268 Vomiting 412 Von Gierke’s disease 128, 136, 144, 331, 365, 430, 567 W Wald’s visual cycle 465f Waldenstrom’s macroglobulinemia 375, 690 Warburg’s hypothesis 114, 712 Water soluble vitamins 463 Watson-Crick model of DNA structure 575 Weak and strong acids 391 Wernick’s disease 141 Westergard multirule chart 444 Western blot 700 analysis for proteins 634 Wet beriberi 478 Whipple’s disease 242 White adipose tissue 162 WHO classification of malnutrition 535t Williams-Beuren syndrome 723 Wilson’s disease 353, 355, 384, 430, 521 hepatolenticular degeneration 352 Wobbling phenomenon 599 Wolman’s disease 344 X Xanthaslasma 342 791 Xanthine 560 oxidase 434, 436 deficiency 569 Xanthomas 342 Xanthoproteic test 31 Xanthosine monophosphate 564 Xanthurenic acid 240 aciduria 483 Xeroderma pigmentosum 584, 585 Xerophthalmia 467 X-linked adrenoleukodystrophy 23 recessive 133 Xylitol dehydrogenase 135 Y Y-linked inheritance 610 Z Zanamavir 621 Zellweger syndrome 13, 156, 185, 186, 603 Zidovudine 621 Zimmerman reaction 666 Zinc 51, 522 chloride 550 deficiency manifestations 522 toxicity 522 Zollinger-Ellison syndrome 357, 681 ... carbonic acid which dissociates into CO2 and H2O CO2 is thus eliminated by the lungs HHb + O2 HbO2 + H+ + – HCO3 + H H2CO3 H2CO3 H2O + CO2 iv The activity of the carbonic anhydrase (also called... regulation of pH are: A Excretion of H+ (Fig 29 .2) B Reabsorption of bicarbonate (recovery of bicarbonate) (Fig 29 .3) C Excretion of titratable acid (net acid excretion) (Fig 29 .4) D Excretion of NH4+... (NaHCO3/H2CO3) It accounts for 65% of buffering capacity in plasma and 40% of buffering action in the whole body Box 29 .2: Mechanisms of regulation of pH First line of defense Second line of defense