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Inherited Variation and Polymorphism in DNA


The original Human Genome Project and the subsequent study of now many thousands of individuals worldwide have provided a vast amount of DNA sequence information. With this information in hand, one can begin to characterize the types and frequencies of polymorphic variation found in the human genome and to generate catalogues of human DNA sequence diversity around the globe. DNA polymorphisms can be classified according to how the DNA sequence varies between the different alleles.

Single Nucleotide Polymorphisms

The simplest and most common of all polymorphisms are single nucleotide polymorphisms (SNPs). A locus characterized by a SNP usually has only two alleles, corresponding to the two different bases occupying that particular location in the genome. As mentioned previously, SNPs are common and are observed on average once every 1000 bp in the genome. However, the distribution of SNPs is uneven around the genome; many more SNPs are found in noncoding parts of the genome, in introns and in sequences that are some distance from known genes. Nonetheless, there is still a significant number of SNPs that do occur in genes and other known functional elements in the genome. For the set of protein-coding genes, over 100,000 exonic SNPs have been documented to date. Approximately half of these do not alter the predicted amino acid sequence of the encoded protein and are thus termed synonymous, whereas the other half do alter the amino acid sequence and are said to be nonsynonymous. Other SNPs introduce or change a stop codon, and yet others alter a known splice site; such SNPs are candidates to have significant functional consequences.

The significance for health of the vast majority of SNPs is unknown and is the subject of ongoing research. The fact that SNPs are common does not mean that they are without effect on health or longevity. What it does mean is that any effect of common SNPs is likely to involve a relatively subtle altering of disease susceptibility rather than a direct cause of serious illness.

Insertion-Deletion Polymorphisms

A second class of polymorphism is the result of variations caused by insertion or deletion (in/dels or simply indels) of anywhere from a single base pair up to approximately 1000 bp, although larger indels have been documented as well. Over a million indels have been described, numbering in the hundreds of thousands in any one individual’s genome. Approximately half of all indels are referred to as “simple” because they have only two alleles – that is, the presence or absence of the inserted or deleted segment.

Microsatellite Polymorphisms

Other indels, however, are multiallelic due to variable numbers of the segment of DNA that is inserted in tandem at a particular location, thereby constituting what is referred to as a microsatellite. They consist of stretches of DNA composed of units of two, three, or four nucleotides, such as TGTGTG, CAACAACAA, or AAATAAATAAAT, repeated between one and a few dozen times at a particular site in the genome. The different alleles in a microsatellite polymorphism are the result of differing numbers of repeated nucleotide units contained within any one microsatellite and are therefore sometimes also referred to as short tandem repeat (STR) polymorphisms. A microsatellite locus often has many alleles (repeat lengths) that can be rapidly evaluated by standard laboratory procedures to distinguish different individuals and to infer familial relationships. Many tens of thousands of microsatellite polymorphic loci are known throughout the human genome. Finally, microsatellites are a particularly useful group of indels. Determining the alleles at multiple microsatellite loci is currently the method of choice for DNA fingerprinting used for identity testing.

Mobile Element Insertion Polymorphisms

Nearly half of the human genome consists of families of repetitive elements that are dispersed around the genome. Although most of the copies of these repeats are stationary, some of them are mobile and contribute to human genetic diversity through the process of retrotransposition, a process that involves transcription into an RNA, reverse transcription into a DNA sequence, and insertion into another site in the genome. Mobile element polymorphisms are found in nongenic regions of the genome, a small proportion of them are found within genes. At least 5000 of these polymorphic loci have an insertion frequency of greater than 10% in various populations.

Coyp Number Variants

Another important type of human polymorphism includes copy number variants (CNVs). CNVs are conceptually related to indels and microsatellites but consist of variation in the number of copies of larger segments of the genome, ranging in size from 1000 bp to many hundreds of kilobase pairs. Variants larger than 500 kb are found in 5% to 10% of individuals in the general population, whereas variants encompassing more than 1 Mb are found in 1% to 2%. The largest CNVs are sometimes found in regions of the genome characterized by repeated blocks of homologous sequences called segmental duplications (or segdups).

Smaller CNVs in particular may have only two alleles (i.e., the presence or absence of a segment), similar to indels in that regard. Larger CNVs tend to have multiple alleles due to the presence of different numbers of copies of a segment of DNA in tandem. In terms of genome diversity between individuals, the amount of DNA involved in CNVs vastly exceeds the amount that differs because of SNPs. The content of any two human genomes can differ by as much as 50 to 100 Mb because of copy number differences at CNV loci.

Notably, the variable segment at many CNV loci can include one to as several dozen genes, that thusCNVs are frequently implicated in traits that involve altered gene dosage. When a CNV is frequent enough to be polymorphic, it represents a background of common variation that must be understood if alterations in copy number observed in patients are to be interpreted properly. As with all DNA polymorphism, the significance of different CNV alleles in health and disease susceptibility is the subject of intensive investigation.

Inversion Polymorphisms

A final group of polymorphisms to be discussed is inversions, which differ in size from a few base pairs to large regions of the genome (up to several megabase pairs) that can be present in either of two orientations in the genomes of different individuals. Most inversions are characterized by regions of sequence homology at the edges of the inverted segment, implicating a process of homologous recombination in the origin of the inversions. In their balanced form, inversions, regardless of orientation, do not involve a gain or loss of DNA, and the inversion polymorphisms (with two alleles corresponding to the two orientations) can achieve substantial frequencies in the general population.

Regulation of Hemostasis


Key events that initiate and propagate coagulation are the redistribution of negatively charged phospholipids to the cell surface and the exposure of tissue factor to the blood. The appropriate negatively charged phospholipids, primarily phosphatidylserine, can arise as a result of either cellular activation with strong agonists like thrombin together with collagen in the case of platelets or tissue damage or death. The negatively charged phospholipids promote the activation of factor X and IX by the tissue factor-factor VIIa pathway, the activation of prothrombin by factors Va and Xa, and the activation of factor X by factors VIIIa and IXa. In addition, it has been suggested that oxidation of a specific disulfide in tissue factor is important for expression of its procoagulant activity, a process that may be regulated by protein disulfide isomerase, although this concept remains controversial.

Normally tissue factor is not present on cells in contact with blood. Tissue factor is found on extravascular cells surrounding the blood vessel so that a potent procoagulant surface is exposed when the endothelium is breached. This helps to seal the breach. Intravascularly, inflammatory stimuli can induce tissue factor synthesis and expression on leukocytes, particularly monocytes, providing a mechanism for the initiation of coagulation. This response likely contributes to disseminated intravascular coagulation (DIC). Animal studies suggest that this coagulation response plays a role in innate immunity and prevents the dissemination of infectious agents.

Other key events that can play a major role in the pathogenesis of thrombosis, at least in animal models, involve the release of intracellular components, including ribonucleic acid (RNA) and polyphosphates. These can trigger activation of factor XII, which initiates coagulation via the contact pathway. Although factor XII does not appear to contribute to hemostasis, it drives several models of thrombosis, including pulmonary embolism and myocardial infarction.

Polyphosphates are stored in the dense granules of platelets and when released, contribute to the procoagulant potential of the platelet. In regions of cellular death or severe inflammation, histones released from the tissue can bind to these polyphosphates, increasing the procoagulant activity more than 20-fold. Heparin analogues can block polyphosphate stimulation of coagulation by histones. In addition, neutrophils in hyperinflammatory environments can release their nuclear contents to form neutrophil extracellular traps (NETs). These NETs are effective in killing bacteria and other pathogens and also provide a potent agonist for the activation of platelets and the development of thrombi. Interestingly, heparin, an anticoagulant often used in the setting of inflammation, can disrupt the NETs and diminish the activation of platelets by histones and NETs.

Inhibition of Coagulation

There are three major natural anticoagulant mechanisms that serve to limit the coagulation process. These are tissue factor pathway inhibitor (TFPI), which blocks the initiation of coagulation by tissue factor-factor VIIa; the antithrombin-heparin mechanism, which inhibits thrombin and factors VIIa, Xa, and IXa; and the protein C pathway, which inactivates factors Va and VIIIa.

  1. Tissue factor pathway inhibitor (TFPI)
  2. Antithrombin-heparin mechanism
  3. Protein C pathway

Tissue Factor Pathway Inhibitor

TFPI is a complex molecule composed of three similar domains related to a protease inhibitor type known as Kunitz inhibitor. To inhibitor the tissue factor-factor VIIa complex, the Kunitz-1 domain of TFPI binds factor VIIa, whereas the Kunitz-2 domain binds factor Xa, either because the factor X is activated on tissue factor or (probably less effectively) by first reacting with factor Xa in solution and then inhibiting factor VIIa bound to tissue factor, thus blocking the initiation of coagulation. The carboxy terminal portion of TFPI is very basic, potentially facilitating interaction with the endothelium. Protein S can augment the activity of TFPI by increasing the rate of TFPI inactivation of factor Xa. The physiologic importance of TFPI is highlighted by the fact that gene deletion results in embryonic lethality apparently because of thrombosis and subsequent hemorrhage.

  1. Inhibiting Xa (Xa-TFPI complex)
  2. Xa-TFPI complex Inhibits FVIIa-TF complex
  3. TFPI is necessary for life

Antithrombin and Heparin

Antithrombin is the major inhibitor of the coagulation proteases thrombin, factor VIIa, factor Xa, and factor IXa. Antithrombin is a member of a large class of protease inhibitors referred to as serine protease inhibitors and abbreviated sermons. Antithrombin forms a very tight complex with these proteases. This reaction is rather slow with a half-life in the order of 30 seconds in plasma. Heparin markedly accelerates the reaction, thus accounting for most of its anticoagulant activity. There is a “bait” region in antithrombin that is involved in its interaction with the proteases. In the absence of heparin, this bait region is only partially available to the protease, resulting in the slow inhibition. Heparin binding to antithrombin induces a conformational change in antithrombin that enhances protease access to the bait loop.

In addition to the conformational change in antithrombin, heparin has additional roles in the inhibition of coagulation proteases. High-molecular-weight heparin can bind to both antithrombin and the protease, creating a situation where both reactants are brought into close proximity, thus increasing the reaction rate. This function is of variable importance with different proteases of the cascade. It is essential for thrombin inhibition, but plays a less important role in the inhibition of factor Xa. High-molecular-weight heparins accelerate factor Xa inhibition somewhat better than low-molecular-weight forms, but in contrast to most of the other heparin-mediated inhibitory functions, the additional acceleration gained by the high-molecular-weight forms is dependent on calcium ions. It is of interest that as heparins become processed to generate lower-molecular-weight fractions, such as enoxaparin, the capacity to promote thrombin inhibition versus factor Xa inhibition decreases. With the smallest functional form of heparin, the synthetic pentasaccharide fondaparinux, the ability to augment thrombin inhibition is almost completely lost, while good inhibition of factor Xa is maintained. Although heparin is a potent antithrombin-dependent anticoagulant, it is not effective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces.

The importance of antithrombin is documented by the clinical observation that antithrombin deficiency, even to 50% of normal, is associated with significant thrombotic problems in humans and mice. Deletion of the gene in mice causes embryonic lethality, apparently in a mechanism that involves thrombosis followed by hemorrhage. Although heparin-like proteoglycans have been proposed to be important in modulating antithrombin function, immunohistochemical analysis indicates that most of these are localized to the basolateral side of the endothelium. No definitive deletion of heparin sulfate proteoglycans has been reported, possibly because there are alternative mechanisms for its biosynthesis. However, deletion of ryudocan, another heparin-like proteoglycan, is associated with a thrombotic phenotype.

  1. Antithrombin is ineffective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces
  2. Heparin itself has no anticoagulation effect
  3. Heparin accelerates the anticoagulation capacity of antithrombin
  4. Deficiency of heparin-like proteoglycan potentiates patients at risk of thrombosis

The Thrombomodulin and Protein C Anticoagulation Pathway

The protein C pathway serves many roles, probably the primary role being to work to generate activated protein C (APC) that in turn inactivates factors Va and VIIIa to inhibit coagulation. The importance of this anticoagulant activity is readily apparent because patients born without protein C die in infancy of massive thrombotic complication (purport fulminans) unless provided a protein concentrate.

The protein C anticoagulant pathway serves to alter the function of thrombin, converting it from a procoagulant enzyme into the initiator of an anticoagulant response. This occurs when thrombin binds to thrombomodulin, a proteoglycan receptor primarily on the surface of the endothelium. Thrombomodulin binds thrombin with high affinity, depending on the posttranslational modifications of thrombomodulin. Binding thrombin to thrombomodulin blocks most of thrombin’s procoagulant activity such as the ability to clot fibrinogen, activate platelets, and activate factor V but does not prevent thrombin inhibition by antithrombin. The thrombin-thrombomodulin complex gains the ability to rapidly activate protein C. In the microcirculation, where there is high ratio of endothelial surface to blood volume, it has been estimated that the thrombomodulin concentration is in the range of 100 to 500 nM. Thus a single pass through the microcirculation effectively strips thrombin from the blood, initiates protein C activation, and holds a coagulantly inactive thrombin molecule in place for inhibition by antithrombin or protein C inhibitor. Activation of protein C is augmented approximately 20-fold in vivo by the endothelial cell protein C receptor (EPCR). EPCR binds both protein C and APC with similar affinity. The EPCR-APC complex is capable of cytoprotective functions, but at least with soluble EPCR, this complex is not an effective anticoagulant. Instead, when APC dissociates from EPCR, it can interact with protein S to inactivate factors Va and VIIIa and thus inhibit coagulation. Factor V increases the rate at which the APC-protein S complex inactivates factor VIIIa.

Thrombomodulin also increases the rate at which thrombin activates thrombin-activatable fibrinolysis inhibitor (TAFI) to a similar extent as it dose protein C. Once activated, TAFI releases C-terminal lysine and arginine residues of fibrin chains. C-terminal lysine residues on fibrin enhance fibrin degradation by serving as plasminogen- and tissue plasminogen activator-binding sites. Consequently, their removal by activated TAFI (TAFIa) attenuates clot lysis.

More than any other regulatory pathway except tissue factor, the protein C pathway is sensitive to regulation by inflammatory mediators. Tumor necrosis factor-alpha and IL-1beta downregulate thrombomodulin both in cell culture and in at least some patients with sepsis. Downregulation of thrombomodulin has been observed in animal models of diabetes, inflammatory bowel disease, reperfusion injury in the heart, over human atheroma, and in villitis, in addition to sepsis.

  1. Protein C, thrombomodulin, and EPCR are essential for life
  2. Protein C targets against factors Va and VIIIa
  3. EPCR increases the protein C activation by thrombin-thormbomodulin complex by about 20-fold
  4. Protein C’s anticoagulation function needs the help of protein S
  5. Thrombin-thrombomodulin complex removes the C-terminal lysine residues of fibrin, which attenuates clot fibrinolysis.

Regulation of Fibrinolysis

Fibrinolysis is the process by which fibrin clots are dissolved, either through natural mechanisms or with the aid of pharmaceutical interventions. Plasmin is the serine protease that solubilizes fibrin. Plasmin is generated by the activation of its precursor plasminogen either by natural activators, tissue plasminogen activator (tPA), the major activator in the circulation, or urokinase plasminogen activator (uPA), or by administration of recombinant tPA or streptokinase, a bacterial protein that promotes plasmin generation and aids in dissemination of the bacteria. Staphylokinase, a protein from Staphylococcus aureus, is similar to streptokinase and also has been examined as a potential therapeutic.

Fibrin plays an active role in its own degradation because it binds plasminogen and tPA, thereby concentrating them on the fibrin surface and promoting their interaction. The resultant plasmin cleaves fibrin and exposes C-terminal lysine residues that serve as additional plasminogen and tPA binding sites. TAFIa attenuates fibrinolysis by releasing these C-terminal lysine residues. Furthermore, lysine analogues, such as ε-aminocaproic acid or tranexamic acid, bind to tPA and plasminogen. Consequently, these lysine analogues can be used to treat patients with hyperfibrinolysis and can reduce bleeding complications.

Plasmin is not specific for fibrin and degrades a variety of other proteins. Consequently, plasmin is tightly controlled. There are two major inhibitors of fibrinolysis: α2-antiplasmin, and serpin that inactivates plasmin, and plasminogen activator inhibitor 1 (PAI-1), which inhibits tPA and uPA. α2-Antiplasmin is cross-linked to fibrin by activator factor XIII. PAI-1 is an intrinsically unstable serpin that can be stabilized by interaction with vitronectin. Because of its instability, the antigen and functional levels of PAI-1 are often quite different and can vary among individuals. PAI-1 is upregulated by lipopolysaccharide, tumor necrosis factor, and other inflammatory cytokines. PAI-1 levels are increased in vascular diseases such as atherosclerosis and in metabolic syndrome, sepsis, and obesity. Increased levels of PAI-1 result in decreased fibrinolytic activity, which increases the risk for thrombosis. PAI-1 is also stored in platelets and is released with platelet activation. Platelet-derived PAI-1 may limit the degradation of platelet-rich thrombi, such as those that trigger acute coronary syndromes.

Overall the fibrinolytic system is dynamic and responsive to local phenomena, such as platelet-derived PAI-1, as well as to systemic alterations like obesity and inflammation. In this sense, the fibrinolytic control mechanisms share many similarities with the control of coagulation, in which similar considerations affect their function.

Renal Handling of Urea


Renal Handling of Urate

Urate, an anion that is the base form of uric acid, provides a fascinating example of the renal handling of organic anions that is particularly important for clinical medicine and is illustrative of renal pathology. An increase in the plasma concentration of urate can cause gout and is thought to be involved in some forms of heart disease and renal disease; therefore, its removal from the blood is important. However, instead of excreting all the urate it can, the kidneys actually reabsorb most of the filtered urate. Urate is freely filterable. Almost all the filtered rate is reabsorbed early in the proximal tubule, primarily via antiporters (URAT1) that exchange urate for another organic anion. Further on the proximal tubule urate undergoes active tubular secretion. Then, in the straight portion, some of the urate is once again reabsorbed. Because the total rate of reabsorption is normally much greater than the rate of secretion, only a small fraction of the filtered load is excreted.

Although urate reabsorption is greater than secretion, the secretory process is controlled to maintain relative constancy of plasma urate. In other words, if plasma urate begins to increase because of increased urate production, the active proximal secretion of urate is stimulated, thereby increasing urate excretion.

Given these mechanisms of renal urate handling, the reader should be able to deduce the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout: 1) decreased filtration of urate secondary to decreased GFR, 2) excessive reabsorption of urate, and 3) diminished secretion of urate.

Urate, and some other organic solutes, although more membrane permeable in the neutral form, are less soluble in aqueous solution and tend to precipitate. The combination of excess plasma urate and low urinary pH, which converts urate to the neutral uric acid, often leads to the formation of uric acid kidney stones.

Renal Handling of Urea

Urea is a very special substance for the kidney. It is an end product of protein metabolism, waste to be excreted, and also an important component for the regulation of water excretion. Urea differs from all the other organic solutes in several significant ways. 1) There are no membrane transport mechanisms in the proximal tubule; instead, it easily permeates the tight junctions of the proximal tubule where it is reabsorbed paracellularly. 2) Tubular elements beyond the proximal tubule express urea transporters and handle urea in a complex, regulated manner.

Urea is derived from proteins, which form much of the functional and structural substance of body tissues. Proteins are also a source of metabolic fuel. Dietary protein is first digested into its constituent amino acids. These are then used as building blocks for tissue protein, converted to fat or oxidized immediately. During fasting, the body breaks down proteins into amino acids that are used as fuel, in essence consuming itself. The metabolism of amino acids yields a nitrogen moiety (ammonium) and a carbohydrate moiety. The carbohydrate goes on to further metabolic processing, but the ammonium cannot be further oxidized and is a waste product. Ammonium per se is rather toxic to most tissues and the liver immediately converts most ammonium to urea and a smaller, but crucial amount to glutamine. While normal levels of urea are not toxic, the large amounts produced on a daily basis, particularly on a high protein diet, represent a large osmotic load that must be excreted. Whether a person is well fed or fasting, urea production proceeds continuously and constitutes about half of the usual solute content of urine.

The normal level of urea in the blood is quite variable, reflecting variations in both protein intake and renal handling of urea. Over days to weeks, renal urea excretion must match hepatic production; otherwise plasma levels would increase into the pathological range producing a condition called uremia. On a short-term basis (hours to days), urea excretion rate may not exactly match production rate because urea excretion is also regulated for purposes other than keeping a stable plasma level.

The gist of the renal handling of urea is the following: it is freely filtered. About half is reabsorbed passively in the proximal tubule. Then an amount equal to that reabsorbed is secreted back into the loop of Henle. Finally, about half is reabsorbed a second time in the medullary collecting duct. The net result is that about half the filtered load is excreted.

pH Dependence of Passive Reabsorption or Secretion

Many of the organic solutes handled by the kidney are weak acids or bases and exist in both, neutral and ionized forms. The state of ionization affects both the aqueous solubility and membrane permeability of the substance. Neutral solutes are more permeable than ionized solutes. As water is reabsorbed from the tubule, any substance remaining in the tubule becomes progressively more concentrated. And the luminal pH may change substantially during flow through the tubules. Therefore, both the progressive concentration of organic solutes and change in pH strongly influence the degree to which they are reabsorbed by passive diffusion through regions of tubule beyond the proximal tubule.

At low pH weak acids are predominantly neutral, while at high pH they dissociate into an anion and a proton. Imagine the case in which the tubular fluid becomes acidified relative to the plasma, which it does on a typical Western diet. For a weak acid in the tubular fluid, acidification converts much of the acid to the neutral form and therefore, increases its permeability. This favors diffusion out of the lumen (reabsorption). Highly acidic urine tends to increase passive reabsorption of weak acids (and promote less excretion). For many weak bases, the pH dependence is just opposite. At low pH they are protonated cations. As the urine becomes acidified, more is converted to the impermeable charged form and is trapped in the lumen. Less is reabsorbed passively, and more is excreted.

Ammonia and Urea Cycle


Ammonia (NH3) is a small metabolite that results predominantly from protein and amino acid degradation. It is highly membrane-permeant and readily crosses epithelial barriers in its nonionized form.

Ammonia does not have a physiologic function. However, it is important clinically because it is highly toxic to the nervous system. Because ammonia is being formed constantly from the deamination of amino acids derived from proteins, it is important that mechanisms exist to provide for the timely and efficient disposal fo this molecule. The liver is critical for ammonia catabolism because it is the only tissue in which all elements of the urea cycle, also known as the Krebs-Henseleit cycle, are expressed, providing for the conversion of ammonia to urea. Ammonia is also consumed in the synthesis of nonessential amino acids, and in various facets of intermediary metabolism.

Ammonia Formation and Disposition

Ammonia in the circulation originates in a number of different sites. A diagram showing the major contributors to ammonia levels is shown in 14-1. Note that the liver is efficient in taking up ammonia from the portal blood in health, leaving only approximately 15% to spill over into the systemic circulation.

Intestinal Production

The major contributor to plasma ammonia is the intestine, supplying about 50% of the plasma load. Intestinal ammonia is derived via two major mechanisms. First, ammonia is liberated from urea in the intestinal lumen by enzymes known as ureases. Ureases are not expressed by mammalian cells, but are products of many bacteria, and convert urea to ammonia and carbon dioxide. Indeed, this provides the basis for a common diagnostic test, since H. pylori, which colonizes the gastric lumen and has been identified as a cause of peptic ulcer disease, has a potent urease. Therefore, if patients are given a dose of urea labeled with carbon-13, rapid production of labeled carbon dioxide in the breath is suggestive of infection with this microorganism.

Second, after proteins are digested by either host or bacterial proteases, further breakdown of amino acids generates free ammonia. Ammonia in its unionized form crosses the intestinal epithelium freely, and enters the portal circulation to travel to the liver; however, depending on the pH of the colonic contents, a portion of the ammonia will be protonated to ammonium ion. Because the colonic pH is usually slightly acidic, secondary to the production of short-chain fatty acids, the ammonium is thereby trapped in the lumen and can be eliminated in the stool.

Extraintestinal Production

The second largest contributor to plasma ammonia levels is the kidney. Ammonia is also produced in the liver itself during the deamination of amino acids. Minor additional components of plasma ammonia derive from adenylic acid metabolism in muscle cells, as well as glutamine released from senescent red blood cells.

Urea Cycle

The most important site for ammonia catabolism is the liver, where the elements of the urea cycle are expressed in hepatocytes. Ammonia derived from the sources described earlier is converted in the mitochondria to carbamoyl phosphate, which in turn reacts with ornithine to generate citrulline. Citrulline, in turn, reacts in the cytosol with aspartate, produced by the deamination of glutarate, to yield sequentially arginine succinate then arginine itself. The enzyme arginase then dehydrates arginine to yield urea and ornithine, which returns to the mitochondria and can reenter the cycle to generate additional urea. The net reaction is the combination of two molecules of ammonia with one of carbon dioxide, yielding urea and water.

Urea Disposition

A “mass balance” for the disposition of ammonia and urea is presented in Figure 14-2. As a small molecule, urea can cross cell membranes readily. Likewise, it is filtered at the glomerulus and enters the urine. While urea can be passively reabsorbed across the renal tubule as the urine is concentrated, its permeability is less than that of water such that only approximately half of the filtered load can be reabsorbed. Because of this, the kidney serves as the site where the majority of the urea produced by the liver is excreted. However, some circulating urea may passively back diffuse into the gut, where it is acted on by bacterial ureases to again yield ammonia and (CO2?). Some of the ammonia generated is excreted in the form of ammonium ion; the remainder is again reabsorbed to the handled by the liver once more.

EKG Findings Related to Myocardial Infarction


In most infarctions, the EKG will reveal the correct diagnosis. An EKG should be performed immediately on anyone in whom an infarction is even remotely suspected. However, the initial EKG may not always be diagnostic, and the evolution of electrocardiographic changes varies from person to person; therefore, it is necessary to obtain serial cardiograms once the patient is admitted to the hospital. During an acute myocardial infarction, the EKG evolves through three stages: 1) T-wave peaking followed by T-wave inversion, 2) ST-segment elevation, 3) the appearance of new Q waves.

T Wave

With the onset of infarction, the T waves become tall and narrow, a phenomenon called peaking. These peaked T waves are often referred to as hyperacute T waves. Shortly afterward, usually a few hours later, the T waves invert. These T-wave changes reflect myocardial ischemia, the lack of adequate blood flow to the myocardium. Ischemia is potentially reversible: if blood flow is restored or the oxygen demands of the heart are eased, the T waves will revert to normal. On the other hand, if actual myocardial cell death (true infarction) has occurred, T-wave inversion will persist for months to years. T-wave inversion by itself is indicative only of ischemia and is not diagnostic of myocardial infarction. T-wave inversion is a very nonspecific finding. Many things can cause a T wave to flip. One helpful diagnostic feature is that the T waves of myocardial ischemia are inverted symmetrically, whereas in most other circumstances, they are asymmetric, with a gentle downslope and rapid upslope. In patients whose T waves are already inverted, ischemia may cause them to revert to normal, a phenomenon called pseudonormalization. Recognition of pseudonormalization requires comparing the current EKG with a previous tracing. In young persons without any cardiac-related symptoms, T-wave inversion isolated to one geographic region of the heart, particularly one or two midprecordial leads, for example, V3 and V4, is usually a normal variant.

  • Peak and inversion
  • Only reflecting ischemia
  • Symmetrical
  • Pseudonormalization

ST Segment

ST-segment elevation is the second change that occurs acutely in the evolution of an infarction. ST-segment elevation signifies myocardial injury. Injury probably reflects a degree of cellular damage beyond that of mere ischemia, but it, too, is potentially reversible, and in some cases the ST segments may rapidly return to normal. In most instances, however, ST-segment elevation is a reliable sign that true infarction has occurred and that the complete electrocardiographic picture of infarction will evolve unless there is immediate and aggressive therapeutic intervention.

Even in the setting of a true infarction, the ST segments usually return to baseline within a few hours. Persistent ST-segment elevation often indicates the formation of a ventricular aneurysm, a weakening and bulging out of the ventricular wall. Like T-wave inversion, ST-segment elevation can be seen in a number of other conditions in addition to an evolving myocardial infarction. There is even a type of ST-segment elevation that can be seen in normal hearts. This phenomenon has been referred to as early depolarization or J point elevation.

The J point, or junction point, is the place where the ST segment takes off from the QRS complex. J point elevation is very common in young, healthy individuals. The ST segment usually returns to baseline with exercise. J point elevation has long been thought to have no pathologic implications. However, some research has reported a slightly increased risk of death from cardiac causes in patients with J point elevation in the inferior leads. How can the ST-segment elevation of myocardial injury be distinguished from that of J point elevation? With myocardial injury, the elevated ST segment has a distinctive configuration. It is bowed upward and tends to merge imperceptibly with the T wave. In J point elevation, the T wave maintains its independent waveform.

  • Elevation
  • Reflecting true infarction
  • Return to baseline within a few hours
  • J point elevation

Q Waves

The appearance of new Q waves indicates that irreversible myocardial cell death has occurred. The presence of Q waves is diagnostic of myocardial infarction. Q waves usually appear within several hours of the onset of infarction, but in some patients they may take several days to evolve. The ST segment usually has returned to baseline by the time Q waves have appeared. Q waves usually persist for the lifetime of the patient.

Other leads, located some distance from the site of infarction, will see an appear increase in the electrical forces moving toward them. They will record tall positive R waves. These opposing changes seen by distant leads are called reciprocal changes. The concept of reciprocity applies not only to Q waves but also to ST-segment and T-wave changes. Thus, a lead distant from an infarct may record ST-segment depression.

Small Q waves can be seen in the left lateral leads (I, aVL, V5, and V6) and occasionally in the inferior leads (especially II and III) of perfectly normal hearts. These Q waves are caused by the early left-to-right depolarization of the interventricular septum. Pathologic Q waves signifying infarction are wider and deeper. They are often referred to as significant Q waves. The criteria fro significance include: 1) The wave must be greater than 0.04 seconds in duration, 2) the depth of the Q wave must be at least one-third the height of the R wave in the same QRS complex. Because lead aVR occupies a unique position on the frontal plane, it normally has a very deep Q wave. Lead aVR should not be considered when using Q waves to look for possible infarction.