Scott M. Goldman MD, FACS

• Clinical Professor of Surgery, Jefferson Medical College, Philadelphia,
• Pennsylvania
• Chief of Surgery, Main Line Health System, Wynnewood,
• Pennsylvania

Quantitatively the most significant nutrients (macronutrients) fall into three classes: carbohydrates muscle relaxant essential oils buy pletal 100 mg low cost, proteins muscle relaxant without drowsiness buy pletal 100mg with visa, and lipids muscle relaxant antidote purchase pletal amex. The black circles represent glucose units linked by -1 spasms during meditation buy cheapest pletal and pletal,6 bonds at thebranchpoints muscle relaxant and anti inflammatory order pletal discount. Thus to allow absorption of its constituent monosaccharides spasms vs seizures order pletal on line amex, starch must also undergo brush border digestion. At the brush border, straight-chain glucose oligomers can be digested by the hydrolases glucoamylase, sucrase, or isomaltase (see Table 30. All yield free glucose monomers, which can then be absorbed by the mechanisms discussed later. For -limit dextrins, on the other hand, isomaltase activity is critical because it is the only enzyme that can cleave -1,6 bonds that make up the branch points as well as -1,4 bonds. The first takes place in the lumen and is actually initiated in the oral cavity via the activity of salivary amylase, as discussed in Chapter 28. Salivary amylase, however, is not essential for starch digestion, although it may assume greater importance in neonates or patients in whom the output of pancreatic enzymes is impaired by disease. Quantitatively the most significant contributor to the luminal digestion of starch is pancreatic amylase. Thus digestion Uptake of Carbohydrates Water-soluble monosaccharides resulting from digestion must next be transported across the hydrophobic plasma membrane of the enterocyte. Digestion of Proteins Proteins can be hydrolyzed to long peptides simply by virtue of the acidic pH that exists in the gastric lumen. Like acid hydrolysis, the first of these phases takes place in the gastric lumen and is mediated by pepsin, the product of chief cells localized to the gastric glands. When gastric secretion is activated by signals coincident with ingestion of a meal, pepsin is released from the chief cells as the inactive precursor pepsinogen. At acidic pH, this precursor is autocatalytically cleaved to yield the active enzyme. Pepsin is highly specialized to act in the stomach, since it is activated by low pH. The enzyme cleaves proteins at sites of neutral amino acids, with a preference for aromatic or large aliphatic side chains. Because such amino acids occur only relatively infrequently in a given protein, pepsin is not capable of digesting protein fully into a form that can be absorbed by the intestine. Instead it yields a mixture of intact protein, large peptides (the majority), and a limited number of free amino acids. On moving into the small intestine, the partially digested protein encounters the proteases provided in pancreatic juice. Trypsin in turn cleaves all the other protease precursors secreted by the pancreas, thereby resulting in a mixture of enzymes that can almost completely digest the vast majority of dietary proteins. Trypsin is an endopeptidase that cleaves proteins only at internal bonds within the peptide chain rather than releasing individual amino acids from the end of the chain. Trypsin is specific for cleavage at basic amino acids, and such cleavage results in a set of shorter peptides with a basic amino acid at their C-terminus. The two other pancreatic endopeptidases, chymotrypsin and elastase, have a similar mechanism of action but cleave at sites of neutral because fructose transport is not coupled to that of Na+, its uptake is relatively inefficient and can easily be overwhelmed if large quantities of food containing this sugar are ingested. The symptoms that occur from this malabsorption are similar to those experienced by a lactose-intolerant patient who consumes lactose. Protein Assimilation Proteins are also water-soluble polymers that must be digested into their smaller constituents before absorption is possible. Their absorption is more complicated than that of carbohydrates because they contain 20 different amino acids and short oligomers of these amino acids (dipeptides, tripeptides, and perhaps even tetrapeptides) can also be transported by enterocytes. However, some amino acids, termed the essential amino acids, cannot be synthesized by the body either de novo or from other amino acids and thus must be obtained from the diet. The peptides that result from endopeptidase activity are then acted on by pancreatic ectopeptidases. These enzymes cleave single amino acids from the end of a peptide chain, and those present in pancreatic juice are specific for either neutral (carboxypeptidase A) or basic (carboxypeptidase B) amino acids situated at the C-terminus. However, it should be noted that even with the substantial complement of active proteolytic enzymes, some dietary peptides are either relatively or totally resistant to hydrolysis. In particular, peptides containing either proline or glycine are digested very slowly. Fortunately the intestine can take up short peptides in addition to single amino acids. However, some di- and tripeptides may also be transported into the blood in their intact form. In general, amino acid transporters have reasonably broad specificity and usually transport a subset of amino acids. Furthermore, some (but not all) of the amino acid transporters are symporters that carry their substrate amino acids in conjunction with obligatory uptake of Na+. The primary transporter responsible for such uptake is called peptide transporter 1 (PepT1) and is a symporter that transports peptides in conjunction with protons. Amino acids liberated from these peptides that are not required by the enterocyte are in turn exported across the basolateral membrane and enter blood capillaries to be transported to the liver via the portal vein. PepT1 is also of clinical interest because it can mediate the uptake of so-called peptidomimetic drugs, which include a variety of antibiotics as well as cancer chemotherapeutic agents. The mechanisms by which amino acids and peptidomimetic drugs exit the enterocyte are not fully understood but are presumed to involve additional transport proteins. Uptake of Peptides and Amino Acids the body is also endowed with a series of plasma membrane transporters capable of promoting uptake of the watersoluble products of protein digestion. Amino acid transporters are of clinical interest because their absence in a variety of genetic disorders results in diminished ability to transport the relevant amino acid or acids. However, such mutations are often clinically silent, at least from a nutritional standpoint, because the amino acid in question can be assimilated by other transporters with overlapping specificity or in the form of peptides. This does not rule out the possibility of pathology in other organ systems in Lipid Assimilation Lipids, defined as substances that are more soluble in organic solvents than in water, are the third major class of macronutrients making up the human diet. The predominant form of lipid in the human diet is triglyceride, found in oils and other fats. The majority of these triglycerides have long-chain fatty acids (carbon chains > 12 carbons) esterified to the glycerol backbone. Additional lipid is supplied in the form of phospholipids and cholesterol, mostly arising from cell membranes. It is also important to consider that the intestine is presented daily not only with dietary lipid but also with lipid originating from the liver in biliary secretions, as described in more detail in Chapter 32. Indeed, the cholesterol supplied in bile exceeds that provided in the diet on a daily basis in all but the most egg-loving individuals. Finally, though present in only trace amounts, the fat-soluble vitamins (A, D, E, K) are essential nutrients that should be supplied in the diet to avoid disease. These substances are almost entirely insoluble in water and thus require special handling to promote their uptake into the body. Emulsification and Solubilization of Lipids When a fatty meal is ingested, the lipid becomes liquefied at body temperature and floats on the surface of the gastric contents. This would limit the area of the interface between the aqueous and lipid phases of the gastric contents and thus restrict access of enzymes capable of breaking down the lipid to forms that can be absorbed. The mixing action of the stomach churns the dietary lipid into a suspension of fine droplets, which vastly increases the surface area of the lipid phase. Lipid absorption is also facilitated by formation of a micellar solution with the aid of bile acids supplied in biliary secretions. Gastric lipase is released in large quantities from gastric chief cells; it adsorbs to the surface of fat droplets dispersed in the gastric contents and hydrolyzes component triglycerides to diglycerides and free fatty acids. However, little lipid assimilation can take place in the stomach because of the acidic pH of the lumen, which results in protonation of the free fatty acids released by gastric lipase. Lipolysis is also incomplete in the stomach because gastric lipase, despite its optimum catalytic activity at acidic pH, is not capable of hydrolyzing the second position of the triglyceride ester, which means that the molecule cannot be fully broken down into components that can be absorbed into the body. There is also little if any breakdown of cholesterol esters or the esters of fat-soluble vitamins. Indeed, gastric lipolysis is dispensable in healthy individuals because of the marked excess of pancreatic enzymes. Pancreatic juice contains three important lipolytic enzymes that are optimized for activity at neutral pH. This enzyme differs from the stomach enzyme in that it is capable of hydrolyzing both the 1 and 2 positions of triglyceride to yield a large quantity of free fatty acids and monoglycerides. At neutral pH, the head groups of the free fatty acids are charged, and thus these molecules migrate to the surface of the oil droplets. Lipase also displays an apparent paradox in that it is inhibited by bile acids, which also form part of the small intestinal contents. Bile acids adsorb to the surface of the oil droplets and cause lipase to dissociate. However, lipase activity is sustained by an important cofactor, colipase, which is also supplied in pancreatic juice. Colipase is a bridging molecule that binds to bile acids and to lipase; it anchors lipase to the oil droplet even in the presence of bile acids. Pancreatic juice also contains two additional enzymes that are important in fat digestion. The first of these is phospholipase A2, which hydrolyzes phospholipids such as those present in cell membranes. Predictably this enzyme would be quite toxic in the absence of dietary substrates, and thus it is secreted as an inactive pro-form that is activated only when it reaches the small intestine. Furthermore, pancreatic juice contains a relatively nonspecific cholesterol esterase that can break down esters of cholesterol, as its name implies, as well as esters of fatsoluble vitamins and even triglycerides. Interestingly this enzyme requires bile acids for activity (contrast with lipase, discussed earlier), and it is related to an enzyme produced in breast milk that plays an important role in lipolysis in neonates. As lipolysis proceeds, the products are abstracted from the lipid droplet, first into a lamellar (membrane) phase and subsequently into mixed micelles composed of lipolytic products as well as bile acids. Micelles are truly in solution and thus markedly increase lipid solubility in the intestinal contents. This increases the rate at which molecules such as fatty acids diffuse to the absorptive epithelial surface. Nevertheless, given the very large surface area of the small intestine and the appreciable molecular solubility of the products of triglyceride hydrolysis, micelles are not essential for the absorption of triglyceride. Thus patients who have insufficient output of bile acids (caused, for example, by a gallstone that obstructs bile output) do not normally show fat malabsorption. On the other hand, cholesterol and the fat-soluble vitamins are almost totally insoluble in water and accordingly require micelles to be absorbed even after they have been digested. Thus if luminal bile acid concentrations fall below the critical micellar concentration, patients can become deficient in fat-soluble vitamins. Uptake of Lipids and Subsequent Handling the products of fat digestion are believed to be capable of crossing cell membranes readily because of their lipophilicity. However, recent evidence suggests that their uptake may alternatively or additionally be regulated via the activity of specific membrane transporters. Finally, the glycerol backbone of triglycerides may be transported into intestinal epithelial cells by a number of different aquaglyceroporins. Lipids also differ from carbohydrates and proteins in terms of their fate after absorption into the enterocyte. Unlike monosaccharides and amino acids, which leave the enterocyte in molecular form and enter the portal circulation, the products of lipolysis are reesterified in the enterocyte to form triglycerides, phospholipids, and cholesterol esters. Concurrently the enterocyte synthesizes a series of proteins known as apolipoproteins in the rough endoplasmic reticulum. These proteins are then combined with the resynthesized lipids to form a structure known as a chylomicron, which consists of a lipid core (predominantly triglyceride with much less cholesterol, phospholipid, and fat-soluble vitamin esters) coated by the apolipoproteins. The chylomicrons are then exported from the enterocyte by a process of exocytosis. Instead they are taken up into lymphatics in the lamina propria and therefore bypass the portal circulation and, at least for their first pass, the liver. Eventually, chylomicrons in the lymph enter the bloodstream via the thoracic duct and then serve as the vehicle to transport lipids around the body for use by cells in other organs. The only exception to this chylomicron-mediated transport is for medium-chain fatty acids. These acids are relatively water soluble and can also permeate enterocyte tight junctions appreciably, which means that they bypass the intracellular processing steps described earlier and are not packaged into chylomicrons. They therefore enter the portal circulation and are more readily available to other tissues. A diet rich in medium-chain triglycerides may be of particular benefit in patients with inadequate bile acid pools. The fluidity of intestinal contents, especially in the small intestine, is important in allowing the meal to be propelled along the length of the intestine and to permit digested nutrients to diffuse to their site of absorption. In total, these secretions add another 8 L, which means that the intestine is presented with approximately 9 to 10 L of fluid on a daily basis. However, in health only about 2 L of this load is passed to the colon for reabsorption, and eventually only 100 to 200 mL exits in stool. During the postprandial period, such absorption is promoted in the small intestine predominantly via the osmotic effects of nutrient absorption. An osmotic gradient is established across the intestinal epithelium that simultaneously drives movement of water across the tight junctions. Even though net water and electrolyte transport in the small intestine is predominantly absorptive, this does not imply that the tissue fails to participate in electrolyte secretion. Secretion is regulated in response to signals derived from the luminal contents and in response to deformation of the mucosa and intestinal distention. Secretion ensures that the intestinal contents are appropriately fluid while digestion and absorption are ongoing and is important to lubricate the passage of food particles along the length of the intestine. For example, some clinical evidence suggests that constipation and intestinal obstruction, the latter observed in cystic fibrosis, can result when secretion is abnormally low.

In addition to these two patterns muscle relaxant kava buy 50mg pletal with visa, a linear arrangement can result from a traumainduced Koebner phenomenon (an isomorphic response [Table 0 muscle relaxant in surgeries buy generic pletal pills. Linear lesions are frequently seen in acute allergic contact dermatitis due to plants spasms parvon plus generic pletal 100mg otc. The long axis of oval lesions of pityriasis rosea18 and erythema dyschromicum perstans follows these cleavage lines muscle relaxant used for buy cheapest pletal, and this pattern is most obvious on the posterior trunk spasms around heart purchase pletal online from canada. A seborrheic distribution pattern includes the head and neck as well as the upper trunk muscle relaxant xylazine buy line pletal, and it reflects areas rich in sebaceous glands; seborrheic dermatitis, acne vulgaris, and pityriasis versicolor are dermatoses that favor these sites. The term "photodistribution" describes lesions that are accentuated in areas exposed to ultraviolet irradiation, and photodermatoses include polymorphic light eruption, phototoxic drug reactions. Of note, sometimes a disorder will display a combination of distribution patterns; for example, in dermatomyositis, lesions can be both photodistributed and involve extensor surfaces. In addition to differences in the color of inflammatory lesions, individuals with darkly pigmented skin also have an increased frequency of several cutaneous disorders (see section on Color) and certain types of reaction and distribution patterns19. Examples of these reaction patterns include papular eczema and a follicular accentuation of atopic dermatitis and pityriasis versicolor, as well as an annular configuration of seborrheic dermatitis and facial secondary syphilis. An example of a favored distribution pattern is inverse pityriasis rosea in which lesions occur primarily in the axillae and groin rather than on the trunk. Although a sound explanation for these phenomena is not currently available, it is still important to be aware of their occurrence19. Sometimes the distribution is best explained by the phenomenon of locus minoris resistentiae in which certain anatomic sites are more vulnerable than others to a particular disease process20. Examples would be cutaneous infections within a lymphedematous limb and asteatotic eczema within a skin graft site. It is most commonly used to assist in the diagnosis of pigmentary disorders and infectious diseases (Table 0. Temporal Course Central to any medical history, including that of cutaneous disorders, is the temporal course. The patient should be queried as to duration and relative change in intensity or distribution over time. For example, there are some dermatoses that have a cephalocaudal progression over time, such as measles and pityriasis rubra pilaris. Of course, the time course is more prolonged in the latter as compared to the former. The dermatologist is at an advantage because the skin is so accessible, and information provided by the patient can be readily compared to what is seen in the physical examination. With experience, Distribution Stepping back and observing the anatomic distribution pattern of skin lesions can also prove very helpful. However, to complicate matters a bit, there is an "inverse" form of psoriasis in which lesions are present in major body folds, i. Examples of helpful signs include scale (not to be confused with crusts), which often reflects parakeratosis that requires 2 weeks to develop, and intact tense bullae, which are rarely more than a week old. Therefore, if lichenification is present, the lesion has not appeared acutely, despite what the patient may believe. In an otherwise generally healthy patient, there are several diseases whose cutaneous manifestations are often acute in nature, in particular urticaria, morbilliform drug eruption, viral exanthem, acute allergic or irritant contact dermatitis, and pityriasis rosea. This is not to indicate that these diseases necessarily require immediate or emergent management, but rather that they present to the dermatologist abruptly and are distinguished, particularly from neoplasms or chronic dermatoses, by their temporal acuity. Of note, sometimes a more serious and potentially life-threatening cutaneous disease may present with skin findings that can mimic a more common and less serious disorder, especially early on. Finally, although emergencies are unusual in dermatology, there are a few illnesses, particularly those that present with a rash and fever, which are true emergencies and must be recognized promptly and treated appropriately. The next two sections of this introductory chapter focus on the basic principles of dermatopathology and dermoscopy, respectively, and it is important to remember that all the diagnostic techniques (unaided clinical examination, histological examination, dermatoscopic examination) discussed herein are complementary. In other words, synergistic strength and clinicopathologic correlation are achieved when the techniques are used in combination. As a corollary, using any one technique, to the exclusion of the others, may be misleading and potentially result in misdiagnosis. In addition, clinical dermatology represents the "gross macroscopy" of dermatopathology, as clinical examination can be regarded akin to gross examination of biopsy specimens in other organs. Experienced clinicians may anticipate associated histologic findings as they examine a cutaneous lesion or eruption. As a result, a sophisticated differential diagnosis often accompanies a skin biopsy performed by a dermatologist. Moreover, when the microscopic features are clearly delineated in a histopathology report, an experienced dermatologist can utilize clinicopathologic correlation to arrive at a final diagnosis. In a similar fashion, an experienced dermatopathologist can utilize clinical pictures to arrive at a final histopathological diagnosis. The Skin Biopsy In no other field of medicine is the tissue of interest so readily accessible for histologic analysis. As a result, performing a skin biopsy is an integral component of medical decision making in dermatology. A skin biopsy may be performed for a multitude of reasons, including: uncertainty about the clinical diagnosis to investigate a poor response to therapy to exclude or investigate the evolution of one condition into another, or to investigate symptoms in the absence of clinically recognizable disease. Regardless of the rationale for performing a skin biopsy, the securing of appropriate tissue involves more than the mere mechanical procurement. Instead, a multistep process is executed, with forethought, precision and care, in order to maximize diagnostic utility24. Also, because a skin biopsy is often just a small sampling of a larger process, it may not always be representative of the entire disease state. Inappropriate technique or poor tissue handling may limit the diagnostic yield of a skin biopsy; accordingly, clinicians must have an appreciation of the principles of histologic examination. However, this union exists not only because of overlapping subject matter, but because dermatology Site selection Often, the first step in performing a biopsy is to identify an unadulterated primary lesion. Lesions with obfuscating secondary features, such as those resulting from rubbing or traumatic injury. Strongyloidiasis ** ** * not a single site as in cellulitis, necrotizing fasciitis ** more likely in immunocompromised patient *** early on, more serious drug reactions. Immature lesions may not yet manifest characteristic histopathologic changes, and older lesions may be compromised by secondary features. Of course, there are exceptions to this general principle, such as the sampling of early lesions of cutaneous small vessel vasculitis (<24 hours old) or immunobullous diseases, especially when performing direct immunofluorescence. For example, in atrophoderma an incisional biopsy should include both affected and unaffected skin and be sectioned longitudinally, so that subtle differences can be detected (see Ch. In ulcers, nonspecific inflammation of vessels underneath the wound may be misinterpreted as a primary vasculitis, but in a biopsy specimen that includes the surrounding skin, the "vasculitis" disappears a few millimeters away from the ulcer. Ultimately, selection of a proper biopsy site will always be influenced by knowledge of the suspected underlying pathology. Evidence suggests that when properly performed, the diagnostic value of a deep shave may rival that of an incisional/excisional procedure25. In this regard, curettage is less desirable for diagnostic purposes, and it is not appropriate for pigmented lesions that are suspicious for melanoma or for neoplasms of uncertain etiology. For optimal results, the technique employed must encapture tissue from the level of the skin or subcutaneous tissue where the pathologic changes are anticipated, while simultaneously balancing concerns of cosmesis and morbidity. For example, if panniculitis is suspected, a shave would not provide the appropriate tissue to establish or refute such a diagnosis (Table 0. If the sampled lesion can be contained in the punch, then the concern regarding sampling error is rendered moot. It is controversial as to whether punch biopsies, even if performed in a "stacked" fashion, can provide adequate tissue for assessment of deeply infiltrating tumors or panniculitis. Studies suggest that partial punch samplings of melanocytic lesions can lead to misdiagnosis or to erroneous staging and therefore should not be performed26. Handling of the specimen after biopsy Skin specimens must be handled carefully upon extirpation. For example, excessive lateral pressure by forceps on small punch biopsy specimens can distort cellular infiltrates, particularly lymphomas and Merkel cell carcinoma, creating so-called "crush" artifact. These two cell types are also subject to dessication artifact when the biopsy specimen is placed onto gauze rather than into formalin solution. Fixation in paraformaldehyde and glutaraldehyde in a cacodylate buffer is required for electron microscopy. To obtain the most accurate histopathologic assessment, all biopsy specimens sent to a dermatopathologist should be accompanied by relevant clinical data such as: age and sex of the patient, anatomic site(s) involved, pertinent physical findings, and a suspected clinical differential diagnosis. Prior treatments that might impact upon the histologic findings should be disclosed. Inclusion of drawings or clinical photographs may prove useful, especially in difficult or complex cases. It is important to remember that even though an entity has lichenoid features under the microscope. Also, some degree of lichenoid inflammation may be associated with a variety of benign and malignant neoplasms, such as lichenoid keratoses and melanoma, respectively. In these instances, the lichenoid inflammation represents an immunological response to the tumor. The algorithmic approach of pattern analysis is reproducible, and it minimizes subjectivity. However, the method has two important limitations, namely, it is based on artificial disease categories and it cannot include every possible pattern. Furthermore, while pattern analysis clearly narrows the differential diagnosis, a final assessment may require clinical correlation and/or ancillary laboratory testing, imaging, or genetic testing29. Also, the histopathologic appearance of skin disease may vary based upon the temporal course. The histologic findings may be altered by previous treatment(s) or by secondary changes such as rubbing, scratching, or infection. Lastly, pattern analysis is not only applicable to inflammatory skin diseases, but is also used for neoplastic processes. Spongiosis (intercellular edema) is a nonspecific morphologic alteration that is observed in a variety of skin conditions. The degree of spongiosis may vary from microscopic foci to grossly visible vesicles or intraepidermal bullae. There is often associated exocytosis of inflammatory cells, with migration from the vasculature into the epidermis. Spongiotic dermatoses may be further subdivided into acute, subacute and chronic forms. Parakeratosis, a histologic equivalent of scale, often overlies subacute spongiotic dermatitis. In chronic spongiotic dermatitis, the spongiosis may be more difficult to appreciate, being instead overshadowed by epidermal acanthosis (thickening of the epidermis). Also, a predominance of certain inflammatory cells in association with spongiosis, such as eosinophils or neutrophils, may serve as a clue to a hypersensitivity component or infectious process, respectively. Lastly, it is important to recognize that multiple cutaneous disorders with eczematous features, such as allergic contact dermatitis, atopic dermatitis, nummular dermatitis and seborrheic dermatitis, may have histologic evidence of spongiosis, but this pattern is not exclusive to those diseases. Ten patterns defined Over the past several decades, different classification schema based upon pattern analysis have emerged. The number of patterns in any schema has varied from 9 to 28 or more, but in this introductory chapter, 10 major patterns will be discussed. Psoriasiform dermatoses can be further subdivided into those diseases that are exclusively psoriasiform and those that are associated with another pattern. Pseudoepitheliomatous hyperplasia represents a related, but irregular, hyperplasia of the epidermis and/or adnexal structures. It may Psoriasiform dermatitis Basic Principles of Dermatology 15 lesion (excisional) via a scalpel, using standard surgical techniques (see Ch. Optimal biopsy techniques based upon the suspected cutaneous disease are outlined in Table 0. Traditionally, perivascular dermatitis has been subdivided into "superficial" and "superficial and deep" variants, and while this division has some diagnostic value, considerable overlap exists. In addition, inflammatory skin diseases can exhibit a spectrum of findings, depending in part upon severity, as well as the duration of an individual lesion (acute vs chronic). There are disorders without detectable changes within the epidermis, such as deep gyrate erythemas (see Ch. As with spongiotic dermatitis, psoriasiform dermatitis is a histologic concept, not a specific clinical diagnosis, and its presence mandates consideration of a variety of skin diseases that share this particular constellation of histopathologic findings. Vesiculobullous and pustular dermatoses the concept of intraepidermal vesiculation due to spongiosis has been addressed above, but other disease mechanisms may lead to formation of intraepidermal vesicles or bullae. For example, superficial (subcorneal) acantholysis may favor pemphigus foliaceus, while acantholysis within the deeper portion of the epidermis is more characteristic of pemphigus vulgaris. Ballooning degeneration refers to intracellular edema in response to cytotoxic events. When ballooning is severe, keratinocytes rupture, resulting in reticular degeneration and epidermal necrosis. Pustule formation (the intraepidermal accumulation of neutrophils) may be seen in a variety of infectious and non-infectious skin diseases. In a resolving pustule, the neutrophils or their remnants may even appear within a scale-crust in the cornified layer.

However muscle relaxant and painkiller buy pletal 50mg without a prescription, increasing the diameter also increases the surface area of the plasma membrane over which inner negative and outer positive charges are held to each other spasms medication buy pletal with a mastercard. Discharging this increased capacitance tends to slow conduction and mitigate the increase in conduction velocity gained by increasing diameter muscle relaxant on cns order pletal 100 mg online. Myelination Greatly Increases Conduction Velocity In vertebrates spasms 1983 dvd generic pletal 100 mg without prescription, many nerve fibers are coated with myelin muscle relaxant while breastfeeding purchase 50mg pletal mastercard, and such fibers are said to be myelinated muscle relaxant rocuronium buy pletal. The myelin sheath consists of several to more than 100 layers of glial cell plasma membrane. For all but the axons of smallest diameter, a myelinated axon has much greater conduction velocity than does an unmyelinated fiber of the same caliber because the myelin sheath increases the effective membrane resistance of the axon, decreases the capacitance of the axon membrane, and limits the generation of action potentials to the nodes of Ranvier. Because the many wrappings of membrane around the axon increase the effective membrane resistance rm/ra and the length constant are much greater. The increased membrane resistance means that less current is lost through the membrane per length of axon, and thus the amplitude of a conducted signal decreases less with distance along the axon and needs to be regenerated (by opening of Na+ channels) less often. In addition, the thicker myelin-wrapped membrane results in a much larger separation of charges across it than exists across the bare membrane of an axon, so that the charges across it are much less tightly bound to each other. This is analogous to when the plates of a capacitor are moved apart and reduce its capacitance. Because the effect of membrane capacitance is to slow the rate at which the membrane potential can be changed, the reduced capacitance of myelinated axons means that the depolarization occurs more rapidly. In myelinated axons, the Na+ channels that bring about generation of an action potential are highly concentrated Action Potential Conduction Velocity Is Correlated With Axon Diameter the speed of conduction in a nerve fiber is determined by the electrical properties of the cytoplasm and the plasma membrane that surrounds the fiber, as well as by its geometry. In contrast, the action potential slows as it crosses each node (steep sloped line segments). Functional Consequences of Myelination the functional consequences of myelination can be highlighted by a comparison of squid and mammalian axons. Although human nerve fibers are much smaller in diameter than squid giant axons, human axons conduct at comparable or even faster speeds because of myelination. This is certainly one factor that enabled the evolution of mammalian nervous systems with their huge numbers of neurons that are able to generate everything from fast reflexes to efficient and complex mental processing. At the initial time (A and C), an action potential is being generated at the left side of eachaxon. When a stimulus activates a sensory receptor, it initiates a process called sensory transduction by which information about the stimulus. In order for this to happen, the stimulus must produce receptor potentials that are large enough to change the spiking levels of one or more primary afferent fibers that are connected to the receptor. Weaker intensities of stimulation can produce subthreshold receptor potentials, but such stimuli do not change the activity of central sensory neurons and thus are not detected. Thus stimulus threshold is defined as the weakest stimulus that can be reliably detected. Environmental events that evoke sensory transduction can be mechanical, thermal, chemical, or other forms of energy. Note the increased number of small-diameter fibers and the absence of A fibers in the cutaneous nerve. For example, humans cannot sense electrical or magnetic fields, but other animals can sense such stimuli. The transduction process varies with the type of environmental stimulus being detected. Binding of the chemical stimulant to the receptor molecule opens an ion channel, which enables the influx of an ionic current that depolarizes the sensory receptor cell. In this case, an influx of current occurs in the dark; the current ceases when light is applied. This distortion causes inward current flow at the end of the axon and longitudinal and outward current flow along the neighboring parts of the axon. In this situation, transduction occurs in one cell, but spikes are generated in other cells that are synaptically connected to it (see Chapter 6). For example, in the cochlea, the primary afferent fibers get synaptic input from mechanoreceptive hair cells. Sensory transduction in such sense organs can be more complex in this arrangement. In photoreceptors, moreover, the receptor potential is hyperpolarizing, as mentioned earlier, and interruption of the dark current is the signal event. Although the mechanisms of sensory transduction vary between stimulus types, the end result is typically a receptor potential in either the receptor cell or the primary afferent neuron. Receptive Fields the relationship between the location of a stimulus and activation of particular sensory neurons is a major theme in the field of sensory physiology. The receptive field of a sensory neuron is the region that, when stimulated, affects the activity of that neuron. For example, a sensory receptor might be activated by indentation of only a small area of skin. The location of the receptive field is determined by the location of the sensory transduction apparatus responsible for signaling information about the stimulus to the sensory neuron. However, a central sensory neuron can have either an excitatory or an inhibitory receptive field or, indeed, a complex receptive field that includes areas that excite it and areas that inhibit it. This is accomplished primarily through action potentials, which propagate down the axon to the presynaptic terminals and cause neurotransmitter release, signaling the postsynaptic cells. As already explained, the regenerative nature of action potentials allows them to carry signals regardless of the length of the axon, whereas local signals, such as receptor or synaptic potentials (see Chapter 6), decay with distance and are therefore not suitable for this purpose. The tradeoff, however, is that the all-or-none nature of action potentials means that their shape and size do not generally convey information in the way gradations of local potentials do. Instead, the variations in the rate or timing of action potentials appear to be used primarily as the "codes" for transmission of information between neurons. Rate coding refers to information being coded in the firing rate of a neuron, where firing rate is defined as the number of spikes fired per unit time, usually expressed as spikes/second, also called hertz (Hz). For example, the force of a mechanical stimulus to the skin can be encoded in the firing rate of the primary afferent neuron that innervates the skin; the greater the force applied to the skin, the larger the resulting receptor potential in the primary afferent neuron will be and, as a consequence, the faster the rate of action potentials triggered by the receptor potential will be. Research has shown many neurons employ rate coding in the sense that the firing rate of a neuron shows a consistent relationship to particular parameters of sensory stimuli, upcoming movements, or other aspects of behavior. The lower limit of the firing range is, of course, 0 Hz, as neurons cannot fire at negative rates. Timing, or temporal coding, refers to spike codes in which the specific timing of spikes rather than the overall firing rate encodes information. One often-studied version of temporal coding is the synchronization of spikes across neurons. Synchronization of neuronal spiking has been shown to occur in a number of brain regions and has been related to function in a number of instances. An advantage of temporal coding is that it can convey information more quickly than can rate coding, inasmuch as it does not require averaging, which takes time. Moreover, rate coding and temporal coding are not mutually exclusive, inasmuch as overall firing rates can be varied while synchronous events are superimposed. Such multiplexing of codes may increase the information transmission capacity of neuronal pathways. The encoded information is an abstraction based on (1) which sensory receptors are activated, (2) the responses of sensory receptors to the stimulus, and (3) information processing in the sensory pathway. Some stimulus parameters that can be encoded include sensory modality, location, intensity, frequency, and duration. Other aspects of stimuli that are encoded are described in relation to particular sensory systems in later chapters. For example, sustained mechanical stimuli applied to the skin result in sensations of touch or pressure, and transient mechanical stimuli may evoke sensations of flutter or vibration. Vision, audition, taste, and smell are examples of noncutaneous sensory modalities. The specific sensory receptors define the normal energy associated with the modality of a sensory pathway. For example, the visual pathway includes photoreceptors, neurons in the retina, the lateral geniculate nucleus of the thalamus, and the visual areas of the cerebral cortex (see Chapter 8). Thus neurons of the visual system can be regarded as a labeled line, which, when activated by whatever means, results in a visual sensation. The location of a stimulus is signaled by activation of the particular population of sensory neurons whose receptive fields are affected by the stimulus. For example, a somatotopic map is formed by arrays of neurons in the somatosensory cortex that receive information from corresponding locations on the body surface (see Chapter 7). In the visual system, points on the retina are represented by neuronal arrays that form retinotopic maps (see Chapter 8). Because action potentials have a uniform magnitude, some sensory neurons encode intensity by their frequency of discharge (rate coding). The relationship between stimulus intensity and response can be plotted as a stimulus-response function. For many sensory neurons, the stimulus-response function approximates an exponential curve with an exponent that can be less than, equal to , or greater than 1. Stimulusresponse functions with fractional exponents characterize many mechanoreceptors. Thermoreceptors, which detect changes in temperature, have linear stimulus-response curves (exponent of 1). Nociceptors, which detect painful stimuli, may have linear or positively accelerating stimulus-response functions. The positively accelerating stimulus-response functions of nociceptors help explain the urgency that is experienced as the pain sensation increases. Another way in which stimulus intensity is encoded is according to the number of sensory receptors that are activated. A stimulus at the threshold for perception may activate only one or only a few primary afferent neurons of an appropriate class, whereas a strong stimulus of the same type may recruit many similar receptors. Central sensory neurons that receive input from sensory receptors of this particular class would be more powerfully affected as more primary afferent neurons discharge. Greater activity in central sensory neurons may be perceived as a stronger stimulus. Stimuli of different intensities may also activate different sets of sensory receptors. However, mechanoreceptors with different thresholds can overcome this problem: Those with low thresholds can signal over a range of low input intensities, whereas others with higher thresholds can signal higher input intensities. In addition, still higher intensities might recruit nociceptors, and that will also change the perceived quality of the stimulus. Stimulus frequency can sometimes be encoded by action potentials whose interspike intervals correspond exactly to the intervals between stimuli. AtoCarethedischargesof primary afferent fibersduringa ramp-and-hold stimulus shown inD. However, this mechanism is limited by the firing rate limits of neurons as discussed earlier. Other candidate codes depend on the spatiotemporal patterns of firing across populations of neurons. The duration and the onset and offset of events are encoded by different populations of sensory neurons. For example, slowly adapting receptors in the skin produce a repetitive discharge throughout a prolonged stimulus. However, rapidly adapting receptors produce spikes at the onset (or offset) of the same stimulus. The functional implication is that different temporal features of a stimulus can be signaled by receptors with different adaptation rates. An ion channel typically has two states: high conductance (open) and zero conductance (closed). Different regions of an ion channel protein act as gates to open and close the channel. For a voltage-dependent channel, the fraction of time that the channel spends in the open state is a function of the transmembrane potential difference. The action potential is generated by the rapid opening and subsequent voltage inactivation of voltage-dependent Na+ channels and by the delayed opening and closing of voltage-dependent K+ channels. The absolute and relative refractory periods result from voltage inactivation of Na+ channels and the delayed closure of K+ channels in response to membrane repolarization. Subthreshold signals and action potentials are conducted along the length of a cell by local circuit currents. Subthreshold signals are conducted only electrotonically, and thus decrease with distance. The action potential is propagated rather than merely conducted; it is regenerated as it moves along the axon. In this way, an action potential retains the same size and shape as it travels along the axon. A large-diameter axon has greater propagation velocity because increased axon diameter lowers axial resistance and allows greater amounts of current to flow farther down the axon. Myelination dramatically increases the conduction velocity of a nerve axon because myelin increases membrane resistance and lowers membrane capacitance. Myelination allows an action potential to be conducted very rapidly from one node of Ranvier to the next.

Biliary Secretion Another important digestive juice that is mixed with the meal in the small intestinal lumen is bile muscle relaxers to treat addiction order pletal overnight. Bile is produced by the liver muscle relaxant homeopathy buy pletal 50 mg with mastercard, and the mechanisms that are involved muscle relaxant homeopathy purchase pletal without prescription, as well as the specific constituents spasms early pregnancy discount 50 mg pletal fast delivery, will be discussed in greater detail in Chapter 32 when we address the transport and metabolic functions of the liver spasms in lower back buy pletal from india. However muscle relaxant vs anti-inflammatory order pletal in united states online, for purposes of the current discussion, bile is a secretion that serves to aid in digestion and absorption of lipids. Bile flowing out of the liver is stored and concentrated in the gallbladder until it is released in response to ingestion of a meal. When considering the small intestinal phase of meal assimilation, the bile constituents we are most concerned with are the bile acids. These form structures known as micelles that serve to shield the hydrophobic products of lipid digestion from the aqueous environment of the lumen. Bile acids are in essence biological detergents, and large quantities are needed on a daily basis for optimal lipid absorption-as much as 1 to 2 g/day. We will consider the processes involved in assimilation of each of these nutrients in turn, beginning with carbohydrates. Carbohydrate digestion occurs in two phases: in the lumen of the intestine and then on the surface of enterocytes in a process known as brush border digestion. The latter is important in generating simple absorbable sugars only at the point where they can be absorbed. This may therefore limit their exposure to the small number of bacteria present in the small intestinal lumen that might otherwise use these sugars as nutrients. Passive Terminal Ileum Portal vein asbt Active Digestion of Carbohydrates Dietary carbohydrates are composed of several different molecular classes. Starch, the first of these, is a mixture of both straight- and branched-chain polymers of glucose. Starch is a particularly important source of calories, especially in developing countries, and is found predominantly in cereal products. Disaccharides are a second class of carbohydrate nutrients that includes sucrose (consisting of glucose and fructose) and lactose (consisting of glucose and galactose), the latter being an important caloric source in infants. It is, however, a key principle that the intestine can absorb only monosaccharides and not larger carbohydrates. Finally, many food items of vegetable origin contain dietary fiber, which consists of carbohydrate polymers that cannot be digested by human enzymes. These polymers are instead digested by bacteria present largely in the colonic lumen (see Chapter 31), thereby allowing salvage of their caloric value. Dietary disaccharides are hydrolyzed to their component monomers directly on the surface of small intestinal epithelial cells by brush border digestion, mediated by a family of membrane-bound, heavily glycosylated hydrolytic enzymes synthesized by small intestinal epithelial cells. Brush border hydrolases critical to the digestion of dietary carbohydrates include sucrase, isomaltase, glucoamylase, and lactase (Table 30. Glycosylation of these hydrolases is believed to protect them to some extent from degradation by luminal pancreatic proteases. However, between meals the hydrolases are degraded and must therefore be resynthesized by the enterocyte to participate in digesting the next carbohydrate meal. Sucrase/isomaltase and glucoamylase are synthesized in quantities that are in excess of requirements, and assimilation of their products into the body is limited by the availability of specific membrane transporters for these monosaccharides (see Uptake of Carbohydrates). The relative paucity of lactase means that digestion of lactose, rather than uptake of the resulting products, is rate limiting for assimilation. If lactase levels fall below a certain threshold, the disease of lactose intolerance results. Active uptake of conjugated bile acids occurs via the apical sodium-dependent bile acidtransporter(asbt). However, when the meal contents reach the terminal ileum, after lipid absorption has been completed, the conjugated bile acids are reabsorbed by a symporter, the apical Na+-dependent bile acid transporter (asbt), that specifically takes up conjugated bile acids in association with sodium ions. The net effect is to cycle the majority of the bile acid pool between the liver and intestine on a daily basis, coincident with signals arising in the postprandial period. Bile acids also exert biological actions beyond their role as detergents by binding to both cell surface and nuclear receptors in a variety of cell types throughout the body. In this way they regulate their own synthesis as well as other metabolic processes. Carbohydrate Assimilation the most important physiological function of the small intestine is to take up the products of digestion of ingested nutrients. Bicarbonate secretion protects the epithelium, particularly in the most proximal portions of the duodenum immediately downstream from the pylorus, from damage caused by acid and pepsin. Motor Patterns of the Small Intestine the smooth muscle layers in the small intestine produce motility patterns that mix chyme with the various digestive secretions and propel fluid along the length of the intestine so that nutrients (along with water and electrolytes) can be absorbed. Motor patterns of the small intestine during the postprandial period are directed predominantly toward mixing and consist largely of segmenting and retropulsive contractions that retard the meal while digestion is still ongoing. In general these substances are taken up from the luminal contents via the activity of specific transporters. This makes sense as a mechanism to match nutrient delivery to the available capacity to digest and absorb the components of the meal. After the meal has been digested and absorbed, it is desirable to clear any undigested residues from the lumen to prepare the intestine for the next meal. Like segmentation, peristalsis originates when action potentials generated by intrinsic innervation are superimposed on sites of cellular depolarization dictated by the basic electrical rhythm. The dotted lines indicate where contractions will occur next; the arrows depict the direction of movement of the intestinal contents. The pylorus and ileocecal valve open fully during this phase, so even large undigested items can eventually pass from the body. Migrating motor complexes in the duodenum and jejunum as recorded from a fasting human subject by manometry. D1, D2, J1, J2, and J3 indicate sequential recording points along the length of the duodenum and jejunum. On leaving the stomach, the meal enters the small intestine, which consists (sequentially) of the duodenum, jejunum, and ileum. The principal function of the small intestine is to digest and absorb the nutrients contained in the meal. The presence of chyme in the duodenum retards additional gastric emptying, thus helping match nutrient delivery to the ability of the small intestine to digest and absorb such substances. Digestion and absorption in the small intestine are aided by two digestive juices derived from the pancreas (pancreatic juice) and liver (bile). These secretions are triggered by hormonal and neural signals activated by the presence of the meal in the small intestine. Pancreatic secretions arise from the acini and contain various proteins capable of digesting the meal or acting as important cofactors. The secretion is diluted and alkalinized as it passes through the pancreatic ducts. Bile is produced by the liver and stored in the gallbladder until needed in the postprandial period. Bile acids, important components of bile, are biological detergents that solubilize the products of lipid digestion. Carbohydrates and proteins, water-soluble macromolecules, are digested and absorbed by broadly analogous mechanisms. Lipids, the third macronutrient, require special mechanisms to transfer the products of lipolysis to the epithelial surface where they can be absorbed. The small intestine also absorbs fat- and water-soluble vitamins, as well as minerals such as calcium, magnesium, and iron. The small intestine transfers large volumes of fluid into and out of the lumen on a daily basis to facilitate digestion and absorption of nutrients, driven by active transport of ions and other electrolytes. The motor patterns of the small intestine vary depending on whether a meal has been ingested. Immediately after a meal, motility is directed to retaining the meal in the small intestine, mixing it with digestive juices, and providing sufficient time for absorption of nutrients. During fasting, a "housekeeper" complex of intense contractions (the migrating motor complex) sweeps periodically along the length of the stomach and small intestine to clear them of undigested residues. What are the structures of the anatomy of the colon and rectum, and what is the role of the large intestine in storing and desiccating the residues of a meal What are the mechanisms that provide for defecation, and how it can be delayed until convenient In fulfilling these functions, the large intestine uses characteristic motility patterns and expresses transport mechanisms that drive the absorption of fluid, electrolytes, and other solutes from the stool. The large intestine also contains a unique biological ecosystem known as the microbiota, consisting of many trillions of commensal bacteria and other microorganisms that engage in a lifelong symbiotic relationship with their human host. These microorganisms can metabolize components of the meal that are not digested by host enzymes and make their products available to the body via a process known as fermentation. Colonic bacteria also metabolize other endogenous substances such as bile acids and bilirubin, thereby influencing their disposition. There is emerging evidence that the colonic microbiota is critically involved in promoting development of the normal colonic epithelium and in stimulating its differentiated functions. In addition the microbiota can detoxify xenobiotics (substances originating outside the body, such as drugs) and protect the colonic epithelium from infection by invasive pathogens. For example, when the stomach is filled with freshly masticated food, the presence of the meal triggers a long reflex arc that results in increased colonic motility (the gastrocolic reflex) and eventually evacuation of the colonic contents to make way for the residues of the next meal. Similarly the presence of luminal contents in the colon causes release of both endocrine and neurocrine mediators that slow propulsive motility and decrease electrolyte secretion in the small intestine. Signals That Regulate Colonic Function the colon is regulated primarily, though not exclusively, by neural pathways. Colonic motility is influenced by local reflexes that are generated by filling of the lumen, thereby initiating distention and the activation of stretch receptors. Distention of the stomach activates a generalized increase in colonic motility and mass movement of fecal material, as described in more detail later. Similarly the orthocolic reflex is activated on rising from bed and promotes a morning urge to defecate in many individuals. The colon is relatively poorly supplied with cells that release bioactive peptides and other regulatory factors. Patterns of Colonic Motility To appreciate colonic motility the functional anatomy of the colonic musculature will be reviewed first, followed by a discussion of the regulation of colonic motility. Similarly the colonic mucosa is surrounded by continuous layers of circular muscle that can occlude the lumen. Indeed, at intervals the circular muscle contracts to divide the colon into segments called haustra. These latter muscles are distinctive because they maintain a significant level of basal tone and can be contracted further either voluntarily or reflexively when abdominal pressure increases abruptly. Three nonoverlapping bands of longitudinal muscle known as the taeniae coli extend along the length of the colon. Although the circular and longitudinal muscle layers of the colon are electrically coupled, this process is less efficient than in the small intestine. Thus propulsive motility in the colon is less effective than in the small intestine. Activity of the enteric nervous system also provides for the segmenting contractions that form the haustra. Contents can be moved back and forward between haustra, which is a means of retarding passage of the colonic contents and maximizing their contact time with the epithelium. In contrast, when rapid propulsion is called for, the contractions forming the haustra relax and the contour of the colon is smoothened. The rectum lacks circular muscle and is surrounded only by longitudinal muscle fibers. Muscular contractions also form functional "valves" in the rectum that retard movement of feces and are important in delaying the loss of feces until it is convenient, at least in adults. The rectum in turn joins the anal canal, distinguished by the fact that it is surrounded not only by smooth muscle but also by striated (skeletal) muscle. The combination of these muscle layers functionally accounts for two key sphincters that control evacuation of solid waste and flatus from the body. The internal anal sphincter is composed of a thickened band Contraction of the smooth muscle layers in the proximal part of the colon is stimulated by vagal input as well as by the enteric nervous system. On the other hand, the remainder of the colon is innervated by the pelvic nerves, which also control the caliber of the internal anal sphincter. Voluntary input from the spinal cord via branches of the pudendal nerves regulates contraction of the external anal sphincter and muscles of the pelvic floor. Colonic Motility Responses Consistent with its primary function, the two predominant motility patterns of the large intestine are directed not to propulsion of the colonic contents but rather to mixing of the contents and retarding their movement, thereby providing them with ample time in contact with the epithelium. The first is referred to as short-duration contractions, which are designed to provide for mixing. These contractions originate in the circular muscle and are stationary pressure waves that persist for 8 seconds on average. Long-duration contractions, in contrast, are produced by the taeniae coli, last for 20 to 60 seconds, and may propagate over short distances. Both motility patterns are thought to originate largely in response to local conditions such as distention. Note that the basal electrical rhythm that governs the rate and origination sites of smooth muscle contraction in the small intestine does not traverse the ileocecal valve to continue into the colon. On the other hand, probably as a result of both local influences and long reflex arcs, approximately 10 times per day in healthy individuals the colon engages in a motility pattern that is of high intensity and sweeps along the length of the large intestine from the cecum to the rectum. Such contractions, called high-amplitude propagating contractions, move exclusively in an aboral direction and are designed to clear the colon of its contents. However, although such a motility pattern can clearly be associated with defecation, it does not necessarily result in defecation for reasons discussed later. It is also important to note that there is considerable variability among individuals with respect to the rate at which colonic contents are transported from the cecum to the rectum.

Chenodeoxycholic acid is also converted by bacterial enzymes to form lithocholic acid spasms behind knee purchase pletal 50 mg with mastercard, which is relatively cytotoxic spasms under sternum discount pletal 50 mg on-line. Collectively these three products of bacterial metabolism are referred to as secondary bile acids spasms of the esophagus discount pletal 50mg with mastercard. These molecules are conjugated with either glycine or taurine muscle relaxant powder buy pletal with paypal, which significantly depresses their pKa spasms ms 100mg pletal mastercard. The result is that conjugated bile acids are almost totally ionized at the pH prevailing in the small intestinal lumen and thus cannot passively traverse cell membranes spasms 5 month old baby generic pletal 100mg mastercard. Consequently the conjugated bile acids are retained in the intestinal lumen until they are actively absorbed in the terminal ileum via the apical sodium-dependent bile salt transporter (asbt). Conjugated bile acids that escape this uptake step are deconjugated by bacterial enzymes in the colon, and the resulting unconjugated forms are passively reabsorbed across the colonic epithelium because they are no longer charged. Hepatic Aspects of Enterohepatic Circulation of Bile Acids Bile acids assist in digestion and absorption of lipids by acting as detergents rather than enzymes, and thus a significant mass of these molecules is required to solubilize all dietary lipids. Via the enterohepatic circulation, actively reabsorbed conjugated bile acids travel through the portal blood back to the hepatocyte, where they are efficiently taken up by basolateral transporters that may be Na+ dependent or independent (see Table 32. Similarly, bile acids that are deconjugated in the colon also return to the hepatocyte, where they are reconjugated to be secreted into bile. In this way a pool of circulating primary and secondary Bile Acid Synthesis Bile acids are produced by hepatocytes as end products of cholesterol metabolism. The only exception to this rule is lithocholic acid, which is preferentially sulfated in the hepatocyte rather than being conjugated with glycine or taurine. The majority of the sulfate conjugates are lost from the body after each meal because they are not substrates for asbt, thereby avoiding accumulation of a potentially toxic molecule. Some comment should also be made with respect to the role of bile acids in whole-body cholesterol homeostasis. Cholesterol can be excreted in two forms, either as the native molecule or after its conversion to bile acids. The latter account for up to a third of the cholesterol excreted per day despite enterohepatic recycling. Thus one strategy for treating hypercholesterolemia is to interrupt the enterohepatic circulation of bile acids, which drives increased conversion of cholesterol to bile acids; the bile acids are then lost from the body in feces. Other Bile Constituents As noted earlier, bile also contains cholesterol and phosphatidylcholine. The bile acid secretion rate normally averages 30g/24h, whereas the synthesis rate averages 0. The pairs of vertical and horizontal dotted lines depict the normal range for bile acid secretion and synthesis, respectively. Finally, conjugated bilirubin, which is water soluble, and a variety of additional organic anions and cations formed from endogenous metabolites and xenobiotics are secreted into bile across the apical membrane of the hepatocyte. Flow of bile is thereby increased during the postprandial period when bile acids are needed to aid in assimilation of lipid. However, in the period between meals, outflow is blocked by constriction of the sphincter of Oddi, and thus bile is redirected to the gallbladder. Any additional bile acid monomers that become available as a result of concentration are thus immediately incorporated into existing mixed micelles. This also reduces to some extent the risk that cholesterol will precipitate from bile. Prolonged storage of bile increases the chance that nucleation can occur, thus making a good case for never skipping breakfast and perhaps explaining why gallstone disease is relatively prevalent in humans. In addition, intrinsic neural reflexes and vagal pathways, some of which themselves are stimulated by the ability of cholecystokinin to bind to vagal afferents, also contribute to gallbladder contractility. The net result is ejection of a concentrated bolus of bile into the duodenal lumen, where the constituent mixed micelles can aid in lipid uptake. Then, when no longer needed, the bile acids are reclaimed and reenter the enterohepatic circulation to begin the cycle again. However, the other components of bile are largely lost in stool, thus providing for their excretion from the body. Bilirubin Formation and Excretion by the Liver the liver is also important for excretion of bilirubin, which is a metabolite of heme that is potentially toxic to the body. Bilirubin is an antioxidant and also serves as a way to eliminate the excess heme released from the hemoglobin of senescent red blood cells. Indeed, red blood cells account for 80% of bilirubin production, with the remainder coming from additional heme-containing proteins in other tissues such as skeletal muscle and the liver. Bilirubin can cross the blood-brain barrier and, if present in excessive levels, results in brain dysfunction secondary to neuronal cell death and the activation of astrocytes and microglia; it can be fatal if left untreated. Bilirubin and its metabolites are also notable for the fact that they provide color to bile, feces, and to a lesser extent urine. By the same token, when bilirubin accumulates in the circulation as a result of liver disease, it is responsible for the common symptom of jaundice, or yellowing of the skin and conjunctiva. The enzyme heme oxygenase that is present in these cells liberates iron from the heme molecule and produces the green pigment biliverdin. Because bilirubin is essentially insoluble in aqueous solutions at neutral pH, it is transported through the bloodstream bound to albumin. In the microsomal compartment, bilirubin is then conjugated with one or two molecules of glucuronic acid to enhance its aqueous solubility. In both cases, bilirubin conjugates are formed in the liver, but with no means of exit they regurgitate back into plasma for urinary excretion. Notably the conjugated forms of bilirubin cannot be reabsorbed from the intestine, thereby ensuring they can be excreted. However, transport of bilirubin across the hepatocyte (and indeed its initial uptake from the bloodstream) is relatively inefficient, so some conjugated and unconjugated bilirubin is present in plasma even under normal conditions. Both circulate bound to albumin, but the conjugated form is bound more loosely and thus can enter the urine. In the colon, bilirubin conjugates are deconjugated by bacterial enzymes, whereupon the bilirubin liberated is metabolized by bacteria to yield urobilinogen, which is reabsorbed, and urobilins and stercobilins, which are excreted. Absorbed urobilinogen in turn can be taken up by hepatocytes and reconjugated, thus giving the molecule yet another chance to be excreted. Measurement of bilirubin in plasma, as well as assessment of whether it is unconjugated or conjugated, is an important tool in the evaluation of liver disease. Conjugated bilirubinemia on the other hand is characterized by the presence of bilirubin in urine, to which it imparts a dark coloration. The liver is a critical contributor to prevention of ammonia accumulation in the circulation, which is important because like bilirubin, ammonia is toxic to the central nervous system. However, the remainder of the ammonia generated crosses the colonic epithelium passively and is transported to the liver via the portal circulation. A small amount of ammonia (10%) is derived from deamination of amino acids in the liver, by metabolic processes in muscle cells, and via release of glutamine from senescent red blood cells. As just noted, ammonia is a small neutral molecule that readily crosses cell membranes without the benefit of a specific transporter, although some membrane proteins transport ammonia, including certain aquaporins. In chronic liver disease, patients may experience a gradual decline in mental function that reflects the action of both ammonia and other toxins that cannot be cleared by the liver, in a condition known as hepatic encephalopathy. Development of confusion, dementia, and eventually coma in a patient with liver disease is evidence of significant progression, and these symptoms can prove fatal if left untreated. Such tests have several goals: (1) to assess whether hepatocytes have been injured or are dysfunctional, (2) to determine whether bile excretion has been interrupted, and (3) to evaluate whether cholangiocytes have been injured or are dysfunctional. Liver function tests are also used to monitor responses to therapy or rejection reactions after liver transplantation. Nevertheless, liver function tests are discussed briefly because of their link to hepatic physiology. Alkaline phosphatase is expressed in the canalicular membrane, and elevations of this enzyme in plasma suggest localized obstruction to bile flow. Urea is a small neutral molecule that is readily filtered at the glomerulus, and it is reabsorbed by the kidney tubules such that approximately 50% of the filtered urea is excreted in urine (see Chapter 37). Urea that enters the colon is either excreted or metabolized to ammonia via colonic bacteria, with the resulting ammonia being reabsorbed or excreted. In addition, measurement of any of the other characteristic secreted products of the liver can be used to diagnose liver disease. Clinically the most common tests are measurements of serum albumin and a blood clotting parameter, the prothrombin time. If results of these tests are abnormal, when considered together with other aspects of the clinical picture, a diagnosis of liver disease may be established. Blood glucose and ammonia levels are frequently monitored in patients with chronic liver disease. Finally, imaging tests and histological examination of biopsy specimens of liver parenchyma, usually obtained percutaneously, are also important in evaluating and monitoring patients with suspected or proven liver disease. Vital functions of the liver include carbohydrate, lipid, and protein metabolism and synthesis; detoxification of unwanted substances; and excretion of circulating substances that are lipid soluble and carried in the bloodstream bound to albumin. Liver function depends on its unique anatomy, its constituent cell types (especially hepatocytes), and the unusual arrangement of its blood supply. Bile flow is driven by the presence of bile acids, which are amphipathic end products of cholesterol metabolism that are produced by hepatocytes. Bile acids circulate between the liver and intestine to conserve their mass, and water-insoluble metabolites. Bile is stored in the gallbladder between meals, where it is concentrated and released when hormonal and neural signals simultaneously contract the gallbladder and relax the sphincter of Oddi. The liver is critical for disposing of certain substances that would be toxic if allowed to accumulate in the bloodstream, including bilirubin and ammonia. What is the location of the kidneys, and what are their gross anatomical features What are the different parts of the nephron, and what is their locations within the cortex and medulla What are the major components of the glomerulus, and what are the cell types located in each component But let the composition of our internal environment suffer change, let our kidneys fail for even a short time to fulfill their tasks, and our mental integrity, or personality is destroyed. The kidneys regulate (1) body fluid osmolality and volumes, (2) electrolyte balance, and (3) acid-base balance. In addition the kidneys excrete metabolic products and foreign substances and produce and secrete hormones. Control of body fluid osmolality is important for maintenance of normal cell volume in all tissues of the body. Control of body fluid volume is necessary for normal function of the cardiovascular system. Excretion of these electrolytes must be equal to daily intake to maintain appropriate total body balance. If intake of an electrolyte exceeds its excretion, the amount of this electrolyte in the body increases and the individual is in positive balance for that electrolyte. Conversely if excretion of an electrolyte exceeds its intake, its amount in the body decreases and the individual is in negative balance for that electrolyte. For many electrolytes the kidneys are the sole or principal route for excretion from the body. Normal pH is maintained by buffers within body fluids and by the coordinated action of the lungs, liver, and kidneys. These waste products include urea (from amino acids), uric acid (from nucleic acids), creatinine (from muscle creatine), end products of hemoglobin metabolism, and metabolites of hormones. The kidneys eliminate these substances from the body at a rate that matches their production. Finally, the kidneys are important endocrine organs that produce and secrete renin, calcitriol, and erythropoietin. Renin is not a hormone but an enzyme that activates the renin-angiotensin-aldosterone system, which helps regulate blood pressure and Na+ and K+ balance. Calcitriol, a metabolite of vitamin D3, is necessary for normal absorption of Ca++ by the gastrointestinal tract and for its deposition in bone (see Chapter 36). As a result, Ca++ absorption by the intestine is decreased, which over time contributes to the bone formation abnormalities seen in patients with chronic renal disease. Another consequence of many kidney diseases is a reduction in erythropoietin production and secretion. In some instances the impairment in renal function is transient, but in many cases renal function declines progressively. To understand the mechanisms that contribute to renal disease, it is first necessary to understand the normal physiology of renal function. Thus in the following chapters in this section of the book, various aspects of renal function are considered. Both peritoneal dialysis and hemodialysis, as their names suggest, rely on the ability to remove small dialyzable molecules from the blood-including metabolic waste products normally removed by intact kidneys-via diffusion across a selectively permeable membrane into a solution lacking these substances, thereby mitigating both their accumulation and associated adverse health effects. In addition, dialysis helps reestablish both fluid and electrolyte balance via removal of excess fluid, correction of acid-base changes, and normalization of plasma electrolyte concentrations). In peritoneal dialysis, the peritoneal membrane lining the abdominal cavity acts as a dialyzing membrane. Several liters of a defined dialysis solution are typically introduced into the abdominal cavity, and small molecules in blood diffuse across the peritoneal membrane into the solution, which can then be iteratively removed, discarded, and replaced. Patients who are candidates for renal transplantation are often treated with dialysis until an appropriate donor kidney can be procured. Functional Anatomy of the Kidneys Structure and function are closely linked in the kidneys.

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