Robert D. Smink, Jr. MD, FACS

• Senior Clinical Lecturer in Surgery, Lankenau Hospital, Wynnewood, Pennsylvania
• Assistant Clinical Professor of Surgery, Jefferson Medical College, Philadelphia,
• Pennsylvania

This process is termed secondary active transport because the specific gradient is indirectly created by a distinct energy-using process birth control pills and pregnancy levlen 0.15 mg online. Equally important birth control for 3 months safe 0.15 mg levlen, carriers can transport single or multiple substrates and perform the transport in different directions birth control for women mostly cheap 0.15mg levlen mastercard. Symporters birth control for women clothing buy generic levlen from india, such as the Na+/K+-2Cl- cotransporter birth control for skin purchase 0.15 mg levlen visa, move Na+/K+ birth control pills efficiency generic levlen 0.15 mg without prescription, and Cl- in the same direction, whereas antiporters, such as the Na+-H+ exchangers, move the 2 ions in opposite directions. Glucose transport processes, elegantly elucidated by Wright and coworkers, provide a good example of nutrient transport. Although it is clear that Na+ and glucose absorption stimulates water absorption, the mechanism is not fully delineated. The classic explanation is that basolateral exit of glucose creates a hypertonic compartment in the paracellular space, thereby generating an osmotic gradient for fluid entry from the lumen. For a description of similar advances made in our understanding of amino acid and vitamin transport, see Chapters 102 and 103. Nutrient-Coupled Sodium Transport Nutrient transporters are largely the purview of the small intestine. Transport of many hydrophilic nutrients including glucose, amino acids, and some vitamins occurs against their Sodium-Hydrogen Exchangers Exchange of extracellular Na+ for intracellular H+ is a process driven by the electrochemical gradient for Na+ and by a pH gradient that results from a moderately acidic intracellular environment; this process occurs in almost every cell. Electroneutral Na+ absorption may be downregulated during eating and increases postprandially after nutrient absorption. It is expressed on epithelial basolateral membranes and functions as the housekeeper regulator of intracellular pH, cell volume, and growth. Sodium crosses the apical membrane of the epithelial cell down an electrochemical gradient. The mechanisms may be (1) an ion-specific channel that can be blocked by amiloride; (2) a carrier. Cl- moves passively through the paracellular pathway or via cellular transporters (6). Chloride Secretion the principal driving force for fluid secretion is the transcellular movement of Cl- from the serosal to the luminal compartment. The small and large intestine exhibit a basal rate of Cl- secretion that is maintained by the interplay of cell volume, [Cl-]i, and paracrine, autocrine, neuronal, endocrine, luminal, and immune modulators. Disruptions in the balance of these regulatory processes can lead to secretory diarrhea. Although there are some tissue-specific regulatory differences, the mechanisms underlying this secretion are remarkably similar. This complex interplay of transporters is an elegant demonstration of cellular economy. The pump-to-leak relation between K+ channels and the Na+ pump helps maintain the interior of the cell as electronegative, providing the driving force for Cl- exit. Basolateral K+ exit electrically balances the large Cl- flux across the apical membrane. Chloride Channels Three classes of Cl- channels belonging to separate protein families and with distinct electrophysiologic characteristics have been identified in secretory epithelia. Chloride (Anion) Absorption the transepithelial lumen negative potential difference contributes to passive movement of Cl- and other anions via the paracellular pathway in the jejunum. Similarly, exit mechanisms for Cl- across the basolateral membrane involve both channels. In the intact cell, the molecules described in steps 1 to 5 (receptors, cyclase, kinase, anchoring protein, and target transporter) may be in close proximity, allowing for spatial and localized regulation. The adenylate cyclase cascade is localized to the basolateral membrane of epithelial cells. Some studies show that lubiprostone activates ClC2 in the apical membrane of human colonic cell lines. Discrete basolateral entry steps and apical exit steps are integral to chloride secretion across any secretory epithelium. Cl- then exits the cell across the apical membrane by means of a chloride channel; Na+ and water follow passively. The Na+ and K+ that entered with the Cl- are recycled by, respectively, the Na+ pump and a basolateral K+ channel, both of which are critical to maintaining the driving force. The molecular nature and isotypes of these key transporters may vary with the tissue and species. Its location in intestinal epithelia remains to be resolved; a strict basolateral role in cell volume regulation has been found by some,59 whereas others provide evidence for an apical location. In the small intestine, the luminal negative potential difference drives the passive absorption of K+. At least 2 colonic isoforms have been identified: ouabainsensitive isoform in the crypt cells and ouabain-insensitive isoform in the surface cells. In addition to transepithelial transport, various K+ channels are involved in differentiation, apoptosis, and carcinogenesis. K+ channels are regulated by changes in membrane voltage, cytosolic calcium, pH, cell swelling, cell metabolism, and covalent post-translational protein modifications. Found primarily on the basolateral membrane of epithelial cells, K+ channels contribute significantly to intestinal electrolyte homeostasis through several mechanisms. Cell swelling activates K+ channels, leading to a regulatory volume decrease, a function critical for intestinal cells that live in an environment with constant fluctuations in functions remains to be determined (see later). Misfolded or other mutant proteins that reach the apical membrane get targeted to the lysosome for degradation. K+ channels modulate the hyperpolarization of the cell interior required for vectorial voltage-driven transport processes. Basolateral K+ channels contribute to the transepithelial potential difference, which influences paracellular movement. Bicarbonate Transport Bicarbonate is a metabolic product and a critical anion in fluid homeostasis in the intestine. It is secreted by electrogenic and electroneutral processes in the duodenum, ileum, and colon. At the basolateral membrane, A1 catalyzes the adenosine diphosphate ribosylation of Gs (Gs). In addition, interneurons between the small and large intestines underlie the ability of cholera toxin in the small intestine to trigger a reflex secretory response in the colon. All these interactions are compounded by many of the factors acting through cell-specific multiple receptors and signaling pathways. Although it is possible to separate the specific effects of an individual component in vitro, clinically they are inextricably intertwined. Another example is that of a single agonist like cholera toxin that directly acts on epithelial cells while simultaneously stimulating neural, paracrine, and immune responses. Decreased motility leads to bacterial increase in the small intestine, which causes diarrhea by a variety of mechanisms (see Chapters 16, 99, 100 and 105). Model depicting the integral components of the complex systems that regulate intestinal ion transport. The components include (1) neurons responsive to intraluminal mechanical and chemical stimuli. Agents that promote net fluid secretion generally inhibit Na+ absorption and stimulate Cl- secretion, whereas agents that promote net fluid absorption increase Na+ uptake and attenuate Cl- secretion. In a healthy person, net absorption prevails, and when this balance is disrupted, diarrhea can ensue. It is unclear if there is a corollary for a predominant absorptive pattern in a subset of patients with constipation. Intestinal mesenchymal cells, in particular myofibroblasts, are a rich source of cytokines, chemokines, eicosanoids, and growth factors that can alter intestinal transport. Cholinergic stimulation of secretion, predominantly through parasympathetic vagal input, and adrenergic stimulation of absorption through prevertebral and sympathetic ganglia have long been recognized as fundamental neural pathways affecting the intestinal epithelium. Epithelial cells can self-regulate (autocrine) by secreting factors such as eicosanoids, which act on epithelial cell receptors to alter function. A basal cholinergic secretory drive is tempered by sympathetic tone; loss of adrenergic sympathetic innervation in diabetic neuropathy is associated with development of "diabetic diarrhea" and may be corrected by 2-adrenergic agonists. Individual neurotransmitters can have biphasic effects that vary with concentration. Furthermore, agents can act as classic neurotransmitters and alternatively as neuromodulators, finetuning the neuronal circuits of presynaptic sites of neurons or as paracrine mediators. Campylobacter jejuni Clostridium difficile (toxin A) Clostridium perfringens Escherichia coli (heat-labile toxin) Enteropathogenic E. Intestinal inflammation increases the number of immunocytes, the cause of the inflammation determining the type of inflammatory cells. Acute bacterial infections increase polymorphonuclear leukocytes, whereas parasitic infections dramatically enlarge the mast cell population, and celiac disease is characterized by intraepithelial lymphocytes. Thus, the cause of the inflammatory reaction can determine the types of immunocytes recruited, the range of cytokines released, and the specific effects on transport and motility. In interpreting the effects of the inflammatory mediators in normal model systems, it is important to recognize that in vivo, cells damaged by the inflammatory process might not be able to function normally. Mucosal mast cells are strategically located close to enteric neurons, blood vessels, and epithelial cells, and they are central to several inflammatory reactions. Mast cell mediators, including histamine, eicosanoids, and cytokines, elicit secretion by direct effects on the epithelial cells and by indirect neural stimulation and prostaglandin release. The mechanisms of secretion resulting from polymorphonuclear infiltration of the mucosa have recently become better understood. Adenosine is a potent secretagogue, and this adenosinestimulated secretion might serve as a mechanism to cleanse the crypt lumen. Metabolic acidosis is a potent stimulator of electroneutral NaCl absorption, whereas metabolic alkalosis inhibits this process. Any decrease in intravascular volume, such as with hemorrhage, elicits a series of responses that increase fluid absorption. Under normal physiologic conditions, the duodenum and upper jejunum are subject to major fluid shifts as they adjust to dietary intake of hypertonic foods and liquids. Rapid equilibration is usually accomplished by movement of water into the intestinal lumen, and absorptive processes along the remainder of the intestine steadily decrease the luminal volume. The continued presence of a nonabsorbable solute within the intestinal lumen, however, can negate functioning absorptive pathways in the distal intestine. Carbohydrates, usually disaccharides, are a common source of non-absorbable solute. Disaccharides must be hydrolyzed to monosaccharides before they can cross the apical membrane of the small intestine (see Chapter 102). The most common clinical example of maldigestion is lactose intolerance, in which the glucose-galactose disaccharide cannot be broken down because of a deficiency of the specific disaccharidase, lactase. Because the human intestine does not possess lactulase, the disaccharide lactulose reliably increases small intestinal fluid because of luminal hyperosmolarity and bacterial fermentation of the disaccharide. The limited intestinal absorptive capacity for several sugars found in processed foods and drinks. The physiology of carbohydrate-induced osmotic diarrhea is complicated by the fact that non-absorbable solutes in the small intestine can be converted into absorbable solutes by colonic bacteria. However, if the capacity of either of these colonic functions is exceeded, additional unmetabolized carbohydrates in the colon could exacerbate the osmotic effects of non-absorbable solute. The colonic lavage preparations given prior to colonoscopy cleanse the colon by causing an osmotic diarrhea induced by non-absorbable molecules, including polyethylene glycol and sulfate. In clinical situations in which there is malabsorption or a generalized destruction of the epithelium, solutes normally absorbed readily can remain in the intestinal lumen and thereby contribute an osmotic component to an inflammatory diarrhea or a malabsorptive state. Osmolality is an important factor in patients receiving enteral nutrition (see Chapters 6 and 106). Compared with simple sugars, complex carbohydrates provide a significant amount of calories with minimal osmolality. Absorption of dipeptides and tripeptides instead of amino acids reduces intestinal osmolality. This balance between calories and osmolality becomes clinically relevant in effectively designing appropriate tube-feeding regimens. Glucocorticoids are also potent stimulators of Na+ absorption in the small intestine and colon. At low concentrations, glucocorticoids stimulate electroneutral Na+ absorption and suppress electrogenic Na+ absorption, whereas at high concentrations they stimulate both processes. The actions of glucocorticoids are complex, species- and segment-specific, and may be directed at the level of apical Na+ transporters and at the Na+ pump. These effects might account in part for the potent antidiarrheal action of glucocorticoids in a wide variety of clinical settings. Of these absorbagogues, catecholamines such as dopamine and epinephrine act on -adrenergic receptors to elicit similar absorptive properties. The theoretical basis for the use of clonidine as an antidiarrheal agent, particularly in diabetic diarrhea, is rooted in this adrenergic absorptive pathway. Elucidating their therapeutic effect led to the characterization of the mammalian opioid peptides-enkephalins, endorphins, and dynorphins-a classic example of molecular mimicry. Chronic treatment with opiates leads to tolerance, and diarrhea ensues upon abrupt withdrawal. Management of constipation in patients receiving opiates as analgesics can be a clinical challenge. The development of long-acting analogs of somatostatin has transformed this ubiquitously distributed hormone from a physiologically fascinating regulator to a clinically relevant pharmacologic agent (see Chapter 4). In the intestine, enterochromaffin D cells produce somatostatin, which stimulates salt and water absorption in the ileum and colon and blocks the effects of several secretagogues. Their therapeutic effect is due to a combination of inhibiting hormone release from tumors, slowing of intestinal transit, and a direct effect on epithelial cells. Paradoxically, elevated somatostatin levels, as encountered in somatostatinomas or with large pharmacologic doses of octreotide, can precipitate diarrhea secondary to steatorrhea. Serotonin and Adenosine Serotonin plays a critical role in modulating intestinal motility, sensation, and secretion, and is responsible for the diarrhea associated with carcinoid tumors.

Undifferentiated cells have fewer intracellular organelles and microvilli than absorptive cells birth control pills otc order levlen 0.15mg with mastercard. Enterocyte microvilli are estimated to increase the luminal surface area of the cell 14- to 40-fold birth control pills 7 day break buy levlen with a visa. Goblet cells are mucin-producing cells that are scattered among intestinal villi but are more common in the distal ileum and large intestine birth control nuva ring order levlen paypal. Mucin is secreted by 2 pathways: in a neutrally-mediated continuous manner birth control pills yeast infections 0.15mg levlen mastercard, and by the active exocytosis of granules in response to extracellular stimuli birth control 1800s levlen 0.15 mg cheap. Tuft cells are marked by a tuft of long microvilli projecting from the apical surface of the cell birth control xanax order levlen with a visa. Intestinal endocrine cells are sparsely distributed and consist of 11 different cell types (Table 98-1). These are tall columnar cells present in both the crypts and villi and contain prominent secretory granules. Note the absorptive cells that appear as high columnar cells with eosinophilic cytoplasm (arrow). These chemical properties subdivide the cell types, but a unifying concept is derived from their common origin and functional capacity. Neurosecretory granules can be demonstrated as dark granules with nonspecific agents. The differential expression of certain proteins also makes it possible to subdivide neuroendocrine cell populations. M cells are an important site of luminal antigen sampling for immune processing by the mucosal lymphoid system. This process of sampling plays an important role in the development and maintenance of immune tolerance, host defense against pathogens, and intestinal homeostasis. The myenteric plexus (mp) is seen as a pale area with ganglion cells between the inner and outer layers (il, ol) of the muscularis propria (arrow). Parasympathetic and postganglionic sympathetic fibers terminate in parasympathetic ganglion cells, and postganglionic parasympathetic fibers terminate in smooth muscle. Serosa the serosa is the outermost layer of the intestinal wall and is composed of a simple layer of mesothelial cells supported by connective tissue, the adventitia. It represents an extension of the visceral peritoneum and mesentery as it envelops the intestine. Submucosa the submucosa is a fibrous connective tissue layer that lies between the muscularis mucosae and the muscularis propria. The submucosa supports the mucosa in specialized functions of nutrient, fluid, and electrolyte absorption by conveying a rich network of blood vessels, lymphatics, and nerves that ensure efficient handling of absorbates. The secretions that drain into the base of the duodenal crypts contribute to increased luminal pH by promoting pancreatic secretion and gallbladder contraction. Villi are mucosal folds that decrease in size from the proximal to distal small intestine and are of different shapes in the various segments of the small intestine. The villous pattern may vary in different ethnic groups; biopsy specimens from Africans, Indians, South Vietnamese, and Haitians have shorter and thicker villi, an increased number of leaf-shaped villi, and more mononuclear cells in comparison with specimens from North Americans. Enterocytes are tall columnar cells, each with a basally located, clear, oval-shaped nucleus and several nucleoli. The cells are tightly cemented to the basal lamina and adjoined to adjacent enterocytes at the apical pole by intracellular tight junctions. The luminal surface has microvilli that contain necessary enzymes for nutrient absorption; a central core cytoskeleton is made of actin, villin, fimbrin, brush border myosin, and spectrin. It consists of 2 layers of smooth muscle: an inner circular coat and an outer longitudinal coat arranged in a helicoidal pattern. The ganglia in the myenteric plexus are more 1656 Section X SmallandLargeIntestine ability to divide. The constant renewal of enterocytes is regulated by human acyl-coenzyme A synthetase. Above the base are absorptive cells and oligomucin cells; the latter originate from undifferentiated cells and differentiate into goblet cells. Smooth muscle is found in the lamina propria of the small intestinal villus, extending vertically up from the muscularis mucosae. Plasma cells containing primarily immunoglobulin (Ig)A, and mast cells are also present. Ninety percent of the villus epithelial cells are absorptive cells intermingled with goblet and enteroendocrine cells. The outer layer forms the taenia coli, which run in parallel to the long axis of the colon throughout the entire colon. The width of the taeniae extends from 6 to 12 mm, and thickness gradually increases from the cecum to the sigmoid colon. The epithelial layer is smooth with crescentic folds corresponding to external sacculations. The surface epithelium is simple columnar type and is interspersed with vascular cells and goblet cells. The epithelial surface and upper third of the crypts are mostly lined with tall, slender absorptive columnar cells called principal cells. Goblet cells are the second most abundant cells on the surface of the colonic epithelium and produce mucin, which aids in the passage of feces. Colonic epithelial cells are generated from stem cells at the base of the crypts and migrate toward the intestinal lumen after 3 to 5 days on initiation of apoptosis. Most epithelial cells undergo apoptosis when they lose contact with the extracellular matrix and are shed into the lumen through caspase activation. Caspase activation is responsible for the cleavage of essential intracellular proteins that leads to apoptosis and therefore loss of anchorage. Enterochromaffin, enterochromaffin-like, and pancreatic polypeptide-producing cells are also found. Paneth cells are scarce and normally are noted only in the proximal (see Chapter 101). The junction complexes are made up of 3 components: the proximal tight junction (zonula occludens), the intermediate junction (zonula adherens), and the deep junction, which includes the spot desmosome and the macular adherens zone (see Chapter 101). Movement through junctions is by paracellular transport and is the dominant pathway for passive ion and fluid flow. Tight junctions consist of claudins, occludens, and junctional adhesion molecules that bind and prevent passage of molecules between them in a regulated manner. They are leakier and have a lower resistance in the proximal small intestine, and tighter in the distal intestine. Spot desmosomes are thought to augment transmembrane linkages spanning the intercellular gap and are involved in cell wall communications. The basolateral membrane is responsible for carriers to facilitate diffusion of organic solutes not coupled to ion movements. During this migration, these cells mature and differentiate into a secretory lineage (goblet cells, enteroendocrine cells) and enterocytes. The lamina propria of the large intestine contains solitary lymphoid follicles that extend into the submucosa. Lymphoid follicles are more developed in the rectum and decrease in number with age. The anal skin is lined by squamous stratified epithelium and contains hair and sebaceous glands. Vasculature Large arterial branches enter the muscularis propria and pass to the submucosa, where they branch to form large plexuses. Other arteries are destined for villi, each villus receiving 1 or 2 arteries, and set up the anatomic arrangement that allows a countercurrent mechanism, thus aiding absorption. These vessels enter at the base of the villus and form a dense capillary network immediately underneath the epithelium of the entire villus structure. One or several veins originate at the tip of each villus from the superficial capillary plexus, anastomose with the glandular venous plexus, and then enter the submucosa to join the submucosal venous plexus. From the periglandular capillary meshwork, veins form a venous plexus between the base of the crypts and the muscularis mucosae. From this plexus, branches extend into the submucosa and form another venous plexus from which large veins follow the distribution of the arteries and pass through the muscularis propria into the serosa. Anal Canal Microscopically, the anal canal is divided into 3 zones: proximal, intermediate or pectinate, and distal or anal skin. The intermediate or pectinate zone is lined by stratified squamous epithelium but without adnexae. Lymph Vessels the lymphatics of the small intestine are called lacteals and become filled with milky-white lymph called chyle after eating. Each villus contains 1 central lacteal, except in the duodenum, where 2 or more lacteals per villus may be present. The wall of the lacteal consists of endothelial cells, reticulum fibers, and smooth muscle cells. Branches of this plexus extend through the muscularis mucosae to form a submucosal plexus. Branches from the submucosal plexus penetrate the muscularis propria, where they receive branches from plexuses between the inner and outer layers. Lymphatic vessels are absent in the colonic mucosa, but the distribution of lymphatics in the remaining colonic layers is similar to that in the small intestine. The subserosal plexus contains a network of thin nerve fibers without ganglia that connects the extrinsic nerves with the intrinsic plexus. These axons originate from processes of the ganglion cells and extrinsic vagus and sympathetic ganglia. The deep muscular plexus is situated on the mucosal aspect of the circular muscular layer of the muscularis propria. It does not contain ganglia; it innervates the muscularis propria and connects with the myenteric plexus. Transition from rectal glandular mucosa (rg) to proximal anal mucosa lined by stratified squamous epithelium (ep) is evident. B, Pectinate line is characterized by anal mucosa with stratified squamous epithelium (ep) and anal skin (as) containing adnexae (arrow). Fibers from this plexus also form a mucosal plexus that is situated in the lamina propria and provides branches to the intestinal crypts and villi. The ganglion cells of the submucosal plexus are distributed in 2 layers; 1 is adjacent to the circular muscular layer of the muscularis propria, and the other is contiguous to the muscularis mucosae. Ganglion cells have an abundant basophilic cytoplasm, a large vesicular round nucleus, and a prominent nucleolus. Ganglion cells are scarce in the physiologically hypoganglionic segment 1 cm above the anal verge. Through a process called gastrulation, this disk becomes trilaminar and gives rise to the 3 primary germ layers: ectoderm, mesoderm, and endoderm. It also establishes bilateral symmetry, dorsal-ventral orientation, and anteriorposterior axis. The surface facing the yolk sac becomes the definitive endoderm, the surface facing the amniotic sac becomes the ectoderm, and the middle layer is the mesoderm. The oral opening is marked by the buccopharyngeal membrane; the future openings of the urogenital and digestive tracts become identifiable as the cloacal membrane. The folding process brings together the endodermal, mesodermal, and ectodermal layers to the corresponding layers on the opposite side, converting the flat endodermal layer into the intestinal tube. Initially the foregut and hindgut are blindending tubes separated by a midgut that is open to the yolk sac. With folding of the embryo during week 4 of development, the mesodermal layer splits. The portion that adheres to endoderm forms the visceral peritoneum, whereas the part that adheres to ectoderm forms the parietal peritoneum. The primitive intestine results from incorporation of the endoderm-lined yolk sac cavity into the embryo following embryonal cephalocaudal and lateral folding. Ganglia (g) are identified by their oval structure, and nerve trunks are thin (arrow). During the 9th week of development, the epithelium begins to differentiate from the endoderm, with villus formation and differentiation of epithelial cell types. Initially the foregut, midgut, and hindgut are in broad contact with the mesenchyma of the posterior abdominal wall.

It occurs in approximately 24% of patients in the third decade of life to 80% in the sixth decade of life birth control for women over 40 order levlen, but the kidney disease usually dominates the clinical course birth control for women medical best buy levlen. Symptomatic liver disease correlates with advancing age birth control for women 9mm cheap levlen online visa, severity of renal cysts birth control pills green case buy discount levlen 0.15 mg, and renal dysfunction birth control natural method buy discount levlen 0.15 mg on-line. The use of exogenous female sex hormones may accelerate the rate of growth and size of the cysts birth control pills yeast infections purchase genuine levlen online. The 2 polycystins are transmembrane glycoproteins that complex and localize in the primary cilium, a microtubulebased structure found on renal and biliary tubule epithelium and thought to act as a flow sensor and regulator of Ca2+ influx. This coronal T2-weighted image shows a massively enlarged liver with numerous bright fluid-filled cysts. Symptoms occur in patients with more numerous and larger cysts (10% to 15% of patients, usually women), generally with markedly enlarged livers. Abdominal discomfort or pain, postprandial fullness, awareness of an upper abdominal mass, a protuberant abdomen, inability to bend over, and shortness of breath may be present. Severe pain may be experienced with rupture or infection of a cyst, bleeding into a cyst, or torsion of a pedunculated cyst. Jaundice is evident in approximately 5% of patients and is caused by compression of the major intrahepatic or extrahepatic bile ducts. Ascites, if present, is the result of portal hypertension, which generally is caused by associated congenital hepatic fibrosis but occasionally by compression of the hepatic veins by the cysts. Each complex is composed of cystically dilated intra- and interlobular bile ducts embedded in a fibrous stroma. Both autosomal recessive and autosomal dominant modes of inheritance have been proposed. Patients typically present with recurrent episodes of fever and abdominal pain caused by cholangitis. Ductal ectasia predisposes to bile stagnation, which in turn may lead to cholangitis, abscess formation, and septicemia. The result of these complications may be cholangiocarcinoma, which develops in less than 10% of patients. Endoscopic retrograde cannulation of the biliary system may be used to facilitate removal of sludge or stones from the accessible part of the biliary system, and the cysts may be drained by an endoscopic or percutaneous route. Cysts have also been treated by percutaneous injection of a sclerosing substance such as alcohol or doxycycline, but most patients have too many small cysts, so percutaneous injection should be reserved for those with a dominant cyst or excessive risk for surgery. Patients who fail to respond to cyst fenestration may be considered for partial hepatic resection if sufficient relatively uninvolved liver remains after surgery. The morbidity of this approach is substantial, and future liver transplantation may be more difficult after resection. The liver cysts are microscopic rather than macroscopic and present a clinical picture of congenital hepatic fibrosis. Complications of portal hypertension are the usual hepatic manifestations of the disease. Making a definitive diagnosis of a mass in the liver solely on clinical grounds is seldom possible. Nevertheless, detailed history taking will provide important clues about the probable benign or malignant nature of the lesion. The approach to a mass in the liver differs, depending on whether or not cirrhosis is present. Hemangiomas generally show peripheral nodular enhancement in the arterial phase, with progressive centripetal filling in the portal venous and delayed phases. By contrast, hepatocellular adenoma has less intense arterial enhancement and no central scar. If primary or metastatic malignancy is suspected because of the presence of underlying chronic liver disease, a prior or current malignancy, systemic symptoms or signs. A, Algorithm for the approach to the management of a patient, not known to have cirrhosis, with a hepatic mass (often incidental, possibly symptomatic). A metastasis and peripheral cholangiocarcinoma often have peripheral rim enhancement on the arterial phase. If a biopsy is not performed or not diagnostic, then interval follow-up imaging studies are prudent unless the imaging findings are classic in appearance for focal nodular hyperplasia or hemangioma. If the vascular enhancement pattern is atypical, a biopsy of the lesion should be considered. If determining whether a patient has underlying cirrhosis is impossible on clinical and imaging grounds, a biopsy of the nontumorous liver may be done. 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Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients. Measurement of immunoreactive prothrombin precursor and vitamin-Kdependent gamma-carboxylation in human hepatocellular carcinoma tissues: Decreased carboxylation of prothrombin precursor as a cause of des-gamma-carboxyprothrombin synthesis. Plasma des-gammacarboxyprothrombin in the early stage of hepatocellular carcinoma. The role of tumor markers in the diagnosis of hepatocellular carcinoma, with special reference to the des-gamma-carboxy prothrombin. The usefulness of determining des-gamma-carboxy prothrombin by sensitive Chapter 96 HepaticTumorsandCysts 1627. Serum concentrations of human hepatocyte growth factor is a useful indicator for predicting the occurrence of hepatocellular carcinomas in C-viral chronic liver diseases. Transforming growth factor-beta 1 marker of small hepatocellular as a useful serologic carcinoma. 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Regulation of riboflavin intestinal uptake by protein kinase A: Studies with Caco-2 cells birth control jelly purchase generic levlen online. Transport functions of riboflavin carrier in the rat small intestine and colon: Site difference and effects of tricyclic-type drugs birth control for women chapel purchase levlen 0.15mg. Mechanism of transport of riboflavin in rabbit intestinal brush border membrane vesicles birth control pills dangers purchase on line levlen. Oxidative stress is associated with region-specific neuronal death during thiamin deficiency birth control methods national womens health information center cheap levlen 0.15 mg online. Blood serum thiamin and thiamin phosphate esters concentrations in patients with alcohol dependence syndrome before and after thiamin treatment birth control uterine implant buy levlen now. Thiamin and thiamin phosphate ester deficiency assessed by high performance liquid chromatography in four clinical cases of Wernicke encephalopathy birth control pills infertility buy levlen mastercard. Further studies on erythrocytes thiamin transport and phosphorylation in seven patients with thiamin-responsive megaloblastic anaemia. Mutations in a new gene encoding a thiamin transporter cause thiaminresponsive megaloblastic anaemia syndrome. Cloning of the human thiamin transporter, a member of the folate transporter family. Evidence for carriermediated mechanism for thiamin transport to human jejunal basolateral membrane vesicles. In situ localization of enzymes and mucin in normal rat colon embedded in plastic. The distribution of certain enzyme systems in the normal human gastrointestinal tract. Enteropathogenic Escherichia coli inhibits intestinal vitamin B1 (thiamin) uptake: Studies with human-derived intestinal epithelial Caco-2 cells. Impaired intestinal vitamin B1 (thiamin) uptake in thiamin transporter-2-deficient mice. Thiaminresponsive megaloblastic anemia syndrome: A disorder of high-affinity thiamin transport. Targeting and trafficking of the human thiamine transporter-2 in epithelial cells. Tspan-1 interacts with thiamine transporter-1 in human intestinal epithelial cells and modulates its stability. Identification of a mouse thiamin transporter gene as a direct transcriptional target for p53. Differentiationdependent up-regulation of intestinal thiamin uptake: Cellular and molecular mechanisms. Thiamin uptake in human intestinal biopsy specimens, including observations from a patient with acute thiamin deficiency. Adaptive regulation of intestinal thiamin uptake: Molecular mechanisms in wild-type and transgenic mice. Transport of thiamin in the human intestine: Mechanism and regulation in intestinal epithelial cell model Caco-2. Pancreatic beta cells and islets take up thiamin by a regulated carrier-mediated process: Studies using mice and human pancreatic preparations. Chronic alcohol consumption and intestinal thiamin absorption: Effects on physiological and molecular parameters of the uptake process. The challenge to reach nutritional adequacy for vitamin A: Beta-carotene bioavailability and conversion- Evidence in humans. Nutritional aspects of phytoene and phytofluene, carotenoid precursors to lycopene. Historical aspects of the major neurological vitamin deficiency disorders: Overview and fat-soluble vitamin A. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. Quantitative and conceptual contributions of mathematical modeling to current views on vitamin A metabolism, biochemistry, and nutrition. Essential nutrients for bone health and a review of their availability in the average North American diet. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. Vitamin D3 intestinal absorption in vivo: Influence of fatty acids, bile salts, and perfusate pH on absorption. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. Enhancing vitamin E in oilseeds: Unraveling tocopherol and tocotrienol biosynthesis. The pecking order of free radicals and antioxidants: Lipid peroxidation, alpha-tocopherol, and ascorbate. Effects of tocotrienol-rich fraction on exercise endurance capacity and oxidative stress in forced swimming rats. Nitrofurantoininduced hepatic and pulmonary biochemical changes in mice fed different vitamin E doses. Tocotrienols, the vitamin E of the 21st century: Its potential against cancer and other chronic diseases. Isoforms of vitamin E have opposing immunoregulatory functions during inflammation by regulating leukocyte recruitment. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Neurologic complications of bariatric surgery: Involvement of central, peripheral, and enteric nervous systems. Multifaceted role of tocotrienols in cardioprotection supports their structure: Function relation. Human vitamin E requirements assessed with the use of apples fortified with deuterium-labeled alpha-tocopheryl acetate. Differences in the plasma transport and tissue concentrations of tocopherols and tocotrienols: Observations in humans and hamsters. Studies in humans using deuterium-labeled alpha- and gammatocopherols demonstrate faster plasma gamma-tocopherol disappearance and greater gamma-metabolite production. Vitamin K oxygenation, glutamate carboxylation, and processivity: Defining the three critical facets of catalysis by the vitamin K-dependent carboxylase. Vitamin K nutrition, metabolism, and requirements: Current concepts and future research. Vitamin K2 colonic and ileal in vivo absorption: Bile, fatty acids, and pH effects on transport. Effect of age and the milk sugar lactose on calcium absorption by the small intestine. Effect of 1,25-dihydroxyvitamin D3 on calcium and magnesium absorption in the healthy human jejunum and ileum. Molecular mechanisms for regulation of intestinal calcium absorption by vitamin D and other factors. Segmental heterogeneity of cellular and paracellular calcium transport across the rat duodenum and jejunum. Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. Cellular and paracellular magnesium transport across the terminal ileum of the rat and its interaction with the calcium transport. Fe-saturation and proteolysis of human lactoferrin: Effect on brush-border receptormediated uptake of Fe and Mn. Characterization and partial purification of a ferrireductase from human duodenal microvillus membrane. Role of redox systems on Fe3+ uptake by transformed human intestinal epithelial (Caco-2) cells. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Effect of acute zinc depletion on zinc homeostasis and plasma zinc kinetics in men. Homeostatic regulation of zinc absorption and endogenous losses in zinc-deprived men. Studies of zinc transport into brush border membrane vesicles isolated from pig small intestine. The effect of pregnancy and lactation on the absorption of zinc and lysine by the rat duodenum in situ. Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-1 expression. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Copper absorption and copper balance during consecutive periods for rats fed varying levels of dietary copper. Copper absorption and retention in pregnant women fed diets based on animal and plant proteins. Copper absorption and retention in young men at three levels of dietary copper by use of the stable isotope 65Cu. Copper absorption, excretion, and retention by young men consuming low dietary copper determined by using the stable isotope 65Cu. Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. It is now recognized that many malabsorptive disorders, such as celiac disease, might have subtle clinical presentations. Awareness is also increasing that subtle malabsorption of single nutrients like calcium or vitamin B12 can, if unrecognized, lead to complications that may be difficult to reverse or that are even irreversible. The clinical challenge today is to recognize and treat malabsorption despite its subtle manifestations, a challenge made even more difficult by the restricted availability of tests for malabsorption, such as the 72-hour fecal fat determination. Classically, maldigestion is defined as defective intraluminal hydrolysis of nutrients, and malabsorption is defined as defective mucosal absorption. Although this distinction may be useful on pathophysiologic grounds, the clinical presentation and complications of maldigestion and malabsorption are similar. In this article, the terms digestion and absorption or maldigestion and malabsorption are used separately only in the discussion of pathophysiology. When the distinction between these terms is not of clinical relevance, only the terms absorption and malabsorption are used. Malabsorption can be caused by many diseases of the small intestine and also by diseases of the pancreas, liver, biliary tract, and stomach (Box 104-1). In some of these diseases, malabsorption may be the presenting feature; in others, malabsorption may be only a minor clinical problem or detected only as a laboratory abnormality. For clinical purposes, this approach is of limited value because the various clinical pictures caused by malabsorption syndromes are determined mainly by the nature of the malabsorbed substrates. We therefore discuss the mechanisms causing malabsorption on the basis of the malabsorbed substrate. A separate section is devoted to the role of mechanisms that compensate for the consequences of malabsorption. Solubilization is a prerequisite for absorption of such nutrients as fat or calcium. Digestion of macromolecular compounds like polysaccharides, triglycerides, and proteins to their molecular components-monosaccharides, fatty acids, and amino acids, respectively-is achieved by soluble or membrane-bound digestive enzymes. Although such absorption does not play a nutritive role, it may be important for the normal function of the immune system and the pathogenesis of diseases such as food allergy (see Chapter 10). Chemical changes to nutrients may be required for absorption, such as reducing the charge of iron from Fe+3 to Fe+2. Mucosal absorption can occur by active or passive carriermediated transport or simple or facilitated diffusion (see Chapter 101). Postmucosal transport of absorbed substrates occurs in blood vessels and lymphatic vessels. Intestinal sensory and motor function permits detection of the presence of nutrients, facilitates adequate mixing of nutrients with intestinal secretions and delivery to absorptive sites, and provides adequate time for nutrient absorption (see Chapter 99). Neural and hormonal functions are required to stimulate and coordinate digestive secretions, mucosal absorption, and intestinal motility (see Chapters 4 and 99). An overview of pathophysiologic mechanisms of maldigestion and malabsorption is provided in Table 104-1. This table also shows the ingested substrates primarily affected by individual pathophysiologic mechanisms and lists examples of etiologic disorders for these mechanisms. Usually, lymphatic vessels in the mucosa become dilated (lymphangiectasia), and chylomicrons are lost postprandially into the intestinal lumen and also in the fasting state11; steatorrhea in these situations usually is only mild to moderate. Defective Intraluminal Proteolysis Protein digestion may be impaired in patients who have undergone partial or total gastric resection, presumably as a result of poor mixing with digestive secretions, although gastric pepsin deficiency could be contributory. Decreased Lipolysis If exocrine pancreatic function is severely reduced, impairment of pancreatic lipase and colipase secretion results in decreased luminal hydrolysis of dietary fat. Selective congenital lipase or colipase deficiency is a rare cause of pancreatic fat malabsorption. Decreased Mucosal Absorption and Chylomicron Formation Generalized mucosal diseases like celiac disease are often associated with fat malabsorption. Defective uptake of free fatty acids and monoglycerides results from reduced mucosal surface area secondary to villus shortening, reduced enterocyte function, and mucosal inflammation. In mild forms of pancreatic insufficiency, 1792 Section X SmallandLargeIntestine carbohydrate digestion usually is at least partially preserved,18 but severe pancreatic insufficiency results in clinically apparent carbohydrate malabsorption and diarrhea due to decreased luminal hydrolysis of ingested starch. Mucosal Defects of Carbohydrate Digestion and Absorption the most common cause of carbohydrate malabsorption is late-onset lactose malabsorption due to decreased levels of the intestinal brush border enzyme lactase (adult-type hypolactasia, acquired primary lactase deficiency). Depending on ethnic background, lactase is present in less than 5% to more than 90% of the adult population; its deficiency results in a selective malabsorption of lactose.

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Liver biopsy specimens show hepatocyte degeneration and canalicular cholestasis with variable portal tract inflammation birth control pills lawsuit order cheap levlen line. Recovery is usual with discontinuation of the drug birth control pills yes or no levlen 0.15 mg discount, although prolonged cholestasis with ductopenia has been reported birth control for women how are stis levlen 0.15mg with mastercard. Ursodeoxycholic acid has been used to hasten recovery when cholestasis is protracted birth control care center buy generic levlen 0.15 mg line. Rare cases of severe hepatic necrosis have been ascribed to fluconazole birth control 4 day period purchase levlen 0.15 mg visa, but other causes were not excluded took my birth control pill 8 hours late purchase levlen with paypal. Overt clinical hepatitis has been noted in patients receiving voriconazole in a liver intensive care unit and has led to discontinuation of the drug. Serious liver injury is rare with the second-generation thiazolidinediones rosiglitazone and pioglitazone. By contrast, a French pharmacovigilance study concluded that the risk of hepatic reactions with these drugs was similar to that reported with other oral hypoglycemic drugs. Persons in whom jaundice developed with troglitazone should not take other thiazolidinediones. Fatal liver failure has been reported in 2 cases, 1 of whom had underlying cirrhosis. Gliclazide32,246 and glibenclamide also have been associated with hepatocellular liver injury and, with the latter drug, hepatic granulomas. Evidence that preexisting liver disease or other drugs predispose to troglitazone hepatotoxicity is lacking, although a progressive course in one patient was attributed to concurrent use of simvastatin and troglitazone. Progression to acute liver failure was often Drugs Used for Psychiatric and Neurologic Disorders Several neuroleptic agents have been associated with drug hepatitis. Some reactions appear to be immunoallergic, whereas others conform to the pattern of apparent metabolic idiosyncrasy, depending on the structure of the drug. Such reactions have been reported for commonly used antidepressants, such as fluoxetine,247,248 paroxetine,249 venlafaxine,250 trazodone,251 tolcapone,252 and nefazodone. Reactions occurred in 1% of recipients and were often severe, with instances of fatal fulminant liver failure. The hydrazine substituent (which iproniazid shares in part with isoniazid, ethionamide, pyrazinamide, and niacin) was determined to be hepatotoxic moiety. Tricyclic antidepressants bear a structural resemblance to the phenothiazines and are occasional causes of cholestatic or, less commonly, hepatocellular injury. Recovery following cessation of the drug is usual, but prolonged cholestasis has been observed with amitriptyline254 and imipramine. Liver enzyme elevations have been observed in asymptomatic persons taking fluoxetine and paroxetine. Only a few of the reported cases have been linked conclusively with the drug; all showed a pattern of acute hepatocellular injury. In liver biopsy specimens from 3 patients, steatosis and mild lobular hepatitis were observed. In one study,269 minor degrees of hepatocellular injury were noted in up to 50% of cases, but tolerance eventually developed. There are isolated reports of jaundice, indicating a rare potential for more severe hepatotoxicity. Although the mechanism of liver injury is unclear, metabolic idiosyncrasy seems likely. Dantrolene, a skeletal muscle relaxant used to treat spasticity, causes hepatitis in about 1% of exposed persons, with a case-fatality rate of approximately 28%. One third of patients are asymptomatic, and the remainder present with jaundice and symptoms of hepatitis. Hepatocellular necrosis, often submassive or massive, has been noted on liver biopsy specimens. Other neurotropic drugs and muscle relaxants implicated as idiosyncratic hepatotoxins include tizanidine (a centrally acting muscle relaxant), alverine (a smooth muscle relaxant),272 and riluzole. Two cases of acute hepatitis with microvesicular steatosis have since been reported, with onset 4 and 8 weeks, respectively, after commencement. Liver biochemical test elevations resolved rapidly after riluzole was discontinued. Centrilobular necrosis was observed on liver histologic examination at autopsy in one case. Post-marketing surveillance has identified 3 additional patients with acute hepatocellular injury caused by tolcapone. The general consensus, however, is that tolcapone is safe if patients are monitored appropriately. Thereafter, the frequency of testing is left to the discretion of the treating doctor. In 3 reported cases of bentazepam hepatotoxicity, the clinicopathologic pattern resembled chronic hepatitis, but without autoantibodies or other immunologic features. Lumiracoxib was associated with severe hepatotoxicity277,278 and was withdrawn from use. When serious hepatocellular injury was attributed to celecoxib, female gender was a predisposing factor. Liver biochemical abnormalities were consistent with a pattern of hepatocellular or mixed liver injury. Single case reports have implicated many other agents, as referred to briefly in the text. Liver histology shows centrilobular or bridging necrosis and occasionally bland cholestasis. Extrahepatic features of drug hypersensitivity are common, as is eosinophilia (30%). The pattern of liver biochemical test levels is typically mixed because of the infiltrative nature of hepatic granulomas and the frequent presence of some hepatocellular necrosis or cholestasis. For several drugs that cause granulomatous hepatitis, continued exposure leads to more severe types of liver disease such as cholestatic hepatitis, with or without bile duct injury and hepatic necrosis (Table 88-7). Small-vessel vasculitis is another potential complication and may involve the kidneys, bone marrow, skin, and lungs; the mortality rate is high. The number of drugs and foreign compounds associated with hepatic granulomas exceeds 40 (Table 88-7). Not all of these agents is associated with systemic inflammation or with persuasive evidence of causality. For drug reactions, however, the definition often has been made inappropriately on hepatic histologic features alone. The histologic features include interface hepatitis, bridging necrosis, and fibrosis. Because these features may be present as early as 6 weeks after the onset of severe reactions, they do not confirm chronicity. The diagnosis of chronic hepatitis is more convincing when clinical or biochemical evidence of hepatitis has been present for more than 3 months and when clinical and laboratory features of chronic liver disease or histologic evidence of established hepatic fibrosis are present. Drugs are an uncommon cause of chronic hepatitis (Table 88-8), because the most commonly implicated agents. In the past, causes included oxyphenisatin and tienilic acid, which are no longer available. Older patients appear to be at greater risk (as in the case of nitrofurantoin), and the reaction is virtually unknown in children. Drugs associated with chronic hepatitis more commonly cause acute hepatitis, and the latent period to recognition tends to be longer in cases of chronic hepatitis; therefore, the duration of drug ingestion may be a risk factor for chronic hepatitis. In the first, cases appear to be identical to acute hepatitis but more severe, more prolonged, or later in onset, perhaps as a result of failure of recognition. Clinical and laboratory features of chronic liver disease are rare, and hallmarks of autoimmunity are absent. Management consists of withdrawal of the drug and treatment of liver failure (see Table 88-8). Autoantibodies, particularly antinuclear and smooth muscle antibodies, are frequent. Immunosuppressive treatment is not indicated; the clinical condition improves spontaneously after withdrawal of the causative drug. Only 4 cases have been fatalities, and 5 cases can reasonably be regarded as chronic hepatitis. A prodromal illness characterized by anorexia, nausea, vomiting, and malaise heralds the onset of liver injury, which usually occurs within 3 months (range, 1 to 11 months) of the start of treatment. Liver biopsy specimens reveal acute lobular hepatitis, and in severe cases, bridging or confluent necrosis, interface hepatitis, and fibrous expansion of the portal tracts have been noted. The prognosis is usually good; resolution occurs after discontinuation of the drug. These cases usually improve spontaneously after discontinuation of the drug, but glucocorticoids have been used successfully in a few protracted cases. Patients need to be advised to report adverse effects, and clinicians must be aware that diclofenac can cause both acute and chronic hepatitis. The clinical syndrome of cholestasis is characterized by pruritus, dark urine, pale stools, and, in more serious cases, jaundice. Hepatobiliary imaging is critical to exclude biliary obstruction and a hepatic or pancreatic mass lesion. In the absence of such findings, drug-induced cholestasis is more likely, and a liver biopsy is often advisable. When the temporal relationship to drug ingestion indicates a high probability of a drug reaction, particularly when the agent is known to be potentially hepatotoxic, the incriminated drug should be discontinued and the patient observed for improvement. Management should focus on symptom relief, with particular attention to pruritus (see Chapter 91). Minocycline Minocycline has been associated with rare cases of druginduced systemic lupus erythematosus syndrome (rash, polyarthritis, hyperglobulinemia, and antinuclear antibodies), chronic hepatitis with autoimmune features, and both syndromes in the same patient. In the United States, minocycline is the most common drug associated with idiosyncratic drug hepatotoxicity in children. Cyclosporine is associated with liver biochemical test abnormalities; the features resemble those of cholestasis, but hyperbilirubinemia usually is predominant. Tacrolimus can also cause cholestasis,301 whereas sirolimus has been implicated in cases of mild acute hepatitis. Prompt discontinuation of a causative agent prevents an adverse outcome and avoids unnecessary invasive investigations or surgery. A mild transient prodrome of nausea and malaise may occur and is followed by pruritus and jaundice. Reactions do not appear to be more common with increasing age but are rare in children. The onset of cholestatic hepatitis is generally 1 to 6 weeks after the start of chlorpromazine and occasionally 5 to 14 days after its discontinuation. Pruritus is common and occurs later with chlorpromazine hepatitis than with drug-induced cholestasis without hepatitis. In a small proportion of affected patients, right upper quadrant abdominal pain is severe. Most patients recover completely: one third within 4 weeks, another third between 4 and 8 weeks, and the remainder after 8 weeks. Anabolic Steroids At high doses, anabolic steroids often produce reversible bland cholestasis, usually within 1 to 6 months after the start of treatment. Recovery usually follows drug withdrawal, but protracted cholestasis with biliary ductopenia can occur. Features of hypersensitivity such as fever, rash, and eosinophilia are seen in 30% to 60% of patients. Bile duct injury (usually mild) and perivenular cholestasis with lipofuscin deposits are often present. Other histologic features include hepatic granulomas, biliary ductopenia, and cirrhosis. Histologic lesions in the liver include lobular and portal tract inflammation, often with neutrophils and eosinophils as well as mononuclear cells. This type of reaction overlaps with drug-induced acute hepatitis (occasionally resulting in acute liver failure), cholestasis without hepatitis, and cholestasis with bile duct injury. Causative agents include chlorpromazine; antidepressants and other psychotropic agents; erythromycins, other macrolides, and related ketolide antibiotics (telithromycin,311 clindamycin,312 sulfonamides, oxypenicillins,313 ketoconazole [see earlier])219; sulfonylureas; sulindac314; ibuprofen; phenylbutazone; piroxicam315; captopril316; flutamide317; enalapril168; pravastatin171; atorvastatin172; ticlopidine318; ciprofloxacin and other fluoroquinolones319; and metformin. As a group, the fluoroquinolones have been associated with acute hepatocellular, cholestatic, and mixed reactions. The full spectrum of hepatic reactions includes asymptomatic liver biochemical test abnormalities in 20% to 50% of recipients and rare cases of fulminant hepatic necrosis. Compounds associated with this syndrome include carbamazepine,332 dextropropoxyphene333 and methylenediamine, an industrial toxin responsible for Epping jaundice, an outbreak of jaundice associated with the ingestion of bread made from contaminated flour (see Chapter 89). In severe cases, intestinal malabsorption, weight loss, and bruising caused by vitamin K deficiency may occur; xanthelasma, tuberous xanthomata, and other complications of severe hypercholesterolemia have also been noted. Firm hepatomegaly may be found on physical examination, but splenomegaly is unusual unless portal hypertension develops. Most cases resolve, but there are rare reports of severe biliary ductopenia and biliary cirrhosis. It has caused cholestasis with bile duct injury in at least 25 reported cases,333 some proved by inadvertent rechallenge. The illness is often heralded by abdominal pain that may be severe and simulates other causes of cholangitis.