Christina T. Mora Mangano, MD, fa ha

• Professor, Department of Anesthesia
• Stanford University
• Chief, Division of Cardiovascular Anesthesia
• Stanford University Medical Center
• Palo Alto, California

A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography infection jaw bone buy chloramphenicol with visa. Therapeutic efficacy of laparoscopic cholecystectomy in the treatment of biliary dyskinesia antimicrobial 1 purchase 250 mg chloramphenicol with mastercard. Pain patterns after distension of the gallbladder in patients with acute cholecystitis bacteria mod 164 cheap chloramphenicol 500 mg overnight delivery. Identification of inappropriate radiological referrals with suspected gallstones: a prospective audit antibiotics for sinus infection biaxin buy chloramphenicol 500mg overnight delivery. Nonsteroidal antiinflammatory drug use and gallstone disease prevalence: a case-control study antibiotics for kitten uti buy chloramphenicol 250 mg with mastercard. Roles of lithogenic bile and cystic duct occlusion in the pathogenesis of acute cholecystitis 2012 antimicrobial susceptibility testing standards quality 250mg chloramphenicol. Complications of gallstone disease: Mirizzi syndrome, cholecystocholedochal fistula, and gallstone ileus. Laparoscopic cholecystectomy in patients with porcelain gallbladder based on the preoperative ultrasound findings. Although nonsurgical treatment of gallstones has proved effective in carefully selected patients, only a limited number of patients are candidates for this treatment option. Nonsurgical treatments are effective only in patients with small, radiolucent cholesterol gallstones. In addition, long-term success with medical treatment of gallstones occurs only in patients in whom the lithogenic disturbance that led to gallstone formation is transient. For most patients, gallstone formation represents an imbalance in biliary lipid excretion, gallbladder stasis, or infection of the bile (see Chapter 65). In these patients, successful dissolution is followed by recurrence of gallstones in 30% to 50% of patients within 5 years. Dissolution Therapy the rationale for oral dissolution therapy is the reversal of the condition that led to formation of cholesterol gallstones, namely, the supersaturation of bile with cholesterol (see Chapter 65). Cholesterol stones dissolve if the surrounding medium can solubilize the cholesterol in the stones. These agents encourage the removal of cholesterol from stones via micellar solubilization, formation of a liquid crystalline phase, or both. Chenodeoxycholic acid was the first bile acid used for gallstone dissolution but has been abandoned because of side effects, including diarrhea and increased serum aminotransferase and cholesterol levels. The use of oral dissolution therapy does not address the problem of gallbladder stasis. Improvements in endoscopic, radiologic, and chemical therapies for gallstones have enhanced the overall management of these patients. Laparoscopic cholecystectomy is the standard method for the management of patients with biliary pain and complications of gallstone disease, such as acute cholecystitis, gallstone pancreatitis, and choledocholithiasis (see also Chapter 65). Contact dissolution of gallstones with solvents and percutaneous cholecystolithotomy techniques also have been reported, but these modalities have not proved superior to oral dissolution, shock-wave lithotripsy, or laparoscopic cholecystectomy and have been abandoned. The mainstay of current nonsurgical treatment Patient Selection Selection of patients for oral dissolution therapy is a function of the stage of gallstone disease, gallbladder function, and characteristics of the stones. Oral dissolution therapy should be considered for patients with uncomplicated gallstone disease, including those with mild, infrequent biliary pain. In addition, the gallbladder must function, and the cystic duct must be patent to allow unsaturated bile and stones to clear from the gallbladder. The patency of the cystic duct has generally been evaluated by oral cholecystography. These latter modalities assess cystic duct patency as well as gallbladder function. The characteristics of the stones play an important role in determining the efficacy of dissolution treatment. The number of stones does not influence the success of oral dissolution therapy; however, only patients with stones that occupy less than half of the gallbladder volume should be considered for treatment. Although oral dissolution therapy has been effective in stones up to 10 mm in diameter, results are best in stones less than 5 mm in size. C and D, Gallstones for which oral dissolution therapy is inappropriate: C, radiopaque gallstones on a plain film; D, large pigmented gallstones. Nighttime dosing is more effective and is associated with better patient adherence than mealtime dosing. Treatment should continue until stone dissolution is documented by 2 consecutive negative ultrasonograms at least 1 month apart. Treatment should be stopped if the patient does not tolerate the drug or experiences a complication of gallstones during therapy or if the stones fail to dissolve after 6 months or dissolve only partially after 6 months with lack of progression to complete dissolution by 2 years. The variability in the reported response rates is a function of differences in patient selection, doses of bile acid, treatment times, and diagnostic techniques used to document stone dissolution. A meta-analysis of all randomized trials of dissolution treatment showed stone dissolution in 37% of patients. In addition, long-term treatment has been reported to decrease the risk of biliary pain and acute cholecystitis, independent of gallstone dissolution. The risk of recurrence is lower in patients with a solitary stone than in those with multiple stones. Lithotripsy should be considered only for patients with mild, uncomplicated biliary pain. Shock-wave lithotripsy is reserved for patients with a solitary stone, measuring less than 2 cm in size. Therapeutic Approach Patients are usually given sedatives and analgesics or anesthetized and placed in the prone position to minimize the distance between the energy source and the stones and to eliminate interference from intestinal gas and the costal margin. Factors that predict the success of lithotripsy include the degree of fragmentation and gallbladder emptying. Important stone characteristics include the size and number of stones as well as their structure and the presence of calcification. Extracorporeal Shock-Wave Lithotripsy the rationale for shock-wave lithotripsy is to diminish the surface-to-volume ratio of a stone, thereby increasing the efficacy of oral dissolution therapy and decreasing stone size to allow small stones and debris to pass directly from the gallbladder into the intestine without causing symptoms. The technique involves the delivery of focused high-pressure sound waves to gallstones. Four types of lithotripters have been developed: underwater sparkgap, piezoelectric crystal, electromagnetic membrane, and, most recently, laser lithotriptors. Regardless of the energy source, the shock waves from the lithotriptor are delivered from an underwater source to the soft tissue. Passage of the shock wave through the soft tissue does not diminish the energy wave significantly. Passage of the shock wave through the anterior and posterior walls of the stone liberates compressive and tensile forces and causes cavitation at the anterior surface of the stone, thereby leading to stone fragmentation. Factors that influence fragmentation include the size, microcrystalline structure, and architecture of the stone. Although the composition of the stone does not influence successful lithotripsy, only cholesterol stone fragments are dissolved effectively by bile acid therapy, which can be used in combination with lithotripsy. Efficacy the percentages of patients who are free of stones after 6 and 12 months is 47% to 77% and 68% to 84%, respectively. Multiple small stone fragments seen 1 day after lithotripsy (B) have disappeared 6 weeks after lithotripsy (C). Side effects of lithotripsy include petechiae of the skin at the site of shock-wave delivery (8%), hematuria (4%), and liver hematomas (<1%). Biliary pain develops in approximately one third of patients; cystic duct obstruction develops in 5%; and complications of stone passage, such as biliary pancreatitis, develop in less than 2%. Open Cholecystectomy Karl Langenbuch, a surgeon in Berlin, is credited with performing the first cholecystectomy in 1882. Since then, cholecystectomy has remained the main therapeutic option for the management of patients with gallstones, largely because of its remarkable success in relieving symptoms and its low morbidity. In prospective studies, 90% to 95% of patients who undergo cholecystectomy experience substantial or complete relief of their symptoms. Bile Duct Stones Extracorporeal shock-wave lithotripsy has also been used in the management of choledocholithiasis. Intracorporeal electrohydraulic lithotripsy has been shown to be effective in this setting as well. These treatment options are reserved for patients who fail conventional endoscopic measures (see Chapter 70), mechanical lithotripsy, or surgical treatment of choledocholithiasis (see later). Appropriate indications for shock-wave lithotripsy are large stones impacted in the bile duct that are not amenable to endoscopic extraction, intrahepatic stones, stones above a biliary stricture, cystic duct remnant stones, and bile duct stones associated with Mirizzi syndrome (compression of the common hepatic duct) (see Chapter 65). Selection of patients for shock-wave treatment of bile duct stones is similar to that for treatment of uncomplicated gallbladder gallstones. Mild, transient hemobilia occurs in 10% of patients, and biliary sepsis develops in 4% following the procedure. Other complications are similar to those seen after lithotripsy for gallbladder stones. Because of the potential for septic complications, preprocedure endoscopic, nasobiliary, or percutaneous biliary drainage is performed. Technique the technique of open cholecystectomy has not changed substantially since its first description. After exploring the abdomen and taking down any adhesions to the gallbladder, the gallbladder is dissected from the gallbladder fossa in a retrograde fashion, from the fundus down to the infundibulum. When the gallbladder has been mobilized, the cystic artery and duct are readily identified. A cholangiogram may be performed to look for bile duct stones or to confirm the anatomy. An alternative approach is to perform a dissection of the triangle of Calot structures, as is done during laparoscopic cholecystectomy (see later), prior to removing the gallbladder from the liver. The triangle of Calot is the space bordered by the cystic duct, cystic artery, and inferior edge of the gallbladder. Dissection and identification of these structures permits safe division of the cystic duct and minimizes the chance of bile duct injury. For example, 7888 cholecystectomies were performed in Utah in 2005; 96% of these operations were laparoscopic cholecystectomies, and 4% were open procedures. A review of the National Hospital Discharge Database from 1997 to 2006 showed that 12% of Results the risk of open cholecystectomy has declined over the years. The mortality rate is considerably lower in patients operated on electively for biliary pain, with an average of less than 0. In a report of the entire Danish experience with cholecystectomy from 1977 to 1981, patients under 50 years of age had a risk of death of 0. Of 11,808 patients who underwent cholecystectomy at the New York Hospital-Cornell Medical Center between 1932 and 1978, the risk of death from elective cholecystectomy for chronic cholecystitis was 0. Likewise, the morbidity rate, mean length of hospital stay, and average hospital charges were significantly higher in the older patients than in the younger group. Most mortality following cholecystectomy is related to cardiac disease, particularly myocardial infarction. In a large survey of 28,621 patients who underwent cholecystectomy in the 1960s, complications occurred in 4. Complications related specifically to cholecystectomy include bile leaks, bile duct injury, and acute pancreatitis. Of these complications, bile duct injury is the most serious and often requires endoscopic therapy and, in some cases, complicated and technically difficult surgical repair. Alternatively, bile duct injury can lead to benign biliary stricture formation and bile duct obstruction with secondary biliary cirrhosis and liver failure. The rate of bile duct injury during open cholecystectomy is not known precisely but has been estimated to be 1 in 200 to 600 cases. Unusual amounts of bleeding, severe inflammation, and emergency operations do not play as great a role in these injuries as might be supposed. Early postoperative mortality following cholecystectomy in the entire female population of Denmark, 1977-1981. Historically, laparoscopic cholecystectomy was an outgrowth of diagnostic laparoscopy and the early efforts of gynecologists at operative laparoscopy. The development of laparoscopic cholecystectomy was predicated on technical advances in miniaturized video cameras and other specialized equipment. Prophylactic antibiotics are not administered routinely to patients with uncomplicated gallstone disease, including biliary pain. Sequential compression stockings are used to reduce the risk of lower extremity thromboembolism. To view the abdominal contents and provide room for instruments, a space is developed by inducing a pneumoperitoneum Laparoscopic Cholecystectomy After the first reports in the late 1980s, laparoscopic cholecystectomy rapidly gained acceptance as the technique of choice for the management of the patient with biliary pain and complications of gallstones. Pneumoperitoneum is achieved by either a closed technique in which a Veress needle is inserted into the peritoneum through a small incision, followed by placement of an operating trocar, or by a direct, open technique in which the operating trocar is placed directly into the abdomen under direct visualization through a small incision. After the pneumoperitoneum has been established, a trocar is placed at the umbilicus and a laparoscope is introduced. Three additional trocars are placed in the upper abdomen under direct vision for inserting operating instruments and retractors. In this approach, the entire hepatocystic triangle is dissected, exposing the cystic duct and artery, infundibulum of the gallbladder, and junction of the gallbladder and cystic duct, before a cholangiogram is performed or the cystic duct and artery are divided. The assistant retracts the gallbladder fundus cephalad, anterior to the liver, and the infundibulum laterally. The surgeon, operating through the epigastric port, identifies and dissects the cystic duct and artery circumferentially. Special care must be taken to identify the junction of the cystic duct and gallbladder, to ensure that the bile duct has not been isolated inadvertently. If the cholangiogram shows normal anatomy and no evidence of choledocholithiasis, the cholangiocatheter is removed and the cystic duct and artery are divided between small metal clips. The gallbladder is then dissected out of the liver bed and delivered through the umbilical incision, usually with a specimen retrieval bag. Care is taken to avoid perforation of the gallbladder during its dissection from the liver because the spillage of gallstones and bile has been shown to increase the risk of postoperative fever and intra-abdominal abscess formation.

An extraordinarily rich plexus of capillaries surrounds bile ducts as they pass through the portal tracts infection 4 weeks after wisdom teeth extraction purchase chloramphenicol no prescription. The peribiliary plexus may modify biliary secretions through the bidirectional exchange of proteins antibiotics for sinus infection webmd purchase discount chloramphenicol online, inorganic ions aem 5700 antimicrobial buy chloramphenicol with visa, and bile acids between blood and bile antibiotic 3 days uti discount chloramphenicol 250 mg overnight delivery. Because blood flows in the direction (from the large toward the small ducts) opposite to that of bile flow virus 20 furaffinity chloramphenicol 250 mg, the peribiliary plexus presents a countercurrent stream of biliaryreabsorbed substances to hepatocytes treatment for uti in goats discount 500mg chloramphenicol visa. The intrahepatic arteries, veins, bile ducts, and hepatocytes are innervated by adrenergic and cholinergic nerves. In the autonomic nervous system, there are a number of regulatory peptides, such as neuropeptide tyrosine, calcitonin gene-related peptide, somatostatin, vasoactive intestinal polypeptide, enkephalin, and bombesin. Neuropeptide tyrosine-positive nerves present in extrahepatic bile ducts may serve to regulate bile flow by autocrine or paracrine mechanisms. The lymphatic vessels of the hepatic, cystic, and proximal portions of the bile duct empty into glands at the hilum of the liver. The absorptive surface of the gallbladder is enhanced by numerous prominent folds. The gallbladder is covered anteriorly by an adventitia that is fused with the capsule of the liver. On its posterior aspect and at the apex, it is covered by the visceral peritoneum. The posterior aspects of the fundus and body lie close to the transverse colon and duodenum, respectively; with perforation of the gallbladder, gallstones can readily penetrate these structures. Hartmann pouch is a bulging of the inferior surface of the infundibulum that lies close to the neck of the gallbladder. Gallstones can become impacted in Hartmann pouch, thereby obstructing the cystic duct and producing cholecystitis. The mucous membrane of the gallbladder neck forms the spiral valve of Heister, which is involved in regulating flow into and out of the gallbladder. The gallbladder is supplied by the cystic artery, which usually arises from the right hepatic artery. The cystic vein provides venous drainage from the gallbladder and cystic ducts and commonly empties into the portal vein and occasionally directly into the hepatic sinusoids. Subserosal and submucosal lymphatics empty into a lymph gland near the neck of the gallbladder. Visceral pain is conducted through sympathetic fibers and is frequently referred to the right subcostal, epigastric, and right scapular regions. Branches of both vagus nerves provide parasympathetic innervation that likely contributes to the regulation of gallbladder motility. The gallbladder wall consists of a mucosa, lamina propria, tunica muscularis, and serosa. Tubuloalveolar glands are found in the region of the neck of the gallbladder and are involved in mucus production. The ducts of Luschka may be observed along the hepatic surface of the gallbladder and open directly into the intrahepatic bile ducts rather than into the gallbladder cavity. These structures are thought to represent a developmental anomaly, and when they are present in the gallbladder bed may be a source of a bile leak after cholecystectomy. These anomalies must be recognized on cholangiography in order to prevent inadvertent transection or ligation of bile ducts during surgery. In most cases, separate ducts drain the right and left hepatic lobes and open into the duodenum. The cystic duct is absent in most cases of agenesis of the gallbladder (see later); rarely, the duct alone may be absent, and the gallbladder empties directly into the common hepatic duct. Agenesis of the gallbladder may be an isolated anomaly or occur in association with other congenital malformations. Incomplete vacuolization of the solid endodermal cord during development can result in congenital strictures of the gallbladder or cystic duct. Ectopic tissues of foregut endodermal origin, including gastric, hepatic, adrenal, pancreatic, and thyroid tissues, may be found within the gallbladder wall. A double gallbladder is another rare malformation that occurs in 1 to 5 per 10,000 persons in the general population. A single gallbladder may be divided by longitudinal septa into multiple chambers, probably secondary to incomplete vacuolization of the solid gallbladder bud during morphogenesis. This defect likely results from migration of the embryonic bud from the hepatic diverticula to the left rather than to the right. In other cases, a caudal bud that advances farther than the cranial bud may become buried within the cranial structure, creating an intrahepatic gallbladder. It is thought that if the caudal bud lags behind the movement of the cranial bud, a floating gallbladder results. In this setting, the gallbladder is covered completely with peritoneum and suspended from the undersurface of the liver by mesentery to the gallbladder or cystic duct; the gallbladder is abnormally mobile and prone to torsion. Rarely, gallbladders have been found in the abdominal wall, falciform ligament, and retroperitoneum. In one variant, the fundus appears to be bent, giving the appearance of a "Phrygian cap. Aberrant folding of the fossa during the early stages of development can result in kinking between the body and the infundibulum of the gallbladder. Kinked gallbladders probably do not lead to clinical symptoms but may be a source of confusion in the interpretation of imaging studies. A number of these disorders are due to defective ontogenesis or a failure of postnatal adaptation to the extrauterine environment. There is a particular emphasis on neonatal cholangiopathies and the unique aspects of biliary disease in the older child. The general features of the many cholestatic liver diseases of the neonate are similar, and a central problem of pediatric hepatology is differentiating intrahepatic from extrahepatic cholestasis (Table 62. Liver dysfunction in the infant, regardless of the cause, is commonly associated with bile secretory failure and cholestatic jaundice. Although cholestasis may be traced to the level of the hepatocyte or the biliary apparatus, in practice there may be considerable overlap among disorders with regard to the initial and subsequent sites of injury. Mechanical obstruction of the biliary tract invariably produces liver dysfunction and in the neonate may be associated with abnormalities of the liver parenchyma, such as giant cell transformation of hepatocytes. Whether giant cells-a frequent nonspecific manifestation of neonatal liver injury-reflect the noxious effects of biliary obstruction or whether the hepatocytes and the biliary epithelium are damaged by a common agent during ontogenesis, such as a virus with tropism for both types of cells, is unknown. Another common histologic variable that often accompanies neonatal cholestasis is bile ductular paucity or a diminution in the number of interlobular bile ducts. Serial liver biopsies usually show a progressive decrease in the number of bile ductules per portal tract, with a variable amount of associated inflammation and fibrosis. Differentiating conjugated hyperbilirubinemia from the common unconjugated physiologic hyperbilirubinemia of the neonate or the prolonged jaundice occasionally associated with breast-feeding is essential. The stools of a patient with well-established biliary atresia are acholic, but early in the course of incomplete or evolving biliary obstruction, the stools may appear normal or only intermittently pigmented. Lifethreatening but treatable disorders such as bacterial infection and a number of inborn errors of metabolism must be excluded. Success of surgical procedures in relieving the biliary obstruction of biliary atresia or a choledochal cyst depends on early diagnosis and surgery. The approach to evaluation of an infant with cholestatic liver disease is outlined in Box 62. The initial assessment should promptly establish whether cholestatic jaundice is present and assess the severity of liver dysfunction. A more detailed investigation may be required and should be guided by the clinical features of the case. Numerous routine and specialized biochemical tests and imaging procedures have been proposed to distinguish intrahepatic from extrahepatic cholestasis in infants and thereby avoid unnecessary surgical exploration. Unfortunately, no single test has proved to have satisfactory discriminatory value, because at least 10% of infants with intrahepatic cholestasis have bile secretory failure sufficient to lead to an overlap in diagnostic test results with those suggestive of biliary atresia. The use of hepatobiliary scintigraphic imaging agents such as 99mTc iminodiacetic acid derivatives may be helpful in differentiating extrahepatic biliary atresia from other causes of neonatal jaundice. Nevertheless, the modality remains useful for assessing cystic duct patency in patients with a hydropic gallbladder or cholelithiasis. Percutaneous transhepatic cholangiopancreatography may be of value in visualizing the biliary tract in selected patients,48 but the technique is more difficult to perform in infants than in adults because the intrahepatic bile ducts are small and because most disorders that occur in infants do not result in dilatation of the biliary tract. Percutaneous liver biopsy is particularly valuable in evaluating cholestatic patients and can be undertaken in even the smallest infants with only sedation and local anesthesia. When doubt about the diagnosis persists, the patency of the biliary tract can be examined directly by a minilaparotomy and operative cholangiography. The disease is not inherited, and there have been several reports of dizygotic and monozygotic twins discordant for biliary atresia. In a study of 461 patients in France, seasonality, time clustering, and time-space clustering could not be demonstrated. In the multistate case-controlled National Birth Defects Prevention Study conducted between 1997 and 2002, babies born to non-Hispanic black mothers were at greater risk than those born to non-Hispanic white mothers. Clinical features support the concept that in most cases, injury to the biliary tract occurs after biliary morphogenesis, usually after birth. Support for potential toxin-induced injury is based on the finding that ingestion of a plant isoflavonoid was associated with the development of biliary atresia in livestock and in a zebrafish model. Another genome-wide association study identified a susceptibility locus for biliary atresia on locus 10q24. The resulting cholangiocyte injury, inflammation, and fibrosis lead to complete bile duct obstruction. How these events are coordinated, why the disease occurs only in the first few months of life, why a minority of infants with perinatal viral infections develop biliary atresia, and why the disease does not recur in a transplanted liver are unanswered questions. Extrahepatic anomalies occur in 10% to 25% of patients and include cardiovascular defects, polysplenia, malrotation, situs inversus, and bowel atresias. These forms of biliary atresia have been referred to as "surgically correctable" but unfortunately account for less than 10% of all cases. Complete fibrous obliteration of at least a portion of the extrahepatic bile ducts is a consistent feature found on microscopic examination of the fibrous remnant. In most patients, bile ducts within the liver that extend to the porta hepatis are patent during the first weeks of life but are destroyed progressively, presumably by the same process that damaged the extrahepatic ducts and by the effects of biliary obstruction. In more than 20% of patients, concentric tubular ductal structures similar to those observed in ductal plate malformations are found, indicating that the disease process interfered with the normal remodeling of the biliary tract. Jaundice is observed by the parents or the physician after the period of physiologic hyperbilirubinemia. The stools of a patient with well-established biliary atresia are acholic, but early in the course the stools may appear normally pigmented or only intermittently pigmented. Screening for biliary atresia in Taiwan by the use of a stool color card given to parents has decreased the number of late referrals for evaluation of cholestasis. Ascites and edema are not present initially, but coagulopathy may result from vitamin K deficiency. Laboratory studies initially reveal evidence of cholestasis, with a serum total bilirubin level of 6 to 12 mg/dL, at least 50% of which is conjugated. Pathology Histopathologic findings on initial liver biopsy specimens are of great importance in the management of patients with biliary atresia. Furthermore, bile ductules show varying injury to the biliary epithelium, including swelling, vacuolization, and even sloughing of cells into the lumen. Portal tracts have variable amounts of infiltrating inflammatory cells, and in approximately 25% of patients, giant cell transformation of hepatocytes may be seen to a degree observed more commonly in neonatal hepatitis. A, Hepatocellular and canalicular cholestasis, multinucleated giant cells (arrow), and portal tract inflammation. When the possibility of biliary atresia has been raised by clinical, pathologic, and imaging findings, exploratory laparotomy and operative cholangiography are necessary to document the site of obstruction and direct attempts at surgical treatment. The operation is completed by the anastomosis of a Roux-en-Y loop of jejunum around the bare edge of the transected tissue to provide a conduit for biliary drainage. Multiple attempts at re-exploration and revision of nonfunctional conduits should be avoided. A 35to 40-cm Roux-en-Y anastomosis is made to the porta hepatis after surgical excision of the atretic extrahepatic biliary tract and a cone of fibrous tissue from the porta hepatis. Multiple small but patent bile ducts may be uncovered by this dissection and drained into the Roux loop. An enlarged depiction of the anastomosis of the jejunal loop to the porta hepatis is shown on the left. Over 98% of these patients had clinical or biochemical evidence of chronic liver disease. Several factors have been found to contribute to the varying outcome after hepatic portoenterostomy. The presence of ductal plate malformation on liver biopsy specimens also predicts poor bile flow after hepatoportoenterostomy. The quantity of the bile flow has been correlated with the total area of the biliary ductules identified in the excised porta hepatis specimen. These congenital anomalies will continue to be referred to as choledochal cysts for historical reasons but are likely heterogeneous in etiology and have in common a spectrum of focal or diffuse extrahepatic bile ductal dilatation with varying degrees of intrahepatic involvement. Cases have been described in utero and in older adult patients, but approximately two thirds of patients seek medical attention before 10 years of age. Whether type V, or Caroli disease, which consists of single or multiple dilatations of the intrahepatic ductal system, should be viewed as a form of choledochal cyst is unsettled. The cause is unknown, but there may be evidence of obstruction at the distal end of the bile duct secondary to stenosis or inspissated bile. Clinical signs, including jaundice, acholic stools, dark urine, and ascites, typically occur during the first months of life. Progressive abdominal distention is a usual feature; bile staining of fluid within umbilical or inguinal hernias may be observed. Mild-to-moderate conjugated hyperbilirubinemia with minimal elevation of serum aminotransferase levels is typical. Abdominal paracentesis reveals clear, bile-stained ascitic fluid, which usually is sterile.

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Liver transplantation for acute intermittent porphyria is complicated by a high rate of hepatic artery thrombosis virus 68 in children generic 250 mg chloramphenicol with mastercard. Liver transplantation for acute intermittent porphyria: biochemical and pathologic studies of the explanted liver antibiotics for uti starting with m discount chloramphenicol generic. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda antibiotic kidney damage buy chloramphenicol 500 mg on line. Resolution of porphyria cutanea tarda in patients with hepatitis C following ledipasvir-sofosbuvir combination therapy antibiotics for dogs with staph cheap 500 mg chloramphenicol visa. A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria bacteria worksheets order cheap chloramphenicol online. 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Features of severe liver disease with portal hypertension in patients with cystic fibrosis. Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy. Cystic fibrosis-related liver disease: research challenges and future perspectives. The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Transcriptional basis for hepatic fibrosis in cystic fibrosis-associated liver disease. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. The nucleotide and amino acid sequences showed 95% identity between the 2 strains. A rapid rate of disease decline among children has occurred since implementation of vaccination. With improvements in these factors, disease susceptibility has shifted from children to older adults. Thereafter, newborns remain susceptible until the virus is reintroduced into the community. The enterohepatic cycles of the virus lifecycle continue until neutralizing antibodies and other immune mechanisms interrupt the cycle. Rarely, acute hepatitis A can have a prolonged or a relapsing course and, occasionally, profound cholestasis can occur. Adults and older adults are more likely to have profound hepatocellular dysfunction, require hospitalization, and have higher mortality rates. Children younger than 2 years of age are usually asymptomatic; jaundice develops in only 20% of them, whereas symptoms develop in most children (80%) 5 years of age or older. Symptoms of hepatitis may last from a few days to 2 weeks and usually decrease with the onset of clinical jaundice. Complete clinical recovery is achieved in 60% of affected persons within 2 months and in almost everyone by 6 months. The overall prognosis of acute hepatitis A in otherwise healthy adults is excellent. In 8 of these patients, complications led to preterm labor at a median of 34 gestational weeks (range, 31 to 37 weeks). Mortality rates were similar between blacks and other people of color, who had rates slightly higher than those of whites. From 2004 to 2008, the mortality rate of acute hepatitis A was consistently higher among male patients than female patients. The available monovalent vaccines were initially licensed for use in children older than age 2 but are now licensed for use after age 12 months. Groups for which vaccination should be offered include travelers to areas of intermediate or high endemicity, persons who require lifelong blood product transfusions, men who have sex with men, persons with chronic liver disease, workers in contact with non-human primates, and people who inject drugs. Other rare extrahepatic manifestations that may be immune-complex related include toxic epidermal necrolysis, fatal myocarditis, renal failure in the absence of liver failure, optic neuritis, transverse myelitis, polyneuritis, and cholecystitis. Hematologic complications include thrombocytopenia, aplastic anemia, and red-cell aplasia. Patients with more protracted illness appear to have a higher frequency of extrahepatic manifestations. The test result is positive from the onset of symptoms55 and usually remains positive for approximately 4 months. The possibility exists that a number of persons with asymptomatic hepatitis A still posed an infectious risk to others. Extensive use of the vaccines in clinical trials and postmarketing surveillance support the safety and efficacy of these products. The final products are purified and formalin-inactivated; they contain alum as an adjuvant. In children, the most common side effects have been soreness at the injection site (15%), feeding problems (8%), headache (4%), and induration at the injection site (4%). Even if medical advice is sought before travel, the time is usually insufficient for completing the standard immunization schedule. The response to vaccination, however, may be reduced because of a blunted immune system. Picornaviridae: classification and nomenclature of viruses: fifth report of the international Committee on Taxonomy of viruses. Study of the chemical nature of Frp/3 cell recognition units for hepatitis A virus. Identification of a surface glycoprotein on African green monkey kidney cells as a receptor for hepatitis A virus. Genetic relatedness of hepatitis A virus strains recovered from different geographic regions. Long-term antibody persistence after vaccination with a 2-dose Havrix (inactivated hepatitis A vaccine): 20 years of observed data, and long-term modelbased predictions. Single-dose administration of inactivated hepatitis A vaccination in the context of hepatitis A vaccine recommendations. Acute hepatitis A infection in pregnancy is associated with high rates of gestational complications and preterm labor.

Bile acids are the primary solute in bile antibiotic powder order chloramphenicol, constituting approximately 67% of bile oral antibiotics for acne effectiveness chloramphenicol 250 mg without a prescription. Cholic acid bacteria have nucleus discount chloramphenicol 250 mg with amex, chenodeoxycholic acid bacteria klebsiella cheap chloramphenicol 500 mg with amex, and deoxycholic acid constitute more than 95% of the biliary bile acids antibiotic resistance in bacteria is the result of order generic chloramphenicol canada, and virtually all the biliary bile acids are in conjugated form antibiotic 600 mg order chloramphenicol 250mg visa. In this process, cholesterol, a lipophilic compound, is converted into a water-soluble product. The newly synthesized bile acids are termed primary bile acids to distinguish them from the products of bacterial metabolism, which are termed secondary bile acids. The kinetics of bile acid synthesis and turnover in humans is summarized in Table 64. Secondary metabolism of bile acids includes 7-dehydroxylation by the intestinal flora, deconjugation by the intestinal flora, epimerization of the 3- and 7-hydroxyl groups by the intestinal flora, hepatic reduction of the 7-oxo derivative of chenodeoxycholic acid to 7-oxo lithocholic acid, and hepatic re-epimerization of 3-hydroxy bile acids. Bile acids are also sulfated primarily at the C-3 position by the liver and kidney. Steady-state kinetics of serum bile acids in healthy human subjects: single and dual isotope techniques using stable isotopes and mass spectrometry. Measurement of parameters of cholic acid kinetics in plasma using a microscale stable isotope dilution technique: application to rodents and humans. In the alternative pathway, cholesterol is first hydroxylated on the side chain by C-24, C-25, or C-27 sterol hydroxylases. The overall process of bile acid biosynthesis is complex, involving 17 different enzymes divided into 2 broad groups. Sterol ring modifications precede side chain changes in the classical pathway, whereas side chain modifications occur before or during changes to the sterol ring structure in the alternative pathway. These complex molecular titrations link bile acid synthesis to changes in intestinal as well as hepatic bile acid levels. For the alternative pathway of bile acid synthesis, the primary mechanism for regulation appears to be post-transcriptional. This involves cholesterol delivery by members of the steroidogenic acute regulatory protein family to the inner mitochondrial membrane, the site of sterol 27-hydroxylation. However, the alternative pathway can also be regulated transcriptionally by bile acids. This conjugation makes the bile acid more hydrophilic and increases the acidic strength of its side chain, in essence converting a weak acid (pKa 5. The major function of conjugation to glycine or taurine is to decrease the passive diffusion of bile acids across cell membranes during their transit in the enterohepatic circulation. As a result, efficient uptake and export of conjugated bile acids requires the presence of specific membrane carriers. Compared with unconjugated bile acids, conjugated bile acids are also more soluble at acidic pH and more resistant to precipitation in the presence of high concentrations of calcium. The net effect of conjugation is to maintain high intraluminal concentrations of bile acids in the biliary tract, gallbladder and small intestine to facilitate lipid solubilization, digestion, and absorption. The physiologic significance of this bile acid modification is illustrated by the finding that patients with inherited defects in bile acid conjugation present with fat-soluble vitamin malabsorption and steatorrhea and respond favorably to administration of conjugated bile acids such as glycocholic acid. Although most of the conjugated bile acids secreted into the small intestine are efficiently absorbed intact, gut bacteria-derived bile salt hydrolases will remove the glycine or taurine group from 15% of the bile acids in the small intestine. These deconjugated bile acids can pass into the colon or be absorbed by passive or active mechanisms from the small intestine and returned to the liver, where they are reconjugated to glycine or taurine and resecreted into bile along with newly synthesized bile acids. This process of intestinal deconjugation and hepatic reconjugation is a normal part of bile acid metabolism. Under normal physiologic conditions in adults, these polyhydroxylated bile acids are typically present at only very low levels. However, these unusual bile acid species are present at higher levels in newborns, in patients after bariatric surgery, and in patients with cholestatic liver disease. At a fundamental level, the enterohepatic circulation of bile acids can be considered to consist of a series of storage chambers (gallbladder and small intestine), valves (sphincter of Oddi and ileocecal valve), mechanical pumps (small intestine), and chemical pumps (hepatocyte, cholangiocyte, and ileocyte). Efficient intestinal reabsorption and hepatic extraction of bile acids enable an effective recycling and conservation mechanism that largely restricts bile acids to the intestinal and hepatobiliary compartments. During fasting, bile acids move down the biliary tract and are concentrated approximately 10-fold in the gallbladder, resulting in lower levels of bile acids in the small intestine, portal vein, systemic circulation, and liver. However, basal rates of hepatic bile acid secretion are maintained, and enterohepatic cycling continues for that portion of the bile acid pool that is not sequestered in the gallbladder. In response to a meal, cholecystokinin is released from the intestinal mucosa and acts on the of bile acids carried out by the gut microbiota is epimerization of the -hydroxyl groups to generate their corresponding -hydroxy derivatives ("iso" bile acids), such as isolithocholic acid and isodeoxycholic acid. A concentrated solution of mixed micelles (bile acids, phospholipids, and cholesterol) then passes via the bile duct from the gallbladder bile into the small intestine. In the intestinal lumen, these micelles facilitate fat digestion and absorption by stimulating the action of pancreatic lipase on triglyceride, solubilizing the hydrolytic products such as long chain saturated fatty acids and shuttling these hydrophobic lipids across the unstirred water layer to the mucosal surface. During digestion of a large meal, the gallbladder remains contracted, and bile acids secreted by the liver bypass the gallbladder and empty directly into the duodenum. During this period, the intraluminal bile acid concentration in the small intestine is 5 to 10 mmol/L, well above the threshold concentration of approximately 1. During the interdigestive period, the sphincter of Oddi contracts and the gallbladder relaxes, causing a larger fraction of the bile acids secreted into bile to enter the gallbladder for storage. This pulsatile rhythm of bile acid secretion is maintained even after cholecystectomy. When the gallbladder is absent, bile acids are stored in the proximal small intestine during fasting, with the intestinal migrating motor complex driving the distal movement of the intraluminal bile acid pool (see Chapter 99). Following ingestion of a meal, small intestinal contractions accelerate and propel the stored bile acids to the distal ileum, where they are actively reabsorbed and carried back to the liver for resecretion into bile. The enterohepatic cycling of bile acids is extremely efficient; less than 10% of the intestinal bile acids escape reabsorption and are eliminated in the feces. Bile acids are absorbed from the small intestine by passive absorption down the length of the intestine and by active transport in the terminal ileum. The bile acid pool cycles 2 to 3 times per meal, and the intestine may reabsorb between 10 and 30 g of bile acid per day. Hepatic conversion of cholesterol to bile acid balances fecal excretion to maintain the bile acid pool size. The presence of an ileal active transport system and enterohepatic circulation dissociates hepatic bile acid secretion from bile acid synthesis, thereby improving the efficiency of intestinal nutrient digestion and absorption. Because bile acid secretion induces hepatic bile flow, maintenance of the enterohepatic circulation also promotes continuous secretion of bile. The dissociation of bile acid biosynthesis from intestinal delivery is also aided by the presence of a gallbladder because the availability of a concentrative storage reservoir permits bile acids to be delivered in a controlled fashion at high concentrations to the duodenum. The ileal bile acid transporter and gallbladder are complementary rather than redundant, and they function together to conserve bile acids. In the presence of a gallbladder but absence of an active ileal bile acid transporter, the bile acids secreted into the intestine would not be efficiently reabsorbed. Emptying of the gallbladder contents would necessarily be followed by a refractory period during which the supply of bile acids is insufficient to promote efficient lipid digestion and absorption. The refractory period would last until hepatic synthesis restores the bile acid pool. Absorption of the protonated unconjugated bile acid molecule generates a bicarbonate anion, which together with hepatic resecretion of the bile acid produces a bicarbonate-rich choleresis. In addition, because ductal bile normally contains almost all conjugated bile acids under normal physiologic conditions, the contribution of cholehepatic shunting of unconjugated bile acids to bile flow was originally thought to be negligible. However, the significance of this pathway in humans still remains to be determined. Compounds such as the conjugated bile acids that are actively pumped across the canalicular membrane generate bile flow and are termed primary solutes. Besides bile acids, primary solutes include glutathione, conjugated bilirubin, heavy metals, and conjugates of various metabolites and xenobiotics. Water, plasma electrolytes, calcium, glucose, amino acids, bicarbonate, and other low-molecular-weight solutes that flow into the canaliculus in response to the osmotic gradient are termed secondary solutes. The choleretic activity of each primary solute is defined as the volume of bile flow induced per amount of solute secreted. For natural bile acid species, the choleretic activity ranges from 8 to 40 L of bile flow induced per micromole of bile acid secreted. The secretion of other primary solutes besides bile acids such as glutathione and bicarbonate by the hepatocyte and biliary epithelium also contributes to bile formation. Newly secreted hepatic canalicular bile is modified during its transit through the biliary tract via the action of cholangiocytes. The ductular modifications to canalicular bile include (1) the absorption of solutes such as glucose, amino acids, and bile acids; (2) the movement of water through specific channels (aquaporins) and paracellularly; and (3) the secretion of solutes such as bicarbonate and chloride. The contribution of this ductular secretion varies among species, with estimates suggesting that it may account for up to 30% of bile flow in humans but less than 10% of bile flow in animals such as rats. To maintain this process, hepatocytes must transport bile acids efficiently from the portal blood into bile. Bile acid flux through the liver and the number of participating hepatocytes vary. In the fasting state, uptake of bile acids is highest in the periportal hepatocytes (closest to the portal venules), whereas during feeding, more distal hepatocytes in the liver acinus are recruited to participate. Conversely, production and secretion of newly synthesized bile acids is highest in pericentral hepatocytes (closest to the central vein). In this fashion, the periportal hepatocytes transport a larger fraction of the bile acid pool and are thought to be major drivers of bile aciddependent bile flow. Uptake by the liver is typically expressed as fractional extraction, or first-pass extraction, and represents the percentage of bile acids removed during a single passage through the hepatic acinus. The fractional extraction of bile acids from sinusoidal blood ranges from 50% to 90% and remains constant irrespective of systemic bile acid concentrations. Due to the rapid differential hepatic clearance, the concentration of total bile acids in the systemic circulation is low, averaging 2 to 5 mol/L and 5 to 15 mol/L in the fasting and fed states, respectively, and the bile acid composition in the systemic circulation does not strictly mirror that of the other compartments in the body. The sinusoidal membrane also contains a sodium-hydrogen exchanger and a sodium-bicarbonate cotransporter (symporter). Because of their importance for bile secretion, the bile acid transporters are highlighted; however, the hepatocyte sinusoidal and canalicular membranes also express specialized transport proteins for a wide spectrum of endogenous and exogenous compounds. This variant, which is prevalent in Asian populations (minor allele frequency ranging from 3. For example, there is little drop in intraluminal bile acid concentrations prior to the ileum, and bile acid malabsorption occurs after ileal resection. Studies using in situ perfused intestinal segments to measure bile acid absorption demonstrated that ileal bile acid transport is a highcapacity system and sufficient to account for the biliary output of bile acids. Ileal active transport is the major route of conjugated bile acid uptake, particularly for the more hydrophilic and taurine-conjugated species. In the proximal small intestine, a fraction of the glycine-conjugated bile acids are protonated and can undergo nonionic passive diffusion when the intraluminal pH becomes transiently acidic during digestion. In addition, metabolism by the gut microbiota in the small intestine and colon generates unconjugated hydrophobic bile acids, which are weak acids and are passively absorbed if they remain in solution. Renal Bile Acid Transport A fraction (10% to 50%, depending on the bile acid species) of the bile acids returning in the portal circulation escapes hepatic first-pass extraction and spills into the systemic circulation. The binding of bile acids to plasma proteins reduces glomerular filtration and minimizes urinary excretion of bile acids. In healthy humans, the kidney filters approximately 100 mol of bile acids each day. Remarkably, only 1 to 2 mol are excreted in the urine because of highly efficient tubular reabsorption. Even in patients with cholestatic liver disease, in whom plasma bile acid concentrations are significantly elevated, the 24-hour urinary excretion of nonsulfated bile acids is much less than the quantity that undergoes glomerular filtration. Subsequent studies have shown that bile acids in the glomerular filtrate are actively reabsorbed from the renal tubules, and this process contributes to the rise in serum bile acid concentrations in patients with cholestatic liver disease. After their efflux, the conjugated or unconjugated bile acids are carried in sinusoidal blood to more pericentral hepatocytes for reuptake and secretion into bile. In addition, the modified bile acids generated by hepatocyte phase 1 or phase 2 metabolism are also effluxed across the sinusoidal membrane and pass into the systemic circulation, where they can be filtered by the kidney and excreted in urine. These hepatoprotective mechanisms, which also include downregulation of the major liver bile acid uptake transporters, are an important part of the adaptive response to conditions of bile acid overload. Although inherited defects in biosynthesis are rare, these disorders serve to illustrate the importance of bile acid synthesis for normal hepatic and intestinal function. Inherited defects in 11 of the enzymes and 1 transporter involved in bile acid biosynthesis have been reported. In addition to these specific defects, disorders that disrupt peroxisome biogenesis such as Zellweger syndrome also affect bile acid synthesis because the bile acid side chain modification steps occur in the peroxisome (see Chapter 77). A single enzyme defect is usually not sufficient to block production of all bile acids, because multiple biosynthetic pathways exist. Clinically, patients with bile acid synthesis defects typically present with steatorrhea, growth retardation, sequelae associated with fat-soluble vitamin malabsorption, and mild to severe liver disease. Depending on the step in the pathway and the nature of the mutation, the consequences of bile acid biosynthesis defects can vary, with the most severe producing neonatal cholestatic liver disease or neurologic disease later in life. The disease is characterized by progressive intrahepatic cholestasis and accumulation of abnormal bile acids. Clinical manifestations include unconjugated hyperbilirubinemia, jaundice, serum aminotransferase elevations, steatorrhea, fat-soluble vitamin deficiency, pruritus, and poor growth. The progression of disease is variable but ultimately results in cirrhosis and hepatic failure in a high proportion of affected persons. Impaired hepatic transport of bile acids and other organic solutes is a prominent feature of both inherited and acquired forms of cholestatic liver disease.