InternalMed_Harrison

InternalMed_Harrison. achieved in patients with chronic hepatitis C who had not undergone transplantation. Unfortunately, tolerability of these protease inhibitor–based regimens remains problematic in this population, particularly in persons with allograft cirrhosis, in whom the frequency of hepatic decompensation is increased. The approval of several new direct-acting antiviral (DAA) agents and of IFN-free DAA regimens against HCV will have a major impact on the management and outcome of both pretransplantation and post-transplantation HCV infection. Such therapeutic approaches (1) permit the clearance of viremia in a substantial proportion of decompensated cirrhotics, thereby preventing recurrent allograft infection and, possibly, even improving the clinical status of these patients, delaying or obviating the need for liver replacement; and (2) achieve sustained virologic responses in a much higher proportion of persons with allograft HCV infection, because of improvements in antiviral treatment efficacy


InternalMed_Harrison

InternalMed_Harrison. need for liver replacement; and (2) achieve sustained virologic responses in a much higher proportion of persons with allograft HCV infection, because of improvements in antiviral treatment efficacy and tolerability.


InternalMed_Harrison

InternalMed_Harrison. A small number of allograft recipients succumb to early HCV-associated liver injury, and a syndrome reminiscent of fibrosing cholestatic hepatitis (see above) has been observed rarely. Because patients with more episodes of rejection receive more immunosuppressive therapy, and because immunosuppressive therapy enhances HCV replication, patients with severe or multiple episodes of rejection are more likely to experience early recurrence of hepatitis C after transplantation. Both high viral levels and older donor age have been linked to recurrent HCV-induced liver disease and to earlier disease recurrence after transplantation.


InternalMed_Harrison

InternalMed_Harrison. Patients who undergo liver transplantation for end-stage alcoholic cirrhosis are at risk of resorting to drinking again after transplantation, a potential source of recurrent alcoholic liver injury. Currently, alcoholic liver disease is one of the more common indications for liver transplantation, accounting for 20–25% of all liver transplantation procedures, and most transplantation centers screen candidates carefully for predictors of continued abstinence. Recidivism is more likely in patients whose sobriety prior to transplantation was <6 months. For abstinent patients with alcoholic cirrhosis, liver transplantation can be undertaken successfully, with outcomes comparable to those for other categories of patients with chronic liver disease, when coordinated by a team approach that includes substance abuse counseling.


InternalMed_Harrison

InternalMed_Harrison. Full rehabilitation is achieved in the majority of patients who survive the early postoperative months and escape chronic rejection or unmanageable infection. Psychosocial maladjustment interferes with medical compliance in a small number of patients, but most manage to adhere to immunosuppressive regimens, which must be continued indefinitely. In one study, 85% of patients who survived their transplant operations returned to gainful activities. In fact, some women have conceived and carried pregnancies to term after transplantation without demonstrable injury to their infants. Diseases of the Gallbladder and Bile Ducts Norton J. Greenberger, Gustav Paumgartner


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InternalMed_Harrison. Diseases of the Gallbladder and Bile Ducts Norton J. Greenberger, Gustav Paumgartner Bile formed in the hepatic lobules is secreted into a complex network of canaliculi, small bile ductules, and larger bile ducts that run with lymphatics and branches of the portal vein and hepatic artery in portal tracts situated between hepatic lobules. These interlobular bile ducts coalesce to form larger septal bile ducts that join to form the right and left hepatic ducts, which in turn, unite to form the common hepatic duct. The common hepatic duct is joined by the cystic duct of the gallbladder to form the common bile duct (CBD), which enters the duodenum (often after joining the main pancreatic duct) through the ampulla of Vater.


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InternalMed_Harrison. Hepatic bile is an isotonic fluid with an electrolyte composition resembling blood plasma. The electrolyte composition of gallbladder bile differs from that of hepatic bile because most of the inorganic anions, chloride and bicarbonate, have been removed by reabsorption across the gallbladder epithelium. As a result of water reabsorption, total solute concentration of bile increases from 3–4 g/dL in hepatic bile to 10–15 g/dL in gallbladder bile. Major solute components of bile by moles percent include bile acids (80%), lecithin and traces of other phospholipids (16%), and unesterified cholesterol (4.0%). In the lithogenic state, the cholesterol value can be as high as 8–10%. Other constituents include conjugated bilirubin; proteins (all immunoglobulins, albumin, metabolites of hormones, and other proteins metabolized in the liver); electrolytes; mucus; and, often, drugs and their metabolites.


InternalMed_Harrison

InternalMed_Harrison. The total daily basal secretion of hepatic bile is ∼500–600 mL. Many substances taken up or synthesized by the hepatocyte are secreted into the bile canaliculi. The canalicular membrane forms microvilli and is associated with microfilaments of actin, microtubules, and other contractile elements. Prior to their secretion into the bile, many substances are taken up into the hepatocyte, while others, such as phospholipids, a portion of primary bile acids, and some cholesterol, are synthesized de novo in the hepatocyte. Three mechanisms are important in regulating bile flow: (1) active transport of bile acids from hepatocytes into the bile canaliculi, (2) active transport of other organic anions, and (3) cholangiocellular secretion. The last is a secretin-mediated and cyclic AMP–dependent mechanism that results in the secretion of a sodiumand bicarbonate-rich fluid into the bile ducts.


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InternalMed_Harrison. Active vectorial secretion of biliary constituents from the portal blood into the bile canaliculi is driven by a set of polarized transport systems at the basolateral (sinusoidal) and the canalicular apical plasma membrane domains of the hepatocyte. Two sinusoidal bile salt uptake systems have been cloned in humans, the Na+/taurocholate cotransporter (NTCP, SLC10A1) and the organic anion–transporting proteins (OATPs), which also transport a large variety of non-bile salt organic anions. Several ATP-dependent canalicular transport systems, “export pumps,” (ATP-binding cassette transport proteins, also known as ABC transporters) have been identified, the most important of which are: the bile salt export pump (BSEP, ABCB11); the anionic conjugate export pump (MRP2, ABCC2), which mediates the canalicular excretion of various amphiphilic conjugates formed by phase II conjugation (e.g., bilirubin monoand diglucuronides and drugs); the multidrug export pump (MDR1, ABCB1) for hydrophobic


InternalMed_Harrison

InternalMed_Harrison. the canalicular excretion of various amphiphilic conjugates formed by phase II conjugation (e.g., bilirubin monoand diglucuronides and drugs); the multidrug export pump (MDR1, ABCB1) for hydrophobic cationic compounds; and the phospholipid export pump (MDR3, ABCB4). Two hemitransporters ABCG5/G8, functioning as a couple, constitute the canalicular cholesterol and phytosterol transporter. F1C1 (ATP8B1) is an aminophospholipid transferase (“flippase”) essential for maintaining the lipid asymmetry of the canalicular membrane. The canalicular membrane also contains ATP-independent transport systems such as the Cl/HCO3 anion exchanger isoform 2 (AE2, SLC4A2)


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InternalMed_Harrison. Diseases of the Gallbladder and Bile Ducts 2076 for canalicular bicarbonate secretion. For most of these transporters, genetic defects have been identified that are associated with various forms of cholestasis or defects of biliary excretion. F1C1 is defective in progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) and results in ablation of all other ATP-dependent transporter functions. BSEP is defective in PFIC2 and BRIC2. Mutations of MRP2 (ABCC2) cause the Dubin-Johnson syndrome, an inherited form of conjugated hyperbilirubinemia (Chap. 359). A defective MDR3 (ABCB4) results in PFIC3. ABCG5/G8, the canalicular half transporters for cholesterol and other neutral sterols, are defective in sitosterolemia. The cystic fibrosis trans-membrane regulator (CFTR, ABCC7) located on bile duct epithelial cells but not on canalicular membranes is defective in cystic fibrosis, which is associated with impaired cholangiocellular


InternalMed_Harrison

InternalMed_Harrison. trans-membrane regulator (CFTR, ABCC7) located on bile duct epithelial cells but not on canalicular membranes is defective in cystic fibrosis, which is associated with impaired cholangiocellular pH regulation during ductular bile formation and chronic cholestatic liver disease, occasionally resulting in biliary cirrhosis.


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InternalMed_Harrison. The primary bile acids, cholic acid and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver, conjugated with glycine or taurine, and secreted into the bile. Secondary bile acids, including deoxycholate and lithocholate, are formed in the colon as bacterial metabolites of the primary bile acids. However, lithocholic acid is much less efficiently absorbed from the colon than deoxycholic acid. Another secondary bile acid, found in low concentration, is ursodeoxycholic acid (UDCA), a stereoisomer of CDCA. In healthy subjects, the ratio of glycine to taurine conjugates in bile is ∼3:1.


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InternalMed_Harrison. Bile acids are detergent-like molecules that in aqueous solutions and above a critical concentration of about 2 mM form molecular aggregates called micelles. Cholesterol alone is sparingly soluble in aqueous environments, and its solubility in bile depends on both the total lipid concentration and the relative molar percentages of bile acids and lecithin. Normal ratios of these constituents favor the formation of solubilizing mixed micelles, while abnormal ratios promote the precipitation of cholesterol crystals in bile via an intermediate liquid crystal phase. In addition to facilitating the biliary excretion of cholesterol, bile acids facilitate the normal intestinal absorption of dietary fats, mainly cholesterol and fat-soluble vitamins, via a micellar transport mechanism (Chap. 349). Bile acids also serve as a major physiologic driving force for hepatic bile flow and aid in water and electrolyte transport in the small bowel and colon.


InternalMed_Harrison

InternalMed_Harrison. Bile acids are efficiently conserved under normal conditions. Unconjugated, and to a lesser degree also conjugated, bile acids are absorbed by passive diffusion along the entire gut. Quantitatively much more important for bile salt recirculation, however, is the active transport mechanism for conjugated bile acids in the distal ileum (Chap. 349). The reabsorbed bile acids enter the portal bloodstream and are taken up rapidly by hepatocytes, reconjugated, and resecreted into bile (enterohepatic circulation).


InternalMed_Harrison

InternalMed_Harrison. The normal bile acid pool size is approximately 2–4 g. During digestion of a meal, the bile acid pool undergoes at least one or more enterohepatic cycles, depending on the size and composition of the meal. Normally, the bile acid pool circulates ∼5–10 times daily. Intestinal reabsorption of the pool is about 95% efficient; therefore, fecal loss of bile acids is in the range of 0.2–0.4 g/d. In the steady state, this fecal loss is compensated by an equal daily synthesis of bile acids by the liver, and, thus, the size of the bile acid pool is maintained. Bile acids in the intestine release fibroblast growth factor 19 (FGF19) into the circulation, which is transported to the liver where it suppresses synthesis of bile acids from cholesterol by inhibiting the rate-limiting enzyme cytochrome P450 7A1 (CYP7A1) and also promotes gallbladder relaxation. While the loss of bile salts in stool is usually matched by increased hepatic synthesis, the maximum rate of synthesis is ∼5 g/d, which may be


InternalMed_Harrison

InternalMed_Harrison. 7A1 (CYP7A1) and also promotes gallbladder relaxation. While the loss of bile salts in stool is usually matched by increased hepatic synthesis, the maximum rate of synthesis is ∼5 g/d, which may be insufficient to replete the bile acid pool size when there is pronounced impairment of intestinal bile salt reabsorption.


InternalMed_Harrison

InternalMed_Harrison. The expression of ABC transporters in the enterohepatic circulation and of the rate-limiting enzymes of bile acid and cholesterol synthesis are regulated in a coordinated fashion by nuclear receptors, which are ligand-activated transcription factors. The hepatic BSEP (ABCB11) is upregulated by the farnesoid X receptor (FXR), a bile acid sensor that also represses bile acid synthesis. The expression of the cholesterol transporter, ABCG5/G8, is upregulated by the liver X receptor (LXR), which is an oxysterol sensor.


InternalMed_Harrison

InternalMed_Harrison. In the fasting state, the sphincter of Oddi offers a high-pressure zone of resistance to bile flow from the CBD into the duodenum. Its tonic contraction serves to (1) prevent reflux of duodenal contents into the pancreatic and bile ducts and (2) promote filling of the gallbladder. The major factor controlling the evacuation of the gallbladder is the peptide hormone cholecystokinin (CCK), which is released from the duodenal mucosa in response to the ingestion of fats and amino acids. CCK produces (1) powerful contraction of the gallbladder, (2) decreased resistance of the sphincter of Oddi, and (3) enhanced flow of biliary contents into the duodenum.


InternalMed_Harrison

InternalMed_Harrison. Hepatic bile is “concentrated” within the gallbladder by energy-dependent transmucosal absorption of water and electrolytes. Almost the entire bile acid pool may be sequestered in the gallbladder following an overnight fast for delivery into the duodenum with the first meal of the day. The normal capacity of the gallbladder is ∼30 mL of bile. Anomalies of the biliary tract are not uncommon and include abnormalities in number, size, and shape (e.g., agenesis of the gallbladder, duplications, rudimentary or oversized “giant” gallbladders, and diverticula). Phrygian cap is a clinically innocuous entity in which a partial or complete septum (or fold) separates the fundus from the body. Anomalies of position or suspension are not uncommon and include left-sided gallbladder, intrahepatic gallbladder, retrodisplacement of the gallbladder, and “floating” gallbladder. The latter condition predisposes to acute torsion, volvulus, or herniation of the gallbladder.


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InternalMed_Harrison. GALLSTONES Epidemiology and Pathogenesis Gallstones are quite prevalent in most Western countries. Gallstone formation increases after age 50. In the United States, the third National Health and Nutrition Examination Survey (NHANES III) has revealed an overall prevalence of gallstones of 7.9% in men and 16.6% in women. The prevalence was high in Mexican Americans (8.9% in men, 26.7% in women), intermediate for non-Hispanic whites (8.6% in men, 16.6% in women), and low for African Americans (5.3% in men, 13.9% in women).


InternalMed_Harrison

InternalMed_Harrison. Gallstones are formed because of abnormal bile composition. They are divided into two major types: cholesterol stones and pigment stones. Cholesterol stones account for more than 90% of all gallstones in Western industrialized countries. Cholesterol gallstones usually contain >50% cholesterol monohydrate plus an admixture of calcium salts, bile pigments, proteins, and fatty acids. Pigment stones are composed primarily of calcium bilirubinate; they contain <20% cholesterol and are classified into “black” and “brown” types, the latter forming secondary to chronic biliary infection.


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InternalMed_Harrison. cHolesterol stones anD biliary sluDGe Cholesterol is essentially water insoluble and requires aqueous dispersion into either micelles or vesicles, both of which require the presence of a second lipid to solubilize the cholesterol. Cholesterol and phospholipids are secreted into bile as unilamellar bilayered vesicles, which are converted into mixed micelles consisting of bile acids, phospholipids, and cholesterol by the action of bile acids. If there is an excess of cholesterol in relation to phospholipids and bile acids, unstable, cholesterol-rich vesicles remain, which aggregate into large multilamellar vesicles from which cholesterol crystals precipitate (Fig. 369-1). There are several important mechanisms in the formation of lithogenic (stone-forming) bile. The most important is increased biliary secretion of cholesterol. This may occur in association with obesity, the metabolic syndrome, high-caloric and cholesterol-rich diets, I. II. Supersaturation III. Nucleation


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InternalMed_Harrison. I. II. Supersaturation III. Nucleation IV. Microstone FIGURE 369-1 Scheme showing pathogenesis of cholesterol gallstone formation. Conditions or factors that increase the ratio of cholesterol to bile acids and phospholipids (lecithin) favor gallstone formation. ABCB4, ATP-binding cassette transporter; ABCG5/8, ATP-binding cassette (ABC) transporter G5/G8; CYP7A1, cytochrome P450 7A1; MDR3, multidrug resistance protein 3, also called phospholipid export pump.


InternalMed_Harrison

InternalMed_Harrison. or drugs (e.g., clofibrate) and may result from increased activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of hepatic cholesterol synthesis, and increased hepatic uptake of cholesterol from blood. In patients with gallstones, dietary cholesterol increases biliary cholesterol secretion. This does not occur in non-gallstone patients on high-cholesterol diets. In addition to environmental factors such as high-caloric and cholesterol-rich diets, genetic factors play an important role in gallstone disease. A large study of symptomatic gallstones in Swedish twins provided strong evidence for a role of genetic factors in gallstone pathogenesis. Genetic factors accounted for 25%, shared environmental factors for 13%, and individual environmental factors for 62% of the phenotypic variation among monozygotic twins. A single nucleotide polymorphism of the gene encoding the hepatic cholesterol transporter ABCG5/G8 has been found in 21% of patients with


InternalMed_Harrison

InternalMed_Harrison. for 62% of the phenotypic variation among monozygotic twins. A single nucleotide polymorphism of the gene encoding the hepatic cholesterol transporter ABCG5/G8 has been found in 21% of patients with gallstones, but only in 9% of the general population. It is thought to cause a gain of function of the cholesterol transporter and to contribute to cholesterol hypersecretion. A high prevalence of gallstones is found among first-degree relatives of gallstone carriers and in certain ethnic populations such as American Indians, Chilean Indians, and Chilean Hispanics. A common genetic trait has been identified for some of these populations by mitochondrial DNA analysis. In some patients, impaired hepatic conversion of cholesterol to bile acids may also occur, resulting in an increase of the lithogenic cholesterol/bile acid ratio. Although most cholesterol stones have a polygenic basis, there are rare monogenic (Mendelian) causes.


InternalMed_Harrison

InternalMed_Harrison. Recently, a mutation in the CYP7A1 gene has been described that 2077 results in a deficiency of the enzyme cholesterol 7-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. The homozygous state is associated with hypercholesterolemia and gallstones. Because the phenotype is expressed in the heterozygote state, mutations in the CYP7A1 gene may contribute to the susceptibility to cholesterol gallstone disease in the population. Mutations in the MDR3 (ABCB4) gene, which encodes the phospholipid export pump in the canalicular membrane of the hepatocyte, may cause defective phospholipid secretion into bile, resulting in cholesterol supersaturation of bile and formation of cholesterol gallstones in the gallbladder and in the bile ducts. Thus, an excess of biliary cholesterol in relation to bile acids and phospholipids is primarily due to hypersecretion of cholesterol, but hyposecretion of bile acids or phospholipids may contribute. An additional


InternalMed_Harrison

InternalMed_Harrison. of biliary cholesterol in relation to bile acids and phospholipids is primarily due to hypersecretion of cholesterol, but hyposecretion of bile acids or phospholipids may contribute. An additional disturbance of bile acid metabolism that is likely to contribute to supersaturation of bile with cholesterol is enhanced conversion of cholic acid to deoxycholic acid, with replacement of the cholic acid pool by an expanded deoxycholic acid pool. It may result from enhanced dehydroxylation of cholic acid and increased absorption of newly formed deoxycholic acid. An increased deoxycholate secretion is associated with hypersecretion of cholesterol into bile.


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InternalMed_Harrison. While supersaturation of bile with cholesterol is an important prerequisite for gallstone formation, it is generally not sufficient by itself to produce cholesterol precipitation in vivo. Most individuals with supersaturated bile do not develop stones because the time required for cholesterol crystals to nucleate and grow is longer than the time bile remains in the gallbladder.


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InternalMed_Harrison. An important mechanism is nucleation of cholesterol monohydrate crystals, which is greatly accelerated in human lithogenic bile. Accelerated nucleation of cholesterol monohydrate in bile may be due to either an excess of pronucleating factors or a deficiency of antinucleating factors. Mucin and certain nonmucin glycoproteins, principally immunoglobulins, appear to be pronucleating factors, while apolipoproteins A-I and A-II and other glycoproteins appear to be antinucleating factors. Pigment particles may possibly play a role as nucleating factors. In a genome-wide analysis of serum bilirubin levels, the uridine diphosphate-glucuronyltransferase 1A1 (UGT1A1) Gilbert’s syndrome gene variant was associated with the presence of gallstone disease. Because most gallstones associated with the UGT1A1 variant were cholesterol stones, this finding points to the role of pigment particles in the pathogenesis of gallbladder stones. Cholesterol mono-hydrate crystal nucleation and crystal growth


InternalMed_Harrison

InternalMed_Harrison. UGT1A1 variant were cholesterol stones, this finding points to the role of pigment particles in the pathogenesis of gallbladder stones. Cholesterol mono-hydrate crystal nucleation and crystal growth probably occur within the mucin gel layer. Vesicle fusion leads to liquid crystals, which, in turn, nucleate into solid cholesterol monohydrate crystals. Continued growth of the crystals occurs by direct nucleation of cholesterol molecules from supersaturated unilamellar or multilamellar biliary vesicles.


InternalMed_Harrison

InternalMed_Harrison. A third important mechanism in cholesterol gallstone formation is gallbladder hypomotility. If the gallbladder emptied all supersaturated or crystal-containing bile completely, stones would not be able to grow. A high percentage of patients with gallstones exhibit abnormalities of gallbladder emptying. Ultrasonographic studies show that gallstone patients display an increased gallbladder volume during fasting and also after a test meal (residual volume) and that fractional emptying after gallbladder stimulation is decreased. The incidence of gallstones is increased in conditions associated with infrequent or impaired gallbladder emptying such as fasting, parenteral nutrition, or pregnancy and in patients using drugs that inhibit gallbladder motility.


InternalMed_Harrison

InternalMed_Harrison. Biliary sludge is a thick, mucous material that, upon microscopic examination, reveals lecithin-cholesterol liquid crystals, cholesterol monohydrate crystals, calcium bilirubinate, and mucin gels. Biliary sludge typically forms a crescent-like layer in the most dependent portion of the gallbladder and is recognized by characteristic echoes on ultrasonography (see below). The presence of biliary sludge implies two abnormalities: (1) the normal balance between gallbladder mucin secretion and elimination has become deranged, and (2) nucleation of biliary solutes has occurred. That biliary sludge may be a precursor form of gallstone disease is evident from several observations. In one study, 96 patients with gallbladder sludge were followed prospectively by serial ultrasound studies. In 18%, biliary sludge disappeared and did


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InternalMed_Harrison. CHAPTER 369 Diseases of the Gallbladder and Bile Ducts 2078 not recur for at least 2 years. In 60%, biliary sludge disappeared and reappeared; in 14%, gallstones (8% asymptomatic, 6% symptomatic) developed; and in 6%, severe biliary pain with or without acute pancreatitis occurred. In 12 patients, cholecystectomies were performed, 6 for gallstone-associated biliary pain and 3 in symptomatic patients with sludge but without gallstones who had prior attacks of pancreatitis; the latter did not recur after cholecystectomy. It should be emphasized that biliary sludge can develop with disorders that cause gallbladder hypomotility; i.e., surgery, burns, total parenteral nutrition, pregnancy, and oral contraceptives—all of which are associated with gallstone formation. However, the presence of biliary sludge implies supersaturation of bile with either cholesterol or calcium bilirubinate. Two other conditions are associated with cholesterol-stone or biliary-sludge formation: pregnancy and


InternalMed_Harrison

InternalMed_Harrison. biliary sludge implies supersaturation of bile with either cholesterol or calcium bilirubinate. Two other conditions are associated with cholesterol-stone or biliary-sludge formation: pregnancy and rapid weight reduction through a very-low-calorie diet. There appear to be two key changes during pregnancy that contribute to a “cholelithogenic state”: (1) a marked increase in cholesterol saturation of bile during the third trimester and (2) sluggish gallbladder contraction in response to a standard meal, resulting in impaired gallbladder emptying. That these changes are related to pregnancy per se is supported by several studies that show reversal of these abnormalities quite rapidly after delivery. During pregnancy, gallbladder sludge develops in 20–30% of women and gallstones in 5–12%. Although biliary sludge is a common finding during pregnancy, it is usually asymptomatic and often resolves spontaneously after delivery. Gallstones, which are less common than sludge and frequently


InternalMed_Harrison

InternalMed_Harrison. Although biliary sludge is a common finding during pregnancy, it is usually asymptomatic and often resolves spontaneously after delivery. Gallstones, which are less common than sludge and frequently associated with biliary colic, may also disappear after delivery because of spontaneous dissolution related to bile becoming unsaturated with cholesterol postpartum. Approximately 10–20% of persons with rapid weight reduction achieved through very-low-calorie dieting develop gallstones. In a study involving 600 patients who completed a 3-month, 520-kcal/d diet, UDCA in a dosage of 600 mg/d proved highly effective in preventing gallstone formation; gallstones developed in only 3% of UDCA recipients, compared to 28% of placebo-treated patients. In obese patients treated by gastric banding, 500 mg/d of UDCA reduced the risk of gallstone formation from 30% to 8% within a follow-up of 6 months. To summarize, cholesterol gallstone disease occurs because of several defects, which include (1) bile


InternalMed_Harrison

InternalMed_Harrison. of UDCA reduced the risk of gallstone formation from 30% to 8% within a follow-up of 6 months. To summarize, cholesterol gallstone disease occurs because of several defects, which include (1) bile supersaturation with cholesterol, (2) nucleation of cholesterol monohydrate with subsequent crystal retention and stone growth, and (3) abnormal gallbladder motor function with delayed emptying and stasis. Other important factors known to predispose to cholesterol-stone formation are summarized in Table 369-1.


InternalMed_Harrison

InternalMed_Harrison. piGment stones Black pigment stones are composed of either pure calcium bilirubinate or polymer-like complexes with calcium and mucin glycoproteins. They are more common in patients who have chronic hemolytic states (with increased conjugated bilirubin in bile), liver cirrhosis, Gilbert’s syndrome, or cystic fibrosis. Gallbladder stones in patients with ileal diseases, ileal resection, or ileal bypass generally are also black pigment stones. Enterohepatic recycling of bilirubin in ileal disease states contributes to their pathogenesis. Brown pigment stones are composed of calcium salts of unconjugated bilirubin with varying amounts of cholesterol and protein. They are caused by the presence of increased amounts of unconjugated, insoluble bilirubin in bile that precipitates to form stones. Deconjugation of an excess of soluble bilirubin monoand diglucuronides may be mediated by endogenous β-glucuronidase but may also occur by spontaneous hydrolysis. Sometimes, the enzyme is also


InternalMed_Harrison

InternalMed_Harrison. Deconjugation of an excess of soluble bilirubin monoand diglucuronides may be mediated by endogenous β-glucuronidase but may also occur by spontaneous hydrolysis. Sometimes, the enzyme is also produced when bile is chronically infected by bacteria, and such stones are brown. Pigment stone formation is frequent in Asia and is often associated with infections in the gallbladder and biliary tree (Table 369-1).


InternalMed_Harrison

InternalMed_Harrison. Diagnosis Procedures of potential use in the diagnosis of cholelithiasis and other diseases of the gallbladder are detailed in Table 369-2. Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis and has replaced oral cholecystography (Fig. 369-2A). Stones as small as 1.5 mm in diameter may be confidently identified provided that firm criteria are used (e.g., acoustic “shadowing” of opacities that are within the gallbladder lumen and that change with the patient’s position [by gravity]). In major medical centers, the false-negative and 1. Demographic/genetic factors: Prevalence highest in North American Indians, Chilean Indians, and Chilean Hispanics, greater in Northern Europe and North America than in Asia, lowest in Japan; familial disposition; hereditary aspects 2. Obesity, metabolic syndrome: Normal bile acid pool and secretion but increased biliary secretion of cholesterol 3.


InternalMed_Harrison

InternalMed_Harrison. Obesity, metabolic syndrome: Normal bile acid pool and secretion but increased biliary secretion of cholesterol 3. Weight loss: Mobilization of tissue cholesterol leads to increased biliary cholesterol secretion while enterohepatic circulation of bile acids is decreased 4. a. Estrogens stimulate hepatic lipoprotein receptors, increase uptake of dietary cholesterol, and increase biliary cholesterol secretion b. Natural estrogens, other estrogens, and oral contraceptives lead to decreased bile salt secretion and decreased conversion of cholesterol to cholesteryl esters 5. Pregnancy: Impaired gallbladder emptying caused by progesterone combined with the influence of estrogens, which increase biliary cholesterol secretion 6. Increasing age: Increased biliary secretion of cholesterol, decreased size of bile acid pool, decreased secretion of bile salts 7. Gallbladder hypomotility leading to stasis and formation of sludge a. b. c. d. Drugs such as octreotide 8.


InternalMed_Harrison

InternalMed_Harrison. Gallbladder hypomotility leading to stasis and formation of sludge a. b. c. d. Drugs such as octreotide 8. Clofibrate therapy: Increased biliary secretion of cholesterol 9. a. b. Genetic defect of the CYP7A1 gene 10. Decreased phospholipid secretion: Genetic defect of the MDR3 gene 11. a. High-calorie, high-fat diet b. 1. Demographic/genetic factors: Asia, rural setting 2. 3. 4. 5. 6. Chronic biliary tract infection, parasite infections 7. 8. Ileal disease, ileal resection or bypass false-positive rates for ultrasound in gallstone patients are ∼2–4%. Biliary sludge is material of low echogenic activity that typically forms a layer in the most dependent position of the gallbladder. This layer shifts with postural changes but fails to produce acoustic shadowing; these two characteristics distinguish sludges from gallstones. Ultrasound can also be used to assess the emptying function of the gallbladder.


InternalMed_Harrison

InternalMed_Harrison. The plain abdominal film may detect gallstones containing sufficient calcium to be radiopaque (10–15% of cholesterol and ∼50% of pigment stones). Plain radiography may also be of use in the diagnosis of emphysematous cholecystitis, porcelain gallbladder, limey bile, and gallstone ileus. Oral cholecystography (OCG) has historically been a useful procedure for the diagnosis of gallstones but has been replaced by ultrasound and is regarded as obsolete. It may be used to assess the patency of the cystic duct and gallbladder emptying function. Further, OCG can also delineate the size and number of gallstones and determine whether they are calcified.


InternalMed_Harrison

InternalMed_Harrison. Radiopharmaceuticals such as 99mTc-labeled N-substituted iminodiacetic acids (HIDA, DIDA, DISIDA, etc.) are rapidly extracted from the blood and are excreted into the biliary tree in high concentration even in the presence of mild to moderate serum bilirubin elevations. Failure to image the gallbladder in the presence of biliary ductal visualization may indicate cystic duct obstruction, acute or chronic cholecystitis, or surgical absence of the organ. Such scans have some application in the diagnosis of acute cholecystitis.


InternalMed_Harrison

InternalMed_Harrison. Symptoms of Gallstone Disease Gallstones usually produce symptoms by causing inflammation or obstruction following their migration into the cystic duct or CBD. The most specific and characteristic symptom of gallstone disease is biliary colic that is a constant and often long-lasting pain (see below). Obstruction of the cystic duct or CBD by a stone produces increased intraluminal pressure and distention of the viscus that cannot be relieved by repetitive biliary contractions. The resultant visceral pain is characteristically a severe, steady ache or fullness in the epigastrium or right upper quadrant (RUQ) of the abdomen with frequent radiation to the interscapular area, right scapula, or shoulder.


InternalMed_Harrison

InternalMed_Harrison. Biliary colic begins quite suddenly and may persist with severe intensity for 30 min to 5 h, subsiding gradually or rapidly. It is steady rather than intermittent, as would be suggested by the word colic, which must be regarded as a misnomer, although it is in widespread use. An episode of biliary pain persisting beyond 5 h should raise the suspicion of acute cholecystitis (see below). Nausea and vomiting frequently accompany episodes of biliary pain. An elevated level of serum bilirubin and/or alkaline phosphatase suggests a common duct stone. Fever or chills (rigors) with biliary pain usually imply a complication, i.e., cholecystitis, pancreatitis, or cholangitis. Complaints of short-lasting, vague epigastric fullness, dyspepsia, eructation, or flatulence, especially following a fatty meal, should not be confused with biliary pain. Such symptoms are frequently elicited from patients with or without gallstone disease Diseases of the Gallbladder and Bile Ducts


InternalMed_Harrison

InternalMed_Harrison. Diseases of the Gallbladder and Bile Ducts FIGURE 369-2 Examples of ultrasound and radiologic studies of the biliary tract. A. An ultrasound study showing a distended gallbladder (GB) containing a single large stone (arrow), which casts an acoustic shadow. B. Endoscopic retrograde cholangiopancreatogram (ERCP) showing normal biliary tract anatomy. In addition to the endoscope and large vertical gallbladder filled with contrast dye, the common hepatic duct (CHD), common bile duct (CBD), and pancreatic duct (PD) are shown. The arrow points to the ampulla of Vater. C. Endoscopic retrograde cholangiogram (ERC) showing choledocholithiasis. The biliary tract is dilated and contains multiple radiolucent calculi. D. ERCP showing sclerosing cholangitis. The common bile duct shows areas that are strictured and narrowed.


InternalMed_Harrison

InternalMed_Harrison. 2080 but are not specific for biliary calculi. Biliary colic may be precipitated by eating a fatty meal, by consumption of a large meal following a period of prolonged fasting, or by eating a normal meal; it is frequently nocturnal, occurring within a few hours of retiring.


InternalMed_Harrison

InternalMed_Harrison. Natural History Gallstone disease discovered in an asymptomatic patient or in a patient whose symptoms are not referable to cholelithiasis is a common clinical problem. Sixty to 80% of persons with asymptomatic gallstones remain asymptomatic over follow-up periods of up to 25 years. The probability of developing symptoms within 5 years after diagnosis is 2–4% per year and decreases in the years thereafter to 1–2%. The yearly incidence of complications is about 0.1–0.3%. Patients remaining asymptomatic for 15 years were found to be unlikely to develop symptoms during further follow-up, and most patients who did develop complications from their gallstones experienced prior warning symptoms. Similar conclusions apply to diabetic patients with silent gallstones. Decision analysis has suggested that (1) the cumulative risk of death due to gallstone disease while on expectant management is small, and (2) prophylactic cholecystectomy is not warranted.


InternalMed_Harrison

InternalMed_Harrison. Complications requiring cholecystectomy are much more common in gallstone patients who have developed symptoms of biliary pain. Patients found to have gallstones at a young age are more likely to develop symptoms from cholelithiasis than are patients >60 years at the time of initial diagnosis. Patients with diabetes mellitus and gallstones may be somewhat more susceptible to septic complications, but the magnitude of risk of septic biliary complications in diabetic patients is incompletely defined.


InternalMed_Harrison

InternalMed_Harrison. In asymptomatic gallstone patients, the risk of developing symptoms or complications requiring surgery is quite small (see above). Thus, a recommendation for cholecystectomy in a patient with gallstones should probably be based on assessment of three factors: (1) the presence of symptoms that are frequent enough or severe enough to interfere with the patient’s general routine; the presence of a prior complication of gallstone disease, i.e., history of acute cholecystitis, pancreatitis, gallstone fistula, etc.; or the presence of an underlying condition predisposing the patient to increased risk of gallstone complications (e.g., calcified or porcelain gallbladder and/or a previous attack of acute cholecystitis regardless of current symptomatic status). Patients with very large gallstones (>3 cm in diameter) and patients harboring gallstones in a congenitally anomalous gallbladder might also be considered for prophylactic cholecystectomy. Although young age is a worrisome factor in


InternalMed_Harrison

InternalMed_Harrison. (>3 cm in diameter) and patients harboring gallstones in a congenitally anomalous gallbladder might also be considered for prophylactic cholecystectomy. Although young age is a worrisome factor in asymptomatic gallstone patients, few authorities would now recommend routine cholecystectomy in all young patients with silent stones. Laparoscopic cholecystectomy is a minimal-access approach for the removal of the gallbladder together with its stones. Its advantages include a markedly shortened hospital stay, minimal disability, and decreased cost, and it is the procedure of choice for most patients referred for elective cholecystectomy.


InternalMed_Harrison

InternalMed_Harrison. From several studies involving >4000 patients undergoing laparoscopic cholecystectomy, the following key points emerge: complications develop in ∼4% of patients, (2) conversion to laparotomy occurs in 5%, (3) the death rate is remarkably low (i.e., <0.1%), and (4) the rate of bile duct injuries is low (i.e., 0.2–0.6%) and comparable with open cholecystectomy. These data indicate why laparoscopic cholecystectomy has become the “gold standard” for treating symptomatic cholelithiasis.


InternalMed_Harrison

InternalMed_Harrison. In carefully selected patients with a functioning gallbladder and with radiolucent stones <10 mm in diameter, complete dissolution can be achieved in ∼50% of patients within 6 months to 2 years. For good results within a reasonable time period, this therapy should be limited to radiolucent stones smaller than 5 mm in diameter. The dose of UDCA should be 10–15 mg/kg per day. Stones larger than 10 mm in size rarely dissolve. Pigment stones are not responsive to UDCA therapy. Probably ≤10% of patients with symptomatic cholelithiasis are candidates for such treatment. However, in addition to the vexing problem of recurrent stones (30–50% over 3–5 years of follow-up), there is also the factor of taking an expensive drug for up to 2 years. The advantages and success of laparoscopic cholecystectomy have largely reduced the role of gallstone dissolution to patients who wish to avoid or are not candidates for elective cholecystectomy. However, patients with cholesterol gallstone disease who


InternalMed_Harrison

InternalMed_Harrison. have largely reduced the role of gallstone dissolution to patients who wish to avoid or are not candidates for elective cholecystectomy. However, patients with cholesterol gallstone disease who develop recurrent choledocholithiasis after cholecystectomy should be on long-term treatment with UDCA.


InternalMed_Harrison

InternalMed_Harrison. ACUTE AND CHRONIC CHOLECYSTITIS Acute Cholecystitis Acute inflammation of the gallbladder wall usually follows obstruction of the cystic duct by a stone. Inflammatory response can be evoked by three factors: (1) mechanical inflammation produced by increased intraluminal pressure and distention with resulting ischemia of the gallbladder mucosa and wall, (2) chemical inflammation caused by the release of lysolecithin (due to the action of phospholipase on lecithin in bile) and other local tissue factors, and (3) bacterial inflammation, which may play a role in 50–85% of patients with acute cholecystitis. The organisms most frequently isolated by culture of gallbladder bile in these patients include Escherichia coli, Klebsiella spp., Streptococcus spp., and Clostridium spp.


InternalMed_Harrison

InternalMed_Harrison. Acute cholecystitis often begins as an attack of biliary pain that progressively worsens. Approximately 60–70% of patients report having experienced prior attacks that resolved spontaneously. As the episode progresses, however, the pain of acute cholecystitis becomes more generalized in the right upper abdomen. As with biliary colic, the pain of cholecystitis may radiate to the interscapular area, right scapula, or shoulder. Peritoneal signs of inflammation such as increased pain with jarring or on deep respiration may be apparent. The patient is anorectic and often nauseated. Vomiting is relatively common and may produce symptoms and signs of vascular and extracellular volume depletion. Jaundice is unusual early in the course of acute cholecystitis but may occur when edematous inflammatory changes involve the bile ducts and surrounding lymph nodes.


InternalMed_Harrison

InternalMed_Harrison. A low-grade fever is characteristically present, but shaking chills or rigors are not uncommon. The RUQ of the abdomen is almost invariably tender to palpation. An enlarged, tense gallbladder is palpable in 25–50% of patients. Deep inspiration or cough during subcostal palpation of the RUQ usually produces increased pain and inspiratory arrest (Murphy’s sign). Localized rebound tenderness in the RUQ is common, as are abdominal distention and hypoactive bowel sounds from paralytic ileus, but generalized peritoneal signs and abdominal rigidity are usually lacking, in the absence of perforation.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of acute cholecystitis is usually made on the basis of a characteristic history and physical examination. The triad of sudden onset of RUQ tenderness, fever, and leukocytosis is highly suggestive. Typically, leukocytosis in the range of 10,000–15,000 cells per microliter with a left shift on differential count is found. The serum bilirubin is mildly elevated (<85.5 μmol/L [5 mg/dL]) in fewer than half of patients, whereas about one-fourth have modest elevations in serum aminotransferases (usually less than a fivefold elevation). Ultrasound will demonstrate calculi in 90–95% of cases and is useful for detection of signs of gallbladder inflammation including thickening of the wall, pericholecystic fluid, and dilatation of the bile duct. The radionuclide (e.g., HIDA) biliary scan may be confirmatory if bile duct imaging is seen without visualization of the gallbladder.


InternalMed_Harrison

InternalMed_Harrison. Approximately 75% of patients treated medically have remission of acute symptoms within 2–7 days following hospitalization. In 25%, however, a complication of acute cholecystitis will occur despite conservative treatment (see below). In this setting, prompt surgical intervention is required. Of the 75% of patients with acute cholecystitis who undergo remission of symptoms, ∼25% will experience a recurrence of cholecystitis within 1 year, and 60% will have at least one recurrent bout within 6 years. In view of the natural history of the disease, acute cholecystitis is best treated by early surgery whenever possible.


InternalMed_Harrison

InternalMed_Harrison. Mirizzi’s syndrome is a rare complication in which a gallstone becomes impacted in the cystic duct or neck of the gallbladder causing compression of the CBD, resulting in CBD obstruction and jaundice. Ultrasound shows gallstone(s) lying outside the hepatic duct. Endoscopic retrograde cholangiopancreatography (ERCP) (Fig. 369-2B), percutaneous transhepatic cholangiography (PTC), or magnetic resonance cholangiopancreatography (MRCP) will usually demonstrate the characteristic extrinsic compression of the CBD. Surgery consists of removing the cystic duct, diseased gallbladder, and the impacted stone. The preoperative diagnosis of Mirizzi’s syndrome is important to avoid CBD injury.


InternalMed_Harrison

InternalMed_Harrison. acalculous cHolecystitis In 5–10% of patients with acute cholecystitis, calculi obstructing the cystic duct are not found at surgery. In >50% of such cases, an underlying explanation for acalculous inflammation is not found. An increased risk for the development of acalculous cholecystitis is especially associated with serious trauma or burns, with the postpartum period following prolonged labor, and with orthopedic and other nonbiliary major surgical operations in the postoperative period. It may possibly complicate periods of prolonged parenteral hyperalimentation. For some of these cases, biliary sludge in the cystic duct may be responsible. Other precipitating factors include vasculitis, obstructing adenocarcinoma of the gallbladder, diabetes mellitus, torsion of the gallbladder, “unusual” bacterial infections of the gallbladder (e.g., Leptospira, Streptococcus, Salmonella, or Vibrio cholerae), and parasitic infestation of the gallbladder. Acalculous cholecystitis may also be seen


InternalMed_Harrison

InternalMed_Harrison. bacterial infections of the gallbladder (e.g., Leptospira, Streptococcus, Salmonella, or Vibrio cholerae), and parasitic infestation of the gallbladder. Acalculous cholecystitis may also be seen with a variety of other systemic disease processes (e.g., sarcoidosis, cardiovascular disease, tuberculosis, syphilis, actinomycosis).


InternalMed_Harrison

InternalMed_Harrison. Although the clinical manifestations of acalculous cholecystitis are indistinguishable from those of calculous cholecystitis, the setting of acute gallbladder inflammation complicating severe underlying illness is characteristic of acalculous disease. Ultrasound or computed tomography (CT) examinations demonstrating a large, tense, static gallbladder without stones and with evidence of poor emptying over a prolonged period may be diagnostically useful in some cases. The complication rate for acalculous cholecystitis exceeds that for calculous cholecystitis. Successful management of acute acalculous cholecystitis appears to depend primarily on early diagnosis and surgical intervention, with meticulous attention to postoperative care.


InternalMed_Harrison

InternalMed_Harrison. acalculous cHolecystopatHy Disordered motility of the gallbladder can produce recurrent biliary pain in patients without gallstones. Infusion of an octapeptide of CCK can be used to measure the gallbladder ejection fraction during cholescintigraphy. The surgical findings have included abnormalities such as chronic cholecystitis, gallbladder muscle hypertrophy, and/or a markedly narrowed cystic duct. Some of these patients may well have had antecedent gallbladder disease. The following criteria can be used to identify patients with acalculous cholecystopathy: (1) recurrent episodes of typical RUQ pain characteristic of biliary tract pain, (2) abnormal CCK cholescintigraphy demonstrating a gallbladder ejection fraction of <40%, and (3) infusion of CCK reproducing the patient’s pain. An additional clue would be the identification of a large gallbladder on ultrasound examination. Finally, it should be noted that sphincter of Oddi dysfunction can also give rise to recurrent RUQ pain and


InternalMed_Harrison

InternalMed_Harrison. clue would be the identification of a large gallbladder on ultrasound examination. Finally, it should be noted that sphincter of Oddi dysfunction can also give rise to recurrent RUQ pain and CCK-scintigraphic abnormalities.


InternalMed_Harrison

InternalMed_Harrison. empHysematous cHolecystitis So-called emphysematous cholecystitis is thought to begin with acute cholecystitis (calculous or acalculous) followed by ischemia or gangrene of the gallbladder wall and infection by gas-producing organisms. Bacteria most frequently cultured in this setting include anaerobes, such as Clostridium welchii or Clostridium perfringens, and aerobes, such as E. coli. This condition occurs most frequently in elderly men and in patients with diabetes mellitus. The clinical manifestations are essentially indistinguishable from those of nongaseous cholecystitis. The diagnosis is usually made on plain abdominal film by finding gas within the gallbladder lumen, dissecting within the gallbladder wall to form a gaseous ring, or in the pericholecystic tissues. The morbidity and mortality rates with emphysematous cholecystitis are considerable. Prompt surgical intervention coupled with appropriate antibiotics is mandatory.


InternalMed_Harrison

InternalMed_Harrison. Chronic Cholecystitis Chronic inflammation of the gallbladder wall 2081 is almost always associated with the presence of gallstones and is thought to result from repeated bouts of subacute or acute cholecystitis or from persistent mechanical irritation of the gallbladder wall by gallstones. The presence of bacteria in the bile occurs in >25% of patients with chronic cholecystitis. The presence of infected bile in a patient with chronic cholecystitis undergoing elective cholecystectomy probably adds little to the operative risk. Chronic cholecystitis may be asymptomatic for years, may progress to symptomatic gallbladder disease or to acute cholecystitis, or may present with complications (see below).


InternalMed_Harrison

InternalMed_Harrison. Complications of Cholecystitis • empyema anD HyDrops Empyema of the gallbladder usually results from progression of acute cholecystitis with persistent cystic duct obstruction to superinfection of the stagnant bile with a pus-forming bacterial organism. The clinical picture resembles that of cholangitis with high fever; severe RUQ pain; marked leukocytosis; and often, prostration. Empyema of the gallbladder carries a high risk of gram-negative sepsis and/or perforation. Emergency surgical intervention with proper antibiotic coverage is required as soon as the diagnosis is suspected.


InternalMed_Harrison

InternalMed_Harrison. Hydrops or mucocele of the gallbladder may also result from prolonged obstruction of the cystic duct, usually by a large solitary calculus. In this instance, the obstructed gallbladder lumen is progressively distended, over a period of time, by mucus (mucocele) or by a clear transudate (hydrops) produced by mucosal epithelial cells. A visible, easily palpable, nontender mass sometimes extending from the RUQ into the right iliac fossa may be found on physical examination. The patient with hydrops of the gallbladder frequently remains asymptomatic, although chronic RUQ pain may also occur. Cholecystectomy is indicated, because empyema, perforation, or gangrene may complicate the condition.


InternalMed_Harrison

InternalMed_Harrison. GanGrene anD perforation Gangrene of the gallbladder results from ischemia of the wall and patchy or complete tissue necrosis. Underlying conditions often include marked distention of the gallbladder, vasculitis, diabetes mellitus, empyema, or torsion resulting in arterial occlusion. Gangrene usually predisposes to perforation of the gallbladder, but perforation may also occur in chronic cholecystitis without premonitory warning symptoms. Localized perforations are usually contained by the omentum or by adhesions produced by recurrent inflammation of the gallbladder. Bacterial superinfection of the walled-off gallbladder contents results in abscess formation. Most patients are best treated with cholecystectomy, but some seriously ill patients may be managed with cholecystostomy and drainage of the abscess. Free perforation is less common but is associated with a mortality rate of ∼30%. Such patients may experience a sudden transient relief of RUQ pain as the distended gallbladder


InternalMed_Harrison

InternalMed_Harrison. of the abscess. Free perforation is less common but is associated with a mortality rate of ∼30%. Such patients may experience a sudden transient relief of RUQ pain as the distended gallbladder decompresses; this is followed by signs of generalized peritonitis.


InternalMed_Harrison

InternalMed_Harrison. fistula formation anD Gallstone ileus Fistula formation into an adjacent organ adherent to the gallbladder wall may result from inflammation and adhesion formation. Fistulas into the duodenum are most common, followed in frequency by those involving the hepatic flexure of the colon, stomach or jejunum, abdominal wall, and renal pelvis. Clinically “silent” biliary-enteric fistulas occurring as a complication of acute cholecystitis have been found in up to 5% of patients undergoing cholecystectomy. Asymptomatic cholecystoenteric fistulas may sometimes be diagnosed by finding gas in the biliary tree on plain abdominal films. Barium contrast studies or endoscopy of the upper gastrointestinal tract or colon may demonstrate the fistula. Treatment in the symptomatic patient usually consists of cholecystectomy, CBD exploration, and closure of the fistulous tract.


InternalMed_Harrison

InternalMed_Harrison. Gallstone ileus refers to mechanical intestinal obstruction resulting from the passage of a large gallstone into the bowel lumen. The stone customarily enters the duodenum through a cholecystoenteric fistula at that level. The site of obstruction by the impacted gallstone is usually at the ileocecal valve, provided that the more proximal small bowel is of normal caliber. The majority of patients do not give a history of either prior biliary tract symptoms or complaints suggestive of acute cholecystitis or fistula formation. Large stones, >2.5 cm in diameter, are


InternalMed_Harrison

InternalMed_Harrison. Diseases of the Gallbladder and Bile Ducts 2082 thought to predispose to fistula formation by gradual erosion through the gallbladder fundus. Diagnostic confirmation may occasionally be found on the plain abdominal film (e.g., small-intestinal obstruction with gas in the biliary tree and a calcified, ectopic gallstone) or following an upper gastrointestinal series (cholecystoduodenal fistula with small-bowel obstruction at the ileocecal valve). Laparotomy with stone extraction (or propulsion into the colon) remains the procedure of choice to relieve obstruction. Evacuation of large stones within the gallbladder should also be performed. In general, the gallbladder and its attachment to the intestines should be left alone.


InternalMed_Harrison

InternalMed_Harrison. limey (milk of calcium) bile anD porcelain GallblaDDer Calcium salts in the lumen of the gallbladder in sufficient concentration may produce calcium precipitation and diffuse, hazy opacification of bile or a layering effect on plain abdominal roentgenography. This so-called limey bile, or milk of calcium bile, is usually clinically innocuous, but cholecystectomy is recommended, especially when it occurs in a hydropic gallbladder. In the entity called porcelain gallbladder, calcium salt deposition within the wall of a chronically inflamed gallbladder may be detected on the plain abdominal film. Cholecystectomy is advised in all patients with porcelain gallbladder because in a high percentage of cases this finding appears to be associated with the development of carcinoma of the gallbladder.


InternalMed_Harrison

InternalMed_Harrison. Although surgical intervention remains the mainstay of therapy for acute cholecystitis and its complications, a period of in-hospital stabilization may be required before cholecystectomy. Oral intake is eliminated, nasogastric suction may be indicated, and extracellular volume depletion and electrolyte abnormalities are repaired. Meperidine or nonsteroidal anti-inflammatory drugs (NSAIDs) are usually employed for analgesia because they may produce less spasm of the sphincter of Oddi than drugs such as morphine. Intravenous antibiotic therapy is usually indicated in patients with severe acute cholecystitis, even though bacterial superinfection of bile may not have occurred in the early stages of the inflammatory process. Antibiotic therapy is guided by the most common organisms likely to be present, which are E. coli, Klebsiella spp., and Streptococcus spp. Effective antibiotics include ureidopenicillins such as piperacillin or mezlocillin, ampicillin sulbactam, ciprofloxacin,


InternalMed_Harrison

InternalMed_Harrison. to be present, which are E. coli, Klebsiella spp., and Streptococcus spp. Effective antibiotics include ureidopenicillins such as piperacillin or mezlocillin, ampicillin sulbactam, ciprofloxacin, moxifloxacin, and third-generation cephalosporins. Anaerobic coverage by a drug such as metronidazole should be added if gangrenous or emphysematous cholecystitis is suspected. Imipenem and meropenem represent potent parenteral antibiotics that cover the whole spectrum of bacteria causing ascending cholangitis. They should, however, be reserved for the most severe, life-threatening infections when other regimens have failed (Chap. 186). Postoperative complications of wound infection, abscess formation, and sepsis are reduced in antibiotic-treated patients.


InternalMed_Harrison

InternalMed_Harrison. The optimal timing of surgical intervention in patients with acute cholecystitis depends on stabilization of the patient. The clear trend is toward earlier surgery, and this is due in part to requirements for shorter hospital stays. Urgent (emergency) cholecystectomy or cholecystostomy is probably appropriate in most patients in whom a complication of acute cholecystitis such as empyema, emphysematous cholecystitis, or perforation is suspected or confirmed. Patients with uncomplicated acute cholecystitis should undergo early elective laparoscopic cholecystectomy, ideally within 48–72 h after diagnosis. The complication rate is not increased in patients undergoing early as opposed to delayed (>6 weeks after diagnosis) cholecystectomy. Delayed surgical intervention is probably best reserved for (1) patients in whom the overall medical condition imposes an unacceptable risk for early surgery and (2) patients in whom the diagnosis of acute cholecystitis is in doubt. Thus, early


InternalMed_Harrison

InternalMed_Harrison. reserved for (1) patients in whom the overall medical condition imposes an unacceptable risk for early surgery and (2) patients in whom the diagnosis of acute cholecystitis is in doubt. Thus, early cholecystectomy (within 72 h) is the treatment of choice for most patients with acute cholecystitis. Mortality figures for emergency cholecystectomy in most centers range from 1–3%, whereas the mortality risk for early elective cholecystectomy is ∼0.5% in patients under age 60. Of course, the operative risks increase with age-related diseases of other organ systems and with the presence of longor short-term complications of gallbladder disease. Seriously ill or debilitated patients with cholecystitis may be managed with cholecystostomy and tube drainage of the gallbladder. Elective cholecystectomy may then be done at a later date.


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InternalMed_Harrison. Postcholecystectomy Complications Early complications following cholecystectomy include atelectasis and other pulmonary disorders, abscess formation (often subphrenic), external or internal hemorrhage, biliary-enteric fistula, and bile leaks. Jaundice may indicate absorption of bile from an intraabdominal collection following a biliary leak or mechanical obstruction of the CBD by retained calculi, intraductal blood clots, or extrinsic compression.


InternalMed_Harrison

InternalMed_Harrison. Overall, cholecystectomy is a very successful operation that provides total or near-total relief of preoperative symptoms in 75–90% of patients. The most common cause of persistent postcholecystectomy symptoms is an overlooked symptomatic nonbiliary disorder (e.g., reflux esophagitis, peptic ulceration, pancreatitis, or—most often— irritable bowel syndrome). In a small percentage of patients, however, a disorder of the extrahepatic bile ducts may result in persistent symptomatology. These so-called postcholecystectomy syndromes may be due to (1) biliary strictures, (2) retained biliary calculi, (3) cystic duct stump syndrome, (4) stenosis or dyskinesia of the sphincter of Oddi, or (5) bile salt–induced diarrhea or gastritis.


InternalMed_Harrison

InternalMed_Harrison. cystic Duct stump synDrome In the absence of cholangiographically demonstrable retained stones, symptoms resembling biliary pain or cholecystitis in the postcholecystectomy patient have frequently been attributed to disease in a long (>1 cm) cystic duct remnant (cystic duct stump syndrome). Careful analysis, however, reveals that postcholecystectomy complaints are attributable to other causes in almost all patients in whom the symptom complex was originally thought to result from the existence of a long cystic duct stump. Accordingly, considerable care should be taken to investigate the possible role of other factors in the production of postcholecystectomy symptoms before attributing them to cystic duct stump syndrome.


InternalMed_Harrison

InternalMed_Harrison. papillary Dysfunction, papillary stenosis, spasm of tHe spHincter of oDDi, anD biliary Dyskinesia Symptoms of biliary colic accompanied by signs of recurrent, intermittent biliary obstruction may be produced by acalculous cholecystopathy, papillary stenosis, papillary dysfunction, spasm of the sphincter of Oddi, and biliary dyskinesia. Papillary stenosis is thought to result from acute or chronic inflammation of the papilla of Vater or from glandular hyperplasia of the papillary segment. Five criteria have been used to define papillary stenosis: upper abdominal pain, usually RUQ or epigastric; (2) abnormal liver tests; (3) dilatation of the CBD upon ERCP examination; (4) delayed (>45 min) drainage of contrast material from the duct; and increased basal pressure of the sphincter of Oddi, a finding that may be of only minor significance. An alternative to ERCP is magnetic resonance cholangiography (MRC) if ERCP and/or biliary manometry are either unavailable or not feasible. After


InternalMed_Harrison

InternalMed_Harrison. a finding that may be of only minor significance. An alternative to ERCP is magnetic resonance cholangiography (MRC) if ERCP and/or biliary manometry are either unavailable or not feasible. After exclusion of acalculous cholecystopathy, treatment consists of endoscopic or surgical sphincteroplasty to ensure wide patency of the distal portions of both the bile and pancreatic ducts. The greater the number of the preceding criteria present, the greater is the likelihood that a patient does have a degree of papillary stenosis sufficient to justify correction. The factors usually considered as indications for sphincterotomy include (1) prolonged duration of symptoms, (2) lack of response to symptomatic treatment, presence of severe disability, and (4) the patient’s choice of sphincterotomy over surgery (given a clear understanding on his or her part of the risks involved in both procedures).


InternalMed_Harrison

InternalMed_Harrison. Criteria for diagnosing dyskinesia of the sphincter of Oddi are even more controversial than those for papillary stenosis. Proposed mechanisms include spasm of the sphincter, denervation sensitivity resulting in hypertonicity, and abnormalities of the sequencing or frequency rates of sphincteric-contraction waves. When thorough evaluation has failed to demonstrate another cause for the pain, and when cholangiographic and manometric criteria suggest a diagnosis of biliary dyskinesia, medical treatment with nitrites or anticholinergics to attempt pharmacologic relaxation of the sphincter has been proposed. Endoscopic biliary sphincterotomy (EBS) or surgical sphincteroplasty may be indicated in patients who fail to respond to a 2to 3-month trial of medical therapy, especially if basal sphincter of Oddi pressures are elevated. EBS has become the procedure of choice for removing bile duct stones and for other biliary and pancreatic problems.


InternalMed_Harrison

InternalMed_Harrison. bile salt–inDuceD DiarrHea anD Gastritis Postcholecystectomy patients may develop symptoms of dyspepsia, which have been attributed to duodenogastric reflux of bile. However, firm data linking these symptoms to bile gastritis after surgical removal of the gallbladder are lacking. Cholecystectomy induces persistent changes in gut transit, and these changes effect a noticeable modification of bowel habits. Cholecystectomy shortens gut transit time by accelerating passage of the fecal bolus through the colon with marked acceleration in the right colon, thus causing an increase in colonic bile acid output and a shift in bile acid composition toward the more diarrheagenic secondary bile acids, i.e. deoxycholic acid. Diarrhea that is severe enough, i.e., three or more watery movements per day, can be classified as postcholecystectomy diarrhea, and this occurs in 5–10% of patients undergoing elective cholecystectomy. Treatment with bile acid–sequestering agents such as cholestyramine or


InternalMed_Harrison

InternalMed_Harrison. can be classified as postcholecystectomy diarrhea, and this occurs in 5–10% of patients undergoing elective cholecystectomy. Treatment with bile acid–sequestering agents such as cholestyramine or colestipol is often effective in ameliorating troublesome diarrhea.


InternalMed_Harrison

InternalMed_Harrison. The term hyperplastic cholecystoses is used to denote a group of disorders of the gallbladder characterized by excessive proliferation of normal tissue components. Adenomyomatosis is characterized by a benign proliferation of gallbladder surface epithelium with glandlike formations, extramural sinuses, transverse strictures, and/or fundal nodule (“adenoma” or “adenomyoma”) formation. Cholesterolosis is characterized by abnormal deposition of lipid, especially cholesteryl esters, within macrophages in the lamina propria of the gallbladder wall. In its diffuse form (“strawberry gallbladder”), the gallbladder mucosa is brick red and speckled with bright yellow flecks of lipid. The localized form shows solitary or multiple “cholesterol polyps” studding the gallbladder wall. Cholesterol stones of the gallbladder are found in nearly half the cases. Cholecystectomy is indicated in both adenomyomatosis and cholesterolosis when symptomatic or when cholelithiasis is present.


InternalMed_Harrison

InternalMed_Harrison. The prevalence of gallbladder polyps in the adult population is ∼5%, with a marked male predominance. Few significant changes have been found over a 5-year period in asymptomatic patients with gallbladder polyps <10 mm in diameter. Cholecystectomy is recommended in symptomatic patients, as well as in asymptomatic patients >50 years of age, or in those whose polyps are >10 mm in diameter or associated with gallstones or polyp growth on serial ultrasonography.


InternalMed_Harrison

InternalMed_Harrison. CONGENITAL ANOMALIES Biliary Atresia and Hypoplasia Atretic and hypoplastic lesions of the extrahepatic and large intrahepatic bile ducts are the most common biliary anomalies of clinical relevance encountered in infancy. The clinical picture is one of severe obstructive jaundice during the first month of life, with pale stools. When biliary atresia is suspected on the basis of clinical, laboratory, and imaging findings, the diagnosis is confirmed by surgical exploration and operative cholangiography. Approximately 10% of cases of biliary atresia are treatable with Roux-en-Y choledochojejunostomy, with the Kasai procedure (hepatic portoenterostomy) being attempted in the remainder in an effort to restore some bile flow. Most patients, even those having successful biliary-enteric anastomoses, eventually develop chronic cholangitis, extensive hepatic fibrosis, and portal hypertension.


InternalMed_Harrison

InternalMed_Harrison. Choledochal Cysts Cystic dilatation may involve the free portion of the 2083 CBD, i.e., choledochal cyst, or may present as diverticulum formation in the intraduodenal segment. In the latter situation, chronic reflux of pancreatic juice into the biliary tree can produce inflammation and stenosis of the extrahepatic bile ducts leading to cholangitis or biliary obstruction. Because the process may be gradual, ∼50% of patients present with onset of symptoms after age 10. The diagnosis may be made by ultrasound, abdominal CT, MRC, or cholangiography. Only one-third of patients show the classic triad of abdominal pain, jaundice, and an abdominal mass. Ultrasonographic detection of a cyst separate from the gallbladder should suggest the diagnosis of choledochal cyst, which can be confirmed by demonstrating the entrance of extrahepatic bile ducts into the cyst. Surgical treatment involves excision of the “cyst” and biliary-enteric anastomosis. Patients with choledochal cysts are at increased


InternalMed_Harrison

InternalMed_Harrison. the entrance of extrahepatic bile ducts into the cyst. Surgical treatment involves excision of the “cyst” and biliary-enteric anastomosis. Patients with choledochal cysts are at increased risk for the subsequent development of cholangiocarcinoma.


InternalMed_Harrison

InternalMed_Harrison. Congenital Biliary Ectasia Dilatation of intrahepatic bile ducts may involve either the major intrahepatic radicles (Caroli’s disease), the interand intralobular ducts (congenital hepatic fibrosis), or both. In Caroli’s disease, clinical manifestations include recurrent cholangitis, abscess formation in and around the affected ducts, and, often, brown pigment gallstone formation within portions of ectatic intrahepatic biliary radicles. Ultrasound, MRC, and CT are of great diagnostic value in demonstrating cystic dilatation of the intrahepatic bile ducts. Treatment with ongoing antibiotic therapy is usually undertaken in an effort to limit the frequency and severity of recurrent bouts of cholangitis. Progression to secondary biliary cirrhosis with portal hypertension, extrahepatic biliary obstruction, cholangiocarcinoma, or recurrent episodes of sepsis with hepatic abscess formation is common.


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InternalMed_Harrison. CHOLEDOCHOLITHIASIS Pathophysiology and Clinical Manifestations Passage of gallstones into the CBD occurs in ∼10–15% of patients with cholelithiasis. The incidence of common duct stones increases with increasing age of the patient, so that up to 25% of elderly patients may have calculi in the common duct at the time of cholecystectomy. Undetected duct stones are left behind in ∼1–5% of cholecystectomy patients. The overwhelming majority of bile duct stones are cholesterol stones formed in the gallbladder, which then migrate into the extrahepatic biliary tree through the cystic duct. Primary calculi arising de novo in the ducts are usually brown pigment stones developing in patients with (1) hepatobiliary parasitism or chronic, recurrent cholangitis; (2) congenital anomalies of the bile ducts (especially Caroli’s disease); (3) dilated, sclerosed, or strictured ducts; or (4) an MDR3 (ABCB4) gene defect leading to impaired biliary phospholipids secretion (low phospholipid–associated


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InternalMed_Harrison. ducts (especially Caroli’s disease); (3) dilated, sclerosed, or strictured ducts; or (4) an MDR3 (ABCB4) gene defect leading to impaired biliary phospholipids secretion (low phospholipid–associated cholesterol cholelithiasis). Common duct stones may remain asymptomatic for years, may pass spontaneously into the duodenum, or (most often) may present with biliary colic or a complication.


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InternalMed_Harrison. Complications • cHolanGitis Cholangitis may be acute or chronic, and symptoms result from inflammation, which usually is caused by at least partial obstruction to the flow of bile. Bacteria are present on bile culture in ∼75% of patients with acute cholangitis early in the symptomatic course. The characteristic presentation of acute cholangitis involves biliary pain, jaundice, and spiking fevers with chills (Charcot’s triad). Blood cultures are frequently positive, and leukocytosis is typical. Nonsuppurative acute cholangitis is most common and may respond relatively rapidly to supportive measures and to treatment with antibiotics. In suppurative acute cholangitis, however, the presence of pus under pressure in a completely obstructed ductal system leads to symptoms of severe toxicity—mental confusion, bacteremia, and septic shock. Response to antibiotics alone in this setting is relatively poor, multiple hepatic abscesses are often present, and the mortality rate approaches 100%


InternalMed_Harrison

InternalMed_Harrison. confusion, bacteremia, and septic shock. Response to antibiotics alone in this setting is relatively poor, multiple hepatic abscesses are often present, and the mortality rate approaches 100% unless prompt endoscopic or surgical relief of the obstruction and drainage of infected bile are carried out. Endoscopic management of bacterial cholangitis is as effective as surgical intervention. ERCP with endoscopic sphincterotomy is safe and the preferred initial procedure for both establishing a definitive diagnosis and providing effective therapy.


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InternalMed_Harrison. Diseases of the Gallbladder and Bile Ducts 2084 obstructive JaunDice Gradual obstruction of the CBD over a period of weeks or months usually leads to initial manifestations of jaundice or pruritus without associated symptoms of biliary colic or cholangitis. Painless jaundice may occur in patients with choledocholithiasis, but is much more characteristic of biliary obstruction secondary to malignancy of the head of the pancreas, bile ducts, or ampulla of Vater. In patients whose obstruction is secondary to choledocholithiasis, associated chronic calculous cholecystitis is very common, and the gallbladder in this setting may be unable to distend. The absence of a palpable gallbladder in most patients with biliary obstruction from duct stones is the basis for Courvoisier’s law, i.e., that the presence of a palpably enlarged gallbladder suggests that the biliary obstruction is secondary to an underlying malignancy rather than to calculous disease. Biliary obstruction causes progressive


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InternalMed_Harrison. the presence of a palpably enlarged gallbladder suggests that the biliary obstruction is secondary to an underlying malignancy rather than to calculous disease. Biliary obstruction causes progressive dilatation of the intra-hepatic bile ducts as intrabiliary pressures rise. Hepatic bile flow is suppressed, and reabsorption and regurgitation of conjugated bilirubin into the bloodstream lead to jaundice accompanied by dark urine (bilirubinuria) and light-colored (acholic) stools. CBD stones should be suspected in any patient with cholecystitis whose serum bilirubin level is >85.5 μmol/L (5 mg/dL). The maximum bilirubin level is seldom >256.5 μmol/L (15.0 mg/dL) in patients with choledocholithiasis unless concomitant hepatic or renal disease or another factor leading to marked hyperbilirubinemia exists. Serum bilirubin levels ≥342.0 μmol/L (20 mg/dL) should suggest the possibility of neoplastic obstruction. The serum alkaline phosphatase level is almost always elevated in biliary


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InternalMed_Harrison. exists. Serum bilirubin levels ≥342.0 μmol/L (20 mg/dL) should suggest the possibility of neoplastic obstruction. The serum alkaline phosphatase level is almost always elevated in biliary obstruction. A rise in alkaline phosphatase often precedes clinical jaundice and may be the only abnormality in routine liver function tests. There may be a twoto tenfold elevation of serum aminotransferases, especially in association with acute obstruction. Following relief of the obstructing process, serum aminotransferase elevations usually return rapidly to normal, while the serum bilirubin level may take 1–2 weeks to return to normal. The alkaline phosphatase level usually falls slowly, lagging behind the decrease in serum bilirubin.


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InternalMed_Harrison. pancreatitis The most common associated entity discovered in patients with nonalcoholic acute pancreatitis is biliary tract disease. Biochemical evidence of pancreatic inflammation complicates acute cholecystitis in 15% of cases and choledocholithiasis in >30%, and the common factor appears to be the passage of gallstones through the common duct. Coexisting pancreatitis should be suspected in patients with symptoms of cholecystitis who develop (1) back pain or pain to the left of the abdominal midline, (2) prolonged vomiting with paralytic ileus, or (3) a pleural effusion, especially on the left side. Surgical treatment of gallstone disease is usually associated with resolution of the pancreatitis.


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InternalMed_Harrison. seconDary biliary cirrHosis Secondary biliary cirrhosis may complicate prolonged or intermittent duct obstruction with or without recurrent cholangitis. Although this complication may be seen in patients with choledocholithiasis, it is more common in cases of prolonged obstruction from stricture or neoplasm. Once established, secondary biliary cirrhosis may be progressive even after correction of the obstructing process, and increasingly severe hepatic cirrhosis may lead to portal hypertension or to hepatic failure and death. Prolonged biliary obstruction may also be associated with clinically relevant deficiencies of the fat-soluble vitamins A, D, E, and K.


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InternalMed_Harrison. Diagnosis and Treatment The diagnosis of choledocholithiasis is usually made by cholangiography (Table 369-3), either preoperatively by endoscopic retrograde cholangiogram (ERC) (Fig. 369-2C) or MRCP or intraoperatively at the time of cholecystectomy. As many as 15% of patients undergoing cholecystectomy will prove to have CBD stones. When CBD stones are suspected prior to laparoscopic cholecystectomy, preoperative ERCP with endoscopic papillotomy and stone extraction is the preferred approach. It not only provides stone clearance but also defines the anatomy of the biliary tree in relationship to the cystic duct. CBD stones should be suspected in gallstone patients who have any of the following risk factors: (1) a history of jaundice or pancreatitis, (2) abnormal tests of liver function, and (3) ultrasonographic or MRCP evidence of a dilated CBD or stones in the duct. Alternatively, if intraoperative cholangiography reveals retained stones, postoperative ERCP can be carried out. The


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InternalMed_Harrison. and (3) ultrasonographic or MRCP evidence of a dilated CBD or stones in the duct. Alternatively, if intraoperative cholangiography reveals retained stones, postoperative ERCP can be carried out. The need for preoperative ERCP is expected to decrease further as laparoscopic techniques for bile duct exploration improve.


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InternalMed_Harrison. The widespread use of laparoscopic cholecystectomy and ERCP has decreased the incidence of complicated biliary tract disease and the need for choledocholithotomy and T-tube drainage of the bile ducts. EBS followed by spontaneous passage or stone extraction is the treatment of choice in the management of patients with common duct stones, especially in elderly or poor-risk patients. TRAUMA, STRICTURES, AND HEMOBILIA


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InternalMed_Harrison. Most benign strictures of the extrahepatic bile ducts result from surgical trauma and occur in about 1 in 500 cholecystectomies. Strictures may present with bile leak or abscess formation in the immediate postoperative period or with biliary obstruction or cholangitis as long as 2 years or more following the inciting trauma. The diagnosis is established by percutaneous or endoscopic cholangiography. Endoscopic brushing of biliary strictures may be helpful in establishing the nature of the lesion and is more accurate than bile cytology alone. When positive exfoliative cytology is obtained, the diagnosis of a neoplastic stricture is established. This procedure is especially important in patients with primary sclerosing cholangitis (PSC) who are predisposed to the development of cholangiocarcinomas. Successful operative correction of non-PSC bile duct strictures by a skillful surgeon with duct-to-bowel anastomosis is usually possible, although mortality rates from surgical complications,


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InternalMed_Harrison. Successful operative correction of non-PSC bile duct strictures by a skillful surgeon with duct-to-bowel anastomosis is usually possible, although mortality rates from surgical complications, recurrent cholangitis, or secondary biliary cirrhosis are high.


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InternalMed_Harrison. Hemobilia may follow traumatic or operative injury to the liver or bile ducts, intraductal rupture of a hepatic abscess or aneurysm of the hepatic artery, biliary or hepatic tumor hemorrhage, or mechanical complications of choledocholithiasis or hepatobiliary parasitism. Diagnostic procedures such as liver biopsy, PTC, and transhepatic biliary drainage catheter placement may also be complicated by hemobilia. Patients often present with a classic triad of biliary pain, obstructive jaundice, and melena or occult blood in the stools. The diagnosis is sometimes made by cholangiographic evidence of blood clot in the biliary tree, but selective angiographic verification may be required. Although minor episodes of hemobilia may resolve without operative intervention, surgical ligation of the bleeding vessel is frequently required.


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InternalMed_Harrison. Partial or complete biliary obstruction may be produced by extrinsic compression of the ducts. The most common cause of this form of obstructive jaundice is carcinoma of the head of the pancreas. Biliary obstruction may also occur as a complication of either acute or chronic pancreatitis or involvement of lymph nodes in the porta hepatis by lymphoma or metastatic carcinoma. The latter should be distinguished from cholestasis resulting from massive replacement of the liver by tumor.


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InternalMed_Harrison. Infestation of the biliary tract by adult helminths or their ova may produce a chronic, recurrent pyogenic cholangitis with or without multiple hepatic abscesses, ductal stones, or biliary obstruction. This condition is relatively rare but does occur in inhabitants of southern China and elsewhere in Southeast Asia. The organisms most commonly involved are trematodes or flukes, including Clonorchis sinensis, Opisthorchis viverrini or Opisthorchis felineus, and Fasciola hepatica. The biliary tract also may be involved by intraductal migration of adult Ascaris lumbricoides from the duodenum or by intrabiliary rupture of hydatid cysts of the liver produced by Echinococcus spp. The diagnosis is made by cholangiography and the presence of characteristic ova on stool examination. When obstruction is present, the treatment of choice is laparotomy under antibiotic coverage, with common duct exploration and a biliary drainage procedure.


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InternalMed_Harrison. Primary or idiopathic sclerosing cholangitis is characterized by a progressive, inflammatory, sclerosing, and obliterative process Diseases of the Gallbladder and Bile Ducts Most sensitive method to detect ampullary stones Abbreviations: CBD, common bile duct; ERCP, endoscopic retrograde cholangiopancreatography; GB, gallbladder; HBUS, hepatobiliary ultrasound. affecting the extrahepatic and/or the intrahepatic bile ducts. The disorder occurs up to 75% in association with inflammatory bowel disease, especially ulcerative colitis. It may also be associated with autoimmune pancreatitis; multifocal fibrosclerosis syndromes such as retroperitoneal, mediastinal, and/or periureteral fibrosis; Riedel’s struma; or pseudotumor of the orbit.


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InternalMed_Harrison. Immunoglobulin G4 (IgG4)–associated cholangitis is a recently described biliary disease of unknown etiology that presents with biochemical and cholangiographic features indistinguishable from PSC, is often associated with autoimmune pancreatitis and other fibrosing conditions, and is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts and liver tissue. In contrast to PSC, it is not associated with inflammatory bowel disease and should be suspected if associated with increased serum IgG4 and unexplained pancreatic disease. Glucocorticoids are regarded as the initial treatment of choice. Relapse is common after steroid withdrawal, especially with proximal strictures. Long-term treatment with glucocorticoids and/or azathioprine may be needed after relapse or for inadequate response (Chap. 371).


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InternalMed_Harrison. Patients with primary sclerosing cholangitis often present with signs and symptoms of chronic or intermittent biliary obstruction: RUQ abdominal pain, pruritus, jaundice, or acute cholangitis. Late in the course, complete biliary obstruction, secondary biliary cirrhosis, hepatic failure, or portal hypertension with bleeding varices may occur. The diagnosis is usually established by finding multifocal, diffusely distributed strictures with intervening segments of normal or dilated ducts, producing a beaded appearance on cholangiography (Fig. 369-2D). The cholangiographic techniques of choice in suspected 2086 cases are MRCP and ERCP. When a diagnosis of sclerosing cholangitis has been established, a search for associated diseases, especially for chronic inflammatory bowel disease, should be carried out. A recent study describes the natural history and outcome for 305 patients of Swedish descent with primary sclerosing cholangitis; 134 (44%) of the patients were asymptomatic at the time


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InternalMed_Harrison. carried out. A recent study describes the natural history and outcome for 305 patients of Swedish descent with primary sclerosing cholangitis; 134 (44%) of the patients were asymptomatic at the time of diagnosis and, not surprisingly, had a significantly higher survival rate. The independent predictors of a bad prognosis were advanced age, serum bilirubin concentration, and liver histologic changes. Cholangiocarcinoma was found in 24 patients (8%). Inflammatory bowel disease was closely associated with primary sclerosing cholangitis and had a prevalence of 81% in this study population. Small duct PSC is defined by the presence of chronic cholestasis and hepatic histology consistent with PSC but with normal findings on cholangiography. Small duct PSC is found in ∼5% of patients with PSC and may represent an earlier stage of PSC associated with a significantly better long-term prognosis. However, such patients may progress to classic PSC and/or end-stage liver disease with consequent


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InternalMed_Harrison. and may represent an earlier stage of PSC associated with a significantly better long-term prognosis. However, such patients may progress to classic PSC and/or end-stage liver disease with consequent necessity of liver transplantation. In patients with AIDS, cholangiopancreatography may demonstrate a broad range of biliary tract changes as well as pancreatic duct obstruction and occasionally pancreatitis (Chap. 226). Further, biliary tract lesions in AIDS include infection and cholangiopancreatographic changes similar to those of PSC. Changes noted include: (1) diffuse involvement of intrahepatic bile ducts alone, (2) involvement of both intraand extrahepatic bile ducts, (3) ampullary stenosis, (4) stricture of the intrapancreatic portion of the CBD, and (5) pancreatic duct involvement. Associated infectious organisms include Cryptosporidium, Mycobacterium avium-intracellulare, cytomegalovirus, Microsporidia, and Isospora. In addition, acalculous cholecystitis occurs in up to 10% of


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InternalMed_Harrison. Associated infectious organisms include Cryptosporidium, Mycobacterium avium-intracellulare, cytomegalovirus, Microsporidia, and Isospora. In addition, acalculous cholecystitis occurs in up to 10% of patients. ERCP sphincterotomy, while not without risk, provides significant pain reduction in patients with AIDS-associated papillary stenosis. Secondary sclerosing cholangitis may occur as a long-term complication of choledocholithiasis, cholangiocarcinoma, operative or traumatic biliary injury, or contiguous inflammatory processes.


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InternalMed_Harrison. Therapy with cholestyramine may help control symptoms of pruritus, and antibiotics are useful when cholangitis complicates the clinical picture. Vitamin D and calcium supplementation may help prevent the loss of bone mass frequently seen in patients with chronic cholestasis. Glucocorticoids, methotrexate, and cyclosporine have not been shown to be efficacious in PSC. UDCA in high dosage (20 mg/kg) improves serum liver tests, but an effect on survival has not been documented. In cases where high-grade biliary obstruction (dominant strictures) has occurred, balloon dilatation or stenting may be appropriate. Only rarely is surgical intervention indicated. Efforts at biliary-enteric anastomosis or stent placement may, however, be complicated by recurrent cholangitis and further progression of the stenosing process. The prognosis is unfavorable, with a median survival of 9–12 years following the diagnosis, regardless of therapy. Four variables (age, serum bilirubin level, histologic stage,


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InternalMed_Harrison. the stenosing process. The prognosis is unfavorable, with a median survival of 9–12 years following the diagnosis, regardless of therapy. Four variables (age, serum bilirubin level, histologic stage, and splenomegaly) predict survival in patients with PSC and serve as the basis for a risk score. PSC is one of the most common indications for liver transplantation.


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InternalMed_Harrison. Approach to the Patient with Pancreatic Disease Darwin L. Conwell, Norton J. Greenberger, Peter A. Banks SEC Tion 3 DiSoRDERS of THE PAnCREAS As emphasized in Chap. 371, the etiologies as well as clinical manifestations of pancreatitis are quite varied. Although it is well-appreciated that pancreatitis is frequently secondary to biliary tract disease and alcohol abuse, it can also be caused by drugs, genetic mutations, trauma, and viral infections and is associated with metabolic and connective tissue disorders. In ~30% of patients with acute pancreatitis and 25–40% of patients with chronic pancreatitis, the etiology initially can be obscure.


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InternalMed_Harrison. The incidence of acute pancreatitis is about 5–35/100,000 new cases per year worldwide, with a mortality rate of about 3%. The incidence of chronic pancreatitis is about 4–8 new cases per 100,000 per year with a prevalence of 26–42 cases per 100,000. The number of patients admitted to the hospital who suffer with both acute and chronic pancreatitis in the United States is largely increasing and is now estimated to be 274,119 for acute pancreatitis and 19,724 for chronic pancreatitis. Acute pancreatitis is now the most common gastrointestinal diagnosis requiring hospitalization in the United States. Acute and chronic pancreatic disease costs an estimated 3 billion dollars annually in health care expenditures. These numbers may underestimate the true incidence and prevalence, because non–alcohol-induced pancreatitis has been largely ignored. At autopsy, the prevalence of chronic pancreatitis ranges from 0.04 to 5%.


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InternalMed_Harrison. The diagnosis of acute pancreatitis is generally clearly defined based on a combination of laboratory, imaging, and clinical symptoms. The diagnosis of chronic pancreatitis, especially in mild disease, is hampered by the relative inaccessibility of the pancreas to direct examination and the nonspecificity of the abdominal pain associated with chronic pancreatitis. Many patients with chronic pancreatitis do not have elevated blood amylase or lipase levels. Some patients with chronic pancreatitis develop signs and symptoms of pancreatic exocrine insufficiency, and thus, objective evidence for pancreatic disease can be demonstrated. However, there is a very large reservoir of pancreatic exocrine function. More than 90% of the pancreas must be damaged before maldigestion of fat and protein is manifested. Noninvasive, indirect tests of pancreatic exocrine function (fecal elastase) are much more likely to give abnormal results in patients with obvious advanced pancreatic disease (i.e.,


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InternalMed_Harrison. is manifested. Noninvasive, indirect tests of pancreatic exocrine function (fecal elastase) are much more likely to give abnormal results in patients with obvious advanced pancreatic disease (i.e., pancreatic calcification, steatorrhea, or diabetes mellitus) than in patients with occult disease. Invasive, direct tests of pancreatic secretory function (secretin tests) are the most sensitive and specific tests to detect early chronic pancreatic disease when imaging is equivocal or normal.


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InternalMed_Harrison. Several tests have proved of value in the evaluation of pancreatic disease. Examples of specific tests and their usefulness in the diagnosis of acute and chronic pancreatitis are summarized in Table 370-1 and Fig. 370-1. At some institutions, pancreatic function tests are available and performed if the diagnosis of chronic pancreatic disease remains a possibility after noninvasive tests (ultrasound, computed tomography [CT], magnetic resonance cholangiopancreatography [MRCP]) or invasive tests (endoscopic retrograde cholangiopancreatography [ERCP], endoscopic ultrasonography [EUS]) have given normal or Serum lipase Pancreatic inflammation leads to increased serum enzyme Enzyme measurement of choice for diagnosis of acute pancreatitis levels 1. Serum Pancreatic inflammation leads to increased serum enzyme Simple; reliable if test results are three times the upper limit of levels normal 2. Urine Renal clearance of amylase is increased in acute pancreatitis Infrequently used 3.


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InternalMed_Harrison. Urine Renal clearance of amylase is increased in acute pancreatitis Infrequently used 3. Ascitic fluid Disruption of gland or main pancreatic duct leads to Can help establish source of ascites; false positives occur with 4. Pleural fluid Exudative pleural effusion with pancreatitis False positives occur with carcinoma of the lung and esophageal perforation Studies Pertaining to Pancreatic Structure 1. Plain film of the abdomen 2. 3. 4. 5. 6. 7. Pancreatic biopsy with US or CT guidance Can be abnormal in acute and chronic pancreatitis Can provide information on edema, inflammation, calcification, pseudocysts, and mass lesions Permits detailed visualization of pancreas and surrounding structures, pancreatic fluid collection, pseudocyst; assessment of necrosis or interstitial disease Three-dimensional imaging has been used to produce very good images of the pancreatic-biliary ductal system by a noninvasive technique