Bile Formation

The two primary roles of bile in normal physiology are the excretion of organic compounds, such as bilirubin and cholesterol, and the intestinal absorption of lipids. Bile secretion results from the active transport of solutes into the canaliculus, followed by the passive flow of water. Water constitutes about 85% of the volume of bile. The major organic solutes in bile are bilirubin, bile salts, phospholipids, and cholesterol. Bilirubin, the breakdown product of spent red blood cells, is conjugated with glucuronic acid by the hepatic enzyme glucuronyl transferase and is excreted actively into the adjacent canaliculus. Normally, a large enzyme reserve exists to handle excess bilirubin production, which might exist in hemolytic states.

Bile salts are steroid molecules synthesized by the hepatocyte. The primary bile salts in humans, cholic and chenodeoxycholic acid, account for more than 80% of those produced. The primary bile salts, which are then conjugated with either taurine or glycine, can undergo bacterial alteration in the intestine to form the secondary bile salts, deoxycholate and lithocholate. The purpose of bile salts is to solubilize lipids and facilitate their absorption. Phospholipids are synthesized in the liver in conjunction with bile salt synthesis, and lecithin is the primary phospholipid in human bile, constituting more than 95% of its total. The final major solute of bile is cholesterol, which is also produced primarily by the liver with a small contribution from dietary sources.

The normal volume of bile secreted daily by the liver is 750 to 1000 mL. Bile flow depends on neurogenic, humoral, and chemical control. Vagal stimulation increases bile secretion, whereas splanchnic stimulation causes vasoconstriction with decreased hepatic blood flow and thus results in diminished bile secretion. Gastrointestinal hormones—secretin, cholecystokinin, gastrin, and glucagons—all increase bile flow, primarily by increasing water and electrolyte secretion. This action probably occurs at a site distal to the hepatocyte. Finally, the most important factor in regulating the volume of bile flow is the rate of bile salt synthesis by hepatocytes. This rate is regulated by the return of bile salts to the liver by the enterohepatic circulation.

Bile Composition

The components of hepatic and gallbladder bile are essentially the same, but the concentration varies considerably because of the ability of the gallbladder to absorb water (Table 7.1). The gallbladder absorbs water both actively via sodium–hydrogen (Na⁺/H⁺) pumps and passively through aquaporin channels. Both chloride (Cl⁻) and bicarbonate (HCO₃⁻) are absorbed by the gallbladder epithelium via the cystic fibrosis transmembrane regulator (CFTR; Swartz-Basile et al, 2007). The secretion of hydrogen ions and the absorption of bicarbonate by the gallbladder alter the acid-base balance from basic in hepatic bile to acidic in gallbladder bile.

Table 7.1 Composition of Hepatic and Gallbladder Bile

Significant ranges may be seen.

* All determinations are milliequivalents per liter, except for pH.

The gallbladder mucosa also absorbs the calcium (Ca⁺⁺) and magnesium (Mg⁺⁺) cations. However, calcium absorption is not as efficient as the absorption of sodium and water, which leads to a significantly greater relative increase in the concentration of calcium in the gallbladder. Similarly, the concentration of bilirubin, which is not actively absorbed by the gallbladder, may be as high as 10-fold. Thus precipitation of calcium bilirubinate crystals, the major component of pigment gallstones, is much more likely to occur within the gallbladder. In addition, the biliary lipids, bile salts, phospholipids, and cholesterol all become more concentrated in the gallbladder. As the gallbladder bile becomes concentrated, several changes occur in the capacity of bile to solubilize cholesterol. The solubility in the micellar fraction is increased, but the stability of the phospholipid–cholesterol vesicles is greatly decreased. Because cholesterol crystal precipitation occurs preferentially by vesicular, rather than micellar, mechanisms, the net effect of concentrating bile is an increased tendency to form cholesterol crystals (Klein et al, 1996).

Bile Salt Secretion

Bile is secreted from the hepatocyte into canaliculi, which drain their contents into small bile ducts. Secretion of bile salts is the major osmotic force for the generation of bile flow. Bile acids are formed at a rate of 500 to 600 mg per day. The bulk of the bile salt pool is maintained in the gallbladder, followed by the liver, the small intestine, and the extrahepatic bile ducts. Bile acids are synthesized from cholesterol via two main pathways: a classic pathway leads to the formation of cholic acid, and an alternate pathway results in the synthesis of chenodeoxycholic acid. The classic pathway is the predominant mode of bile acid synthesis in humans. As a result, approximately 70% of the bile acid pool consists of cholic acid and its metabolite deoxycholic acid, with chenodeoxycholic acid occurring less commonly in human bile (Kullack-Ublick, 2004).

In plasma, bile acids circulate bound to either albumin or lipoproteins. In the space of Disse within the liver, bile salt uptake into the hepatocytes is very efficient. This process is mediated by sodium-dependent and sodium-independent mechanisms. The sodium-dependent pathway accounts for more than 80% of taurocholate uptake but less than 50% of cholate uptake (Meier & Stieger, 2002). In recent years a number of transport proteins have been identified that play a key role in this process (Fig. 7.1). The bile salt transporter is termed the sodium-taurocholate cotransporting polypeptide (NTCP), and it is exclusively expressed in the liver and located in the basolateral membrane of the hepatocyte. Sodium-independent hepatic uptake of bile acids is mediated primarily by a family of transporters termed the organic anion transporting polypeptides (OATPs). In contrast to NTCP, these transporters have a broader substrate affinity and transport a variety of organic anions, including the bile salts. OATP-C is the major sodium-independent bile salt uptake system, but OATP-A also takes up bile acids, and OATP-8 mediates taurocholate uptake.

FIGURE 7.1 Bile formation in human liver. B, bilirubin; BL, biliary lipids; BRCP, breast cancer–related protein; BS, bile salts; BSEP, bile salt export pump; D/OA, drugs/organic anions; ER, endoplasmic reticulum; HBAB, hepatic bile acid–binding protein; MDR1 and MDR3, multidrug resistance proteins 1 and 3; MRP3, MDR-related protein-3; NTCP, Na⁺–taurocholate cotransporting polypeptide; OATPs (A, C, 8), organic anion transporting polypeptides.

Intracellular bile acid transport occurs within a matter of seconds. Two mechanisms may be responsible for bile acid transcellular movement: one involves transfer of bile acids from the basolateral membrane to the canalicular membrane via bile acid–binding proteins (Crawford, 1996), the other moves cellular bile salt through vesicular transport. In contrast, the transport of bile salts across the canalicular membrane of hepatocytes represents the rate-limiting step in the overall secretion of bile salts from the blood into bile.

Bile salt concentrations are 1000-greater within the canaliculi than in the hepatocytes. This gradient necessitates an active transport mechanism, which is an ATP-dependent process. This bile salt export pump (BSEP) is closely related to the proteins encoded by the multidrug resistance (MDR) gene family of ATP binding cassette (ABC) transporters (Kullack-Ublick, 2004). The ABC transporters mediate the transport of metabolites, peptides, fatty acids, cholesterol, and lipids in the liver, intestines, pancreas, lungs, kidneys, brain, and in macrophages. Although BSEP is the major transporter for monovalent bile salts into the canaliculus, MDR-related protein-2 (MRP2), a member of the multidrug resistance protein family, also transports sulfated and glucuronidated bile salts into the canaliculus. MRP2 also mediates the export of multiple other organic anions, including conjugated bilirubin, leukotrienes, glutathione disulfide, chemotherapeutic agents, uricosurics, antibiotics, toxins, and heavy metals (Gerk & Vore, 2002).

Biliary Lipid Secretion

Compared with bile salts, the biliary lipids, phospholipids, and cholesterol play a secondary role in the formation of bile. Phospholipids and cholesterol are formed primarily from low-density lipoproteins circulating in plasma and from de novo synthesis by hepatocytes. Less is known about the secretion of biliary lipids compared with bile salt secretion; however, biliary lipid secretion is key for cholesterol disposal, intestinal absorption of dietary lipids, and cytoprotection against bile acid–induced hepatocyte and cholangiocyte injury (Arrese & Accatino, 2002).

Phospholipid secretion involves the delivery of phospholipids to the inner leaflet of the canalicular plasma membrane (Elferink & Groen, 2000). In humans the MDR3 transporter translocates phospholipids from the inner to the outer leaflet of the canalicular membrane. Humans with an MDR3 deficiency develop progressive familial intrahepatic cholestasis type 3 (Kullak-Ublick, 2004). These patients have no phosphatidylcholine in bile and therefore do not form mixed micelles with bile salts. As a result, toxic bile salts injure the biliary epithelium, resulting in neonatal cholestasis, cholestasis of pregnancy, and cirrhosis in adults.

Less is known about the role of transporter proteins in cholesterol secretion, but the ABC transporters, ABCG5 and ABCG8, have been demonstrated to be involved in the elimination of plant steroids (Lee, 2004). Cholesterol is highly nonpolar and insoluble in water; thus it is insoluble in bile. The key to maintaining cholesterol in solution is the formation of micelles, a bile salt–phospholipid–cholesterol complex. Bile salts are amphipathic compounds that contain both a hydrophilic and hydrophobic portion. In aqueous solutions, bile salts are oriented with the hydrophilic portion outward. Phospholipids are incorporated into the micellar structure, allowing cholesterol to be added to the hydrophobic central portion of the micelle. In this way, cholesterol can be maintained in solution in an aqueous medium. The concept of mixed micelles as the only cholesterol carrier has been challenged by the demonstration that much of the biliary cholesterol exists in a vesicular form. Structurally, these vesicles are made up of lipid bilayers of cholesterol and phospholipids. In their simplest and smallest form, the vesicles are unilamellar, but an aggregation may take place, leading to multilamellar vesicles. Present theory suggests that in states of excess cholesterol production, these large vesicles may also exceed their capability to transport cholesterol, and cystal precipitation may occur (Fig. 7.2).

FIGURE 7.2 Concentration of bile leads to net transfer of phospholipids and cholesterol from vesicles to micelles. Phospholipids are transferred more efficiently than cholesterol, leading to cholesterol enrichment of the remaining (remodeled) vesicles. Aggregation of these cholesterol-rich vesicles forms multilamellar liquid crystals of cholesterol monohydrate.

(Modified from Vessey DA, 1990: Metabolism of drugs and toxins by the human liver. In Zakin D, Boyer TD [eds]: Hepatology: A Textbook of Liver Disease, 2nd ed. Philadelphia, WB Saunders, p 1492.)

Bilirubin Secretion

Released at the time of degradation of senescent erythrocytes by the reticuloendothelial system, heme is the source of approximately 80% to 85% of the bilirubin produced daily. The remaining 15% to 20% is derived largely from the breakdown of hepatic hemoproteins. Both enzymatic and nonenzymatic pathways for the formation of bilirubin have been proposed. Although both may be important physiologically, the microsomal enzyme hemeoxygenase—found in high concentration throughout the liver, spleen, and bone marrow—plays a major role in the initial conversion of heme to biliverdin, which is then reduced to bilirubin by the cytosolic enzyme biliverdin reductase in a nicotinamide adenine dinucleotide (NADH)-dependent reaction before being released into the circulation. In this “unconjugated” form, bilirubin has a very low solubility, and it is bound avidly to plasma proteins, primarily albumin, before uptake and further processing by the liver. The liver is the sole organ capable of removing the albumin–bilirubin complex from the circulation and esterifying the potentially toxic bilirubin to water-soluble, nontoxic, monoconjugated and deconjugated derivatives.

In the sinusoidal membrane of the hepatocyte, bilirubin is taken up by OATP-C, a membrane transporter belonging to the OATP family (Cui et al, 2001). OATP-C is involved with the uptake of both conjugated and unconjugated bilirubin, but unconjugated bilirubin also can cross hepatic sinusoidal membranes by a diffusion process. In the hepatocyte, bilirubin binds to a driver of gluthathione-S-transferase and is catalyzed by bilirubin uridine-5-diphosphate (UDP)-glycosyltransferase to form bilirubin glucuronides. Mutations in the gene encoding bilirubin UDP-glycosyltransferase are associated with the unconjugated hyperbilirubin syndromes, Crigler-Najjar and Gilbert syndromes (Iganagi, 1998).

Bilirubin glucuronides are excreted into the bile canaliculus primarily via MRP2, which also plays a role in the transport of glucuroniductal bile salts and a wide spectrum of organic anions, including the antibiotic ceftriaxone. MRP3, which is expressed in the basolateral membrane of hepatocytes and cholangiocytes, also participates in the transport of bilirubin monoglucuronide. MRP3 also may prevent intracellular accumulation of conjugated bilirubin, bile salts, and other organic anions in cholestatic situations.

Bile Flow

The bile ducts, gallbladder, and sphincter of Oddi act in concert to modify, store, and regulate the flow of bile. Bile flow is primarily driven by bile salt secretion. During its passage through the bile ductules, canalicular bile is modified by the absorption and secretion of electrolytes and water. Bicarbonate secretion by the bile ducts plays an important role in bile salt–independent bile flow. The gastrointestinal hormone secretin increases bile flow primarily by increasing the active secretion of chloride-rich fluid by the bile ducts. Bile duct secretion is also stimulated by other hormones, such as cholecystokinin and gastrin. The bile duct epithelium is capable of water and electrolyte absorption also, which may be of primary importance in the storage of bile during fasting in patients who have previously undergone cholecystectomy.

The main functions of the gallbladder are to concentrate and store hepatic bile during the fasting state and deliver bile into the duodenum in response to a meal. The usual capacity of the human gallbladder is about 40 to 50 mL. Only a small fraction of the bile produced each day would be stored, were it not for the gallbladder’s remarkable absorptive capacity.

The enterohepatic circulation provides an important negative feedback system on bile salt synthesis. Should the recirculation be interrupted by resection of the terminal ileum or by primary ileal disease, abnormally large losses of bile salts could occur. This situation increases bile salt production to maintain a normal bile salt pool. Similarly, if bile salts are lost through an external biliary fistula, increased bile salt synthesis is necessary. However, except for those unusual circumstances in which excessive losses occur, bile salt synthesis matches losses, maintaining a constant bile salt pool size. During fasting, approximately 90% of the bile acid pool is sequestered in the gallbladder.

Enterohepatic Circulation

Bile salts are synthesized and conjugated in the liver; secreted into bile; stored temporarily in the gallbladder; passed from the gallbladder into the duodenum; absorbed throughout the small intestine, especially in the ileum; and returned to the liver via the portal vein. This cycling of bile acids between the liver and the intestine is referred to as the enterohepatic circulation (Fig. 7.3). The total amount of bile acids in the enterohepatic circulation is defined as the circulating bile pool. In this highly efficient system, nearly 95% of bile salts are reabsorbed. Thus, of the total bile salt pool of 2 to 4 g, which recycles through the enterohepatic cycle 6 to 10 times daily, only about 600 mg is actually excreted into the colon. Bacterial action in the colon on the two primary bile salts, cholate and chenodeoxycholate, results in the formation of the secondary bile salts, deoxycholate and lithocholate. Although some deoxycholate is reabsorbed passively by the colon, the remainder is lost in fecal waste; however, the physiology of bile salt, biliary lipid, bilirubin, bile flow, and the enterohepatic circulation are dramatically altered when the bile ducts become obstructed.

FIGURE 7.3 Enterohepatic circulation of bile salts. Cholesterol is taken up from plasma by the liver. Bile acids are synthesized at a rate of 0.6 g/24 h and are excreted through the biliary system into the small bowel. Most of the bile salts are reabsorbed in the terminal ileum and are returned to the liver to be extracted and reextracted.

(Modified from Dietschy JM, 1972: The biology of bile acids. Arch Intern Med 130:472-474.)

Causes of Jaundice

Jaundice may result from 1) increased production of bilirubin, 2) impaired hepatocyte uptake of bilirubin, 3) impaired conjugation of bilirubin, 4) impaired transport or excretion of bilirubin into the bile canaliculus, or 5) obstruction of the intrahepatic or extrahepatic biliary tree (Table 7.2). Overproduction, impaired uptake, and impaired conjugation of bilirubin all lead to a predominently unconjugated hyperbilirubinemia. Impaired transport and excretion and biliary ductal obstruction result in hyperbilirubinemia that is primarily conjugated. Some patients have multiple defects in normal metabolism. For example, a patient with biliary obstruction from a tumor may develop secondary hepatocellular dysfunction. Therefore these classification systems may be simplifications of more complex disease processes.

Table 7.2 Classification of Jaundice

Diseases causing bile duct obstruction may be further divided into conditions causing 1) complete obstruction, 2) intermittent obstruction, 3) chronic incomplete obstruction, or 4) segmental duct obstruction (Table 7.3). Patients with complete biliary obstruction will have clinical jaundice, and those with intermittent obstruction may develop symptoms (pain, pruritus, fevers) and biochemical changes without necessarily developing clinical jaundice. Patients with chronic incomplete obstruction can eventually develop hepatic fibrosis (see Chapter 6) and biliary cirrhosis (see Chapter 70A).

Table 7.3 Lesions Commonly Associated with Biliary Tract Obstruction

Hepatobiliary

Hepatocytes are arranged in plates along which blood flows from portal to central veins. Within these plates, the small apical domains of adjacent hepatocytes form a tubular lumen, the canaliculus, which is the site of primary bile formation. From the canalicular network, bile flows to the small ductules and subsequently to the larger ducts. With biliary obstruction, the bile canaliculi become dilated, and the microvilli are distorted and swollen. In patients with long-standing obstruction, intrahepatic bile ductule proliferation occurs with an increase in the length and tortuosity of the canaliculi.

The biliary system normally has a low pressure (5 to 10 cm H₂O); however, in the setting of complete or partial biliary obstruction, biliary pressure can approach 30 cm H₂O. As biliary pressure increases, the tight junctions between hepatocytes and bile duct cells are disrupted, resulting in an increase in bile duct and canalicular permeability. Bile contents can freely reflux into liver sinusoids, causing a marked polymorphonuclear leukocyte infiltration into the portal triads. This inflammatory response is followed by increased fibrinogenesis with deposition of reticulin fibers, which undergo conversion to type I collagen (see Chapter 6). The extrahepatic bile ducts exhibit mucosal atrophy and squamous metaplasia followed by inflammatory infiltration and fibrosis in the subepithelial layers of the bile duct (Karsten et al, 1991).

In addition to the structural effects of biliary obstruction on the bile ducts, elevated biliary pressure can alter bile production by hepatocytes. In the setting of biliary obstruction and elevated biliary pressure, bile becomes less lithogenic because of a relative decrease in cholesterol and phospholipid secretion compared with bile acid secretion. With the relief of biliary obstruction and the normalization of biliary pressures, the recovery of cholesterol and phospholipid secretion is more rapid than bile acid secretion, therefore bile is more lithogenic in this setting. This phenomenon may lead to premature occlusion of decompressive bilary stents placed for the management of obstructive jaundice.

Several authors have reported impairment of both macrovascular and microvascular perfusion of the liver in obstructive jaundice. Intravital fluorescence microscopy has shown a significant increase in the number of nonperfused sinusoids after 3 days of extrahepatic obstruction. Moreover, in perfused sinusoids, a 35% decrease in the mean diameter and a 25% decrease in flow velocity were noted (Koeppel et al, 1997). This alteration in hepatic perfusion may help explain the increased risk of hepatocellular dysfunction when performing liver resections in patients with obstructive jaundice (see Chapters 50C and 93A). Extrahepatic biliary obstruction and jaundice can also alter important secretory, metabolic, and synthetic functions of the liver. When biliary pressure rises above 20 cm H₂O, hepatic bile secretion is diminished, and hepatocytes cannot excrete efficiently against the high pressure. As a result, excretory products of the hepatocytes reflux directly into the vascular system, leading to systemic toxicity.

Jaundiced patients have a decreased capacity to excrete drugs, such as antibiotics, that are normally secreted into bile (Blenkharn et al, 1985). The increased concentration of bile acids associated with obstructive jaundice results in inhibition of the hepatic cytochrome P450 enzymes and therefore a decrease in the rate of oxidative metabolism in the liver. In addition, bile acids in abnormally high concentrations can induce apoptosis (programmed cell death) in hepatocytes (Patel et al, 1994). The synthetic function of the hepatocyte is also decreased with obstructive jaundice, as evidenced by decreased plasma levels of albumin, clotting factors, and secretory immunoglobulins (IgA).

Kupffer cells are tissue macrophages that are the predominant cell type of the hepatic reticuloendothelial system (see Chapter 9). Normally, infectious agents, damaged blood cells, cellular debris, fibrin degradation products, and endotoxin absorbed or formed in the portal circulation are effectively filtered by Kupffer cells and removed from the systemic circulation. Kupffer cells also play an interactive role with hepatocytes, modulating synthesis of hepatic proteins. Obstructive jaundice has been shown to have profound effects on Kupffer cells, including decreased endocytosis, phagocytosis, clearance of bacteria and endotoxin, and expression of the major histocompatibility complex class II antigen with a consequent diminished ability to process antigen (Nehez & Anderson, 2002; Puntis & Jiang, 1996). Biliary obstruction also has been shown to increase levels of proinflammatory cytokines, including TNF-α and IL-6 (see Chapters 9 and 10).

Cardiovascular

In addition to hepatic dysfunction, obstructive jaundice may cause severe hemodynamic and cardiac disturbances. Experimental animals with obstructive jaundice tend to be hypotensive and exhibit an exaggerated hypotensive response to hemorrhage. Studies in experimental animals have demonstrated that bile duct ligation 1) decreases cardiac contractility; 2) reduces left ventricular pressures; 3) impairs response to β-agonist drugs, such as isoproterenol and norepinephrine; and 4) decreases peripheral vascular resistance (Ma et al, 1999). In a study of 9 patients with obstructive or cholestatic jaundice, Lumlertgul and colleagues (1991) showed a significantly blunted response in left ventricular ejection fraction compared with normal volunteers following the infusion of the positive inotrope dobutamine. Padillo and others (2001) also have shown a negative correlation between serum bilirubin and left ventricular systolic work in 13 patients with biliary obstruction and no previous history of heart, lung, or kidney disease. Successful internal biliary drainage in patients was associated with a significant increase in cardiac output, compliance, and contractility. The combination of depressed cardiac function and decreased total peripheral resistance most likely makes the jaundiced patient more susceptible to the development of postoperative shock than nonjaundiced patients.

Renal

The association between jaundice and postoperative renal failure has been known for many years. The reported incidence of postoperative acute renal failure has been reported to be as high as 10% but varies depending on the nature of the procedure. Moreover, the mortality rate in jaundiced patients who develop renal failure has been reported to be as high as 70% (Fogarty et al, 1995). Important factors that may play a role in the development of renal failure in obstructive jaundice include 1) depressed cardiac function, 2) hypovolemia, and 3) endotoxemia.

The decreased cardiac function associated with obstructive jaundice leads to a decrease in renal perfusion. Decreased cardiac output may also result in stretching of the atrium and increased production of atrial natriuretic peptide (ANP), a hormone known to cause natriuresis, to counter the action of water- and sodium-retaining hormones, to inhibit the thirst mechanism, and to produce peripheral vasodilation. Plasma levels of ANP have been shown to be increased in both experimental animals and in patients with extrahepatic biliary obstruction (Padillo et al, 2001).

In addition to the direct effects of jaundice on the heart and peripheral vasculature discussed above, the increased serum levels of bile acids associated with obstructive jaundice have a direct diuretic and natriuretic effect on the kidney that results in significant extracellular volume depletion and hypovolemia. In dogs, the infusion of bile into the renal artery results in increased urine flow, natriuresis, and kaliuresis. This diuretic effect may be mediated by increased prostaglandin E₂ (PGE₂) production by the kidney (Green & Better, 1994).

The third factor in the development of renal failure is endotoxemia (Fig. 7.4). Approximately 50% of patients with obstructive jaundice have endotoxin in their peripheral blood (Hunt et al, 1982). This phenomenon may be the result of decreased hepatic clearance of endotoxin by Kupffer cells and a lack of bile salts in the gut lumen that normally prevent absorption of endotoxins and inhibit anaerobic bacterial growth. Endotoxin also causes renal vasoconstriction and redistribution of renal blood flow away from the cortex, and disturbances in coagulation that include the activation of complement, macrophages, leukocytes, and platelets (Hunt et al, 1982). As a result, glomerular and peritubular fibrin is deposited. This factor, in combination with reduced renal cortical blood flow, results in the tubular and cortical necrosis observed in jaundiced patients with renal failure. Mechanisms of the pathophysiology of renal failure in obstructive jaundice are summarized in Figure 7.3.

FIGURE 7.4 Obstructive jaundice leads to renal impairment or acute renal failure. ANP, atrial natriuretic peptide; LV, left ventricular.

Coagulation

Disturbances of blood coagulation are commonly present in jaundiced patients. The most frequently observed abnormality is prolongation of the prothrombin time. This problem results from impaired vitamin K absorption from the gut, secondary to a lack of intestinal bile. This coagulopathy is usually reversible with parenteral administration of vitamin K. Decreased bile levels in the small intestine may result in diminished absorption of other fat-soluble vitamins and fats, which results in weight loss and loss of calcium. This latter factor, as well as the above-mentioned increase in circulating endotoxin, may further contribute to clotting abnormalities.

In experimental animals, endotoxin affects metabolism of factors XI and XII and causes platelet and direct endothelial damage (Hunt et al, 1982). Moreover, endotoxin release in jaundiced patients results in a low-grade, disseminated intravascular coagulation with increased fibrin degradation products. Hunt and colleagues have shown that jaundiced patients with circulating endotoxin or increased fibrin degradation product levels before surgery are at increased risk for hemorrhagic complications. In addition to problems with endotoxemia, patients with coexisting cirrhosis often have additional problems related to thrombocytopenia from hypersplenism and fibrinolysis.

Immune System

Surgery in jaundiced patients is associated with a higher rate of postoperative septic complications compared with those without jaundice, due in large measure to defects in cellular immunity that make them more prone to infection (see Chapters 9 and 11). Cainzos and colleagues (1992) have demonstrated an association between jaundice and altered delayed-type hypersensitivity. Only 16% of 118 jaundiced patients were immunocompetent, compared with 76% of 59 healthy controls, when tested with a panel of seven skin antigens. Several authors have shown impaired T-cell proliferation (Thompson et al, 1990), decreased neutrophil chemotaxis (Andy et al, 1992), and defective bacterial phagocytosis (Scott-Conner et al, 1993) following bile duct ligation in rats. As mentioned earlier, the ability of the reticuloendothelial system, specifically Kupffer cells, to clear bacteria and endotoxin from the circulation also is reduced in obstructive jaundice.

The absence of bile from the intestinal tract also plays a role in the infectious complications seen in patients with obstructive jaundice. It has been shown that bacterial translocation from the gut is increased in the setting of bile duct obstruction (Deitch et al, 1990). Obstruction causes a disruption of the enterohepatic circulation and results in loss of the emulsifying antiendotoxin effect of bile acids; therefore a larger pool of endotoxin is available within the intestine for absorption into the portal circulation. The combination of reduced or absent bile in the intestine and impaired cellular immunity and reticuloendothelial cell function appears to be a major factor contributing to more frequent infective complications in the jaundiced patient.

Acute cholangitis is a bacterial infection of the biliary ductal system, and it varies in severity from mild and self-limited to severe and life threatening (see Chapter 43). The clinical triad associated with cholangitis—fever, jaundice, and pain—was first described in 1877 by Charcot. Cholangitis results from a combination of two factors: significant bacterial concentrations in the bile and biliary obstruction. Although bile from the gallbladder and bile ducts is usually sterile, in the presence of common bile duct stones or other obstructing pathology, the incidence of positive cultures increases; likewise, instrumentation of the biliary tree also greatly increases rates of bile colonization. The most common organisms recovered from the bile in patients with cholangitis include Escherichia coli, Klebsiella pneumonia, the enterococci, and Bacteroides fragilis (Thompson et al, 1990). However, even in the presence of high biliary bacterial concentrations, clinical cholangitis and bacteremia will not develop, unless obstruction causes elevated intraductal pressures (Lipsett & Pitt, 1993).

Normal biliary pressures range from 7 to 14 cm H₂O. In the presence of bacteribilia and normal biliary pressures, hepatic venous blood and perihepatic lymph are sterile. However, with partial or complete biliary obstruction, intrabiliary pressures rise to 18 to 29 cm H₂O, and organisms rapidly appear in both the blood and lymph. The fever and chills associated with cholangitis are the result of systemic bacteremia caused by cholangiovenous and cholangiolymphatic reflux.

The most common causes of biliary obstruction are choledocholithiasis (see Chapter 35), benign strictures (see Chapter 42A, Chapter 42B ), biliary-enteric anastomotic strictures (see Chapter 29, Chapter 42A, Chapter 42B ), and periampullary or proximal biliary cancers (see Chapter 49, Chapter 50A, Chapter 50B, Chapter 50C, Chapter 50D, Chapter 58A, Chapter 58B, Chapter 59 ). Prior to 1980, choledocholithiasis was the cause of approximately 80% of the reported cases of cholangitis. In recent years, however, malignant strictures have become a frequent cause, particularly at tertiary referral centers. Endoscopic cholangiography, percutaneous transhepatic cholangiography, and stent placement via either the endoscopic or percutaneous route are all known to cause bacteremia, and these procedures are frequently performed in patients with a presumptive diagnosis of malignant obstruction.

Wound Healing

Delayed wound healing and a high incidence of wound dehiscence and incisional hernia have been observed in jaundiced patients undergoing surgery. Patients with obstructive jaundice have decreased activity of the enzyme propylhydroxylase in their skin. Propylhydroxylase is necessary for the incorporation of proline amino acid residues into collagen, and its activity has been used as a measure of collagen synthesis. Grande and colleagues (1990) measured skin propylhydroxylase activity in 95 patients with extrahepatic bile duct obstruction and 123 nonjaundiced control patients undergoing cholecystectomy. The jaundiced patients had only 11% of the skin propylhydroxylase activity of the controls. In the subgroup of patients with jaundice secondary to malignancy, propylhydroxylase activity was less than 7% of controls. With relief of obstruction, the activity increased to 22% of controls. Interestingly, in patients with jaundice secondary to benign obstruction, the activity increased to 100% of controls.

Other Factors

Other problems that face jaundiced patients are anorexia, weight loss, and malnutrition. Appetite is adversely influenced by the lack of bile salts in the intestinal tract. In addition, patients with pancreatic or periampullary malignant lesions may have partial duodenal obstruction or abnormal gastric emptying, perhaps secondary to tumor infiltration of the celiac nerve plexus. Patients with pancreatic or ampullary tumors also may have pancreatic endocrine and exocrine insufficiency. This latter problem may further compound other nutritional defects that in turn may exacerbate the immune deficits of the jaundiced patient.

Several recent observations suggest that the many physiologic derangements induced by obstructive jaundice take a long time to reverse. For example, Koyama and colleagues (1981) have shown that hepatic mitochondrial function does not return to normal even 7 weeks after relief of obstruction. This same prolonged effect of obstructive jaundice has been noted with lymphocyte, polymorphonuclear, and Kupffer cell function. Therefore even patients who have had temporary relief of biliary obstruction via percutaneous or endoscopic stents are likely to remain at risk for significant complications following surgery, because derangements in hepatic function are likely still present at the time of operation.

Cardiopulmonary

In assessing cardiopulmonary status, the patient’s age, history of recent myocardial infarction, and the presence of congestive heart failure, significant valvular aortic stenosis, or a disturbance of normal cardiac rhythm have all been correlated with increased operative risk (Goldman et al, 1977). In addition, patients with severe pulmonary disease may not be candidates for extensive abdominal surgery.

Renal

Jaundiced patients, especially those with cirrhosis and cholangitis, are at increased risk of developing renal insufficiency. The maintenance of adequate blood volume and the correction of dehydration are extremely important if renal complications are to be avoided. Fluid management can be quite complex in jaundiced patients, and selected patients may benefit from invasive hemodynamic monitoring with central venous catheters—and less commonly, pulmonary artery catheters—to assist in assessing intravascular volume.

Certain oral bile salts have been shown to be efficacious in preventing the development of postoperative renal dysfunction. In a study by Cahill (1983) 54% of 24 jaundiced patients not given oral bile salts before surgery were found to have systemic endotoxemia, which was associated with renal impairment in two thirds of the cases. In comparison, none of the 8 jaundiced patients given 500 mg of sodium deoxycholate every 8 hours for 48 hours before surgery had portal or systemic endotoxemia. Moreover, none of these 8 patients had evidence of renal impairment.

Nutrition

Malnutrition is a significant risk factor for surgery in the setting of obstructive jaundice (see Chapter 24). Halliday and colleagues (1988) noted that patients who died in the postoperative period following surgery for obstructive jaundice had had a significant reduction in body weight, midarm circumference, total body potassium, and reactivity to skin test antigens prior to operation. In a study from Italy (Foschi et al, 1986), enteral hyperalimentation was found to significantly decrease operative morbidity and mortality in a group of patients treated with 20 days of preoperative percutaneous biliary drainage. Although most patients with benign biliary problems are adequately nourished, various degrees of malnutrition are frequently present in patients with malignant obstruction; therefore patients with malignant obstructive jaundice should be evaluated for evidence of malnutrition and have nutritional support instituted if necessary.

Coagulation

Patients with obstructive jaundice, cholangitis, or cirrhosis are all prone to excessive intraoperative bleeding. The most common clotting defect in patients with obstructive jaundice is prolongation of the prothrombin time (PT), which is usually reversible by the administration of parenteral vitamin K. Patients with severe jaundice and/or cholangitis also may develop disseminated intravascular coagulation (DIC), which may require infusion of platelets and fresh frozen plasma. Reversal of DIC also requires control of the underlying sepsis, which should include biliary drainage in patients with cholangitis in addition to systemic antibiotics.

In cirrhotic patients, clotting abnormalities are often multifactorial and include thrombocytopenia secondary to hypersplenism, prolongation of PT and partial thromboplastin time (PTT), and fibrinolysis. Vitamin K should be administered if the PT is prolonged. If no effect is seen and/or if the PTT is also prolonged, fresh frozen plasma should be given. Thrombocytopenia can usually be managed by intraoperative platelet infusions. If the patient has a shortened clot lysis time and hypofibrinogenemia, ε-aminocaproic acid may be indicated.

Pruritus

Pruritus is often a distressing problem in the jaundiced patient. The exact cause of pruritus remains obscure, but increased circulating levels of bile salts, histamines, and central nervous system opiate receptors have been implicated. In some patients, relief from itching can be obtained by bile salt–binding agents, such as cholestyramine. Various sedatives and antihistamines also can provide relief of itching in jaundiced patients, however, relief of biliary obstruction remains the most effective method for managing pruritis.

Cholangitis

Biliary sepsis also has been identified as a major risk in jaundiced patients (see Chapter 43). Cholangitis occurs when partial or complete obstruction of the bile duct exists, resulting in increased intraluminal pressure and infected bile behind the obstruction. Patients with cholangitis present with right upper quadrant abdominal pain, fever, and jaundice (Charcot triad). Patients with “toxic” cholangitis, Charcot triad plus shock and mental confusion (Reynold pentad), have significant mortality with appropriate antibiotic therapy alone and therefore require emergent biliary decompression.

Gigot and colleagues (1989) identified seven prognostic factors that are indications for urgent biliary decompression: 1) acute renal failure, 2) liver abscess, 3) cirrhosis, 4) high malignant stricture, 5) percutaneous transhepatic cholangiography, 6) female gender, and 7) advanced age. However, emergent surgical treatment is associated with significant morbidity and mortality; therefore both percutaneous and endoscopic biliary drainage have been proposed as effective therapy for the 5% to 10% of patients with cholangitis who are unresponsive to conservative therapy. Lai and colleagues (1992) have shown in a series of 82 patients with severe acute cholangitis that endoscopic drainage is associated with a lower morbidity (34% vs. 66%) and mortality (10% vs. 32%) than operative drainage. A more complete discussion of the bacteriology and antibiotic management of patients with cholangitis can be found in Chapters 11 and 43.

Preoperative Drainage

The preoperative relief of jaundice and the reversal of its systemic effects by either endoscopic or transhepatic biliary decompression has been proposed as a method to decrease the risk of surgery in jaundiced patients. However, several prospective randomized studies have shown that the routine use of preoperative biliary drainage does not reduce operative morbidity or mortality in patients with obstructive jaundice (Hatfield et al, 1982; Lai et al, 1994; McPherson et al, 1984; Pitt et al, 1985; van der Gaag et al, 2010; Table 7.4). In addition, a meta-analysis also concluded that preoperative biliary drainage increased, rather than decreased, overall complications from surgery and the drainage procedure and provided no benefit in terms of reduced mortality or decreased hospital stay (Sewnath et al, 2002). In fact, several retrospective studies have documented a higher incidence of infectious complications (wound infection, pancreatic fistula) and even mortality in patients undergoing pancreatic or biliary tract resection after preoperative biliary decompression (Sewnath et al, 2002; Sohn et al, 2000).

A criticism of some of the prospective studies is that the duration of preoperative drainage (10 to 18 days) may have been inadequate to reverse the multiple metabolic and immunologic abnormalities associated with severe obstructive jaundice. Both animal and human studies demonstrate that the recovery of various metabolic and immune functions requires at least 6 weeks to pass after the relief of biliary obstruction (Clements et al, 1993; Kennedy et al, 1994; Thompson et al, 1990). Similarly, animal studies strongly suggest that return of bile to the intestinal tract has significant advantages over external biliary drainage (Roughneen et al, 1986).

Although the data suggest that routine preoperative biliary drainage may be of limited benefit, it may have some value in selected patients with advanced malnutrition, biliary sepsis, and hilar malignancies that require liver resection. Regarding the latter, it should be emphasized that most of the published data regarding preoperative biliary drainage focuses on patients with periampullary malignancy. Patients with proximal biliary obstruction undergoing major hepatic resection represent an entirely different subgroup, and although no adequately powered study has addressed this issue specifically in this population, some evidence does suggest a benefit of preoperative biliary drainage of the future liver remnant (see Chapters 50B, 50C, and 93A). Preoperatively placed catheters also may be of value in the operating room during difficult biliary dissections in patients with proximal biliary tumors or strictures, and they may aid in the placement of long-term transhepatic stents.