2639 Liver Transplantation CHAPTER 345

Bacterial, fungal, or viral infections are common and may be

life-threatening postoperatively. Early after transplant surgery, common postoperative infections predominate—pneumonia, wound infections, infected intraabdominal collections, urinary tract infections,

and IV line infections—rather than opportunistic infections; these

infections may involve the biliary tree and liver as well. Beyond the first

postoperative month, the toll of immunosuppression becomes evident,

and opportunistic infections—CMV, herpes viruses, fungal infections

(Aspergillus, Candida, cryptococcal disease), mycobacterial infections,

parasitic infections (Pneumocystis, Toxoplasma), and bacterial infections (Nocardia, Legionella, Listeria)—predominate. Rarely, early infections represent those transmitted with the donor liver, either infections

present in the donor or infections acquired during procurement

processing. De novo viral hepatitis infections acquired from the donor

organ or, almost unheard of now, from transfused blood products

occur after typical incubation periods for these agents (well beyond

the first month). Obviously, infections in an immunosuppressed host

demand early recognition and prompt management; prophylactic

antibiotic therapy is administered routinely in the immediate postoperative period. Use of sulfamethoxazole with trimethoprim reduces the

incidence of postoperative Pneumocystis jirovecii pneumonia. Antiviral

prophylaxis for CMV with ganciclovir should be administered in

patients at high risk (e.g., when a CMV-seropositive donor organ is

implanted into a CMV-seronegative recipient).

Neuropsychiatric complications include seizures (commonly associated

with cyclosporine and tacrolimus toxicity), metabolic encephalopathy,

depression, and difficult psychosocial adjustment. Rarely, diseases

are transmitted by the allograft from the donor to the recipient. In

addition to viral and bacterial infections, malignancies of donor origin have occurred. Posttransplantation lymphoproliferative disorders,

especially B-cell lymphoma, are a recognized complication associated

with immunosuppressive drugs such as azathioprine, tacrolimus, and

cyclosporine (see above). Epstein-Barr virus has been shown to play

a contributory role in some of these tumors, which may regress when

immunosuppressive therapy is reduced. De novo neoplasms appear at

increased frequency after liver transplantation, particularly squamous

cell carcinomas of the skin. Routine screening should be performed.

Long-term complications after liver transplantation attributable

primarily to immunosuppressive medications include diabetes mellitus and osteoporosis (associated with glucocorticoids and calcineurin

inhibitors) as well as hypertension, hyperlipidemia, and chronic

renal insufficiency (associated with cyclosporine and tacrolimus).

Monitoring and treating these disorders are routine components of

posttransplantation care; in some cases, they respond to changes in

immunosuppressive regimen, while in others, specific treatment of the

disorder is introduced. Data from a large U.S. database showed that the

prevalence of renal failure was 18% at year 5 and 25% at year 10 after

liver transplantation. Similarly, the high frequency of diabetes, hypertension, hyperlipidemia, obesity, and the metabolic syndrome renders

patients susceptible to cardiovascular disease after liver transplantation; although hepatic complications account for most of the mortality

after liver transplantation, renal failure and cardiovascular disease are

the other leading causes of late mortality after liver transplantation.

■ HEPATIC COMPLICATIONS

Hepatic dysfunction after liver transplantation is similar to the hepatic

complications encountered after major abdominal and cardiothoracic

surgery; however, in addition, hepatic complications include primary

graft failure, vascular compromise, failure or stricture of the biliary

anastomoses, and rejection. As in nontransplantation surgery, postoperative jaundice may result from prehepatic, intrahepatic, and posthepatic

sources. Prehepatic sources represent the massive hemoglobin pigment

load from transfusions, hemolysis, hematomas, ecchymoses, and other

collections of blood. Early intrahepatic liver injury includes effects of

hepatotoxic drugs and anesthesia; hypoperfusion injury associated

with hypotension, sepsis, and shock; and benign postoperative cholestasis. Late intrahepatic sources of liver injury include exacerbation of

primary disease. Posthepatic sources of hepatic dysfunction include

biliary obstruction and reduced renal clearance of conjugated bilirubin.

Hepatic complications unique to liver transplantation include primary

graft failure associated with ischemic injury to the organ during harvesting; vascular compromise associated with thrombosis or stenosis

of the portal vein or hepatic artery anastomoses; vascular anastomotic

leak; stenosis, obstruction, or leakage of the anastomosed common bile

duct; recurrence of primary hepatic disorder (see below); and rejection.

■ TRANSPLANT REJECTION

Despite the use of immunosuppressive drugs, rejection of the transplanted liver still occurs in a proportion of patients, beginning 1–2

weeks after surgery. Clinical signs suggesting rejection are fever, right

upper quadrant pain, and reduced bile pigment and volume. Leukocytosis may occur, but the most reliable indicators are increases in serum

bilirubin and aminotransferase levels. Because these tests lack specificity, distinguishing among rejection, biliary obstruction, primary graft

nonfunction, vascular compromise, viral hepatitis, CMV infection,

drug hepatotoxicity, and recurrent primary disease may be difficult.

Radiographic visualization of the biliary tree and/or percutaneous

liver biopsy often help to establish the correct diagnosis. Morphologic

features of acute rejection include a mixed portal cellular infiltrate,

bile duct injury, and/or endothelial inflammation (“endothelialitis”);

some of these findings are reminiscent of graft-versus-host disease,

primary biliary cholangitis, or recurrent allograft hepatitis C. As soon

as transplant rejection is suspected, treatment consists of IV methylprednisolone in repeated boluses; if this fails to abort rejection, many

centers use thymoglobulin or OKT3. Caution should be exercised

when managing acute rejection with pulse glucocorticoids or OKT3

in patients with HCV infection, because of the high risk of triggering

recurrent allograft hepatitis C. The availability of DAAs for HCV has

effectively obviated this concern.

Chronic rejection is a relatively rare outcome that can follow repeated

bouts of acute rejection or that occurs unrelated to preceding rejection

episodes. Morphologically, chronic rejection is characterized by progressive cholestasis, focal parenchymal necrosis, mononuclear infiltration, vascular lesions (intimal fibrosis, subintimal foam cells, fibrinoid

necrosis), and fibrosis. This process may be reflected as ductopenia—

the vanishing bile duct syndrome, which is more common in patients

undergoing liver transplantation for autoimmune liver disease. Reversibility of chronic rejection is limited; in patients with therapy-resistant

chronic rejection, retransplantation has yielded encouraging results.

OUTCOME

■ SURVIVAL

The survival rate for patients undergoing liver transplantation has

improved steadily since 1983. One-year survival rates have increased

from ~70% in the early 1980s to 85–90% from 2003 to the present time.

Currently, the 5-year survival rate exceeds 60%. An important observation is the relationship between clinical status before transplantation

and outcome. For patients who undergo liver transplantation when

their level of compensation is high (e.g., still working or only partially

disabled), a 1-year survival rate of >85% is common. For those whose

level of decompensation mandates continuous in-hospital care prior

to transplantation, the 1-year survival rate is ~70%, whereas for those

who are so decompensated that they require life support in an intensive

care unit, the 1-year survival rate is ~50%. Since the adoption by UNOS

in 2002 of the MELD system for organ allocation, posttransplantation

survival has been found to be affected adversely for candidates with

MELD scores >25, considered high disease severity. Thus, irrespective

of allocation scheme, high disease severity before transplantation corresponds to diminished posttransplantation survival. Another important distinction in survival has been drawn between high- and low-risk

patient categories. For patients who do not fit any “high-risk” designations, 1- and 5-year survival rates of 85 and 80%, respectively, have

been recorded. In contrast, among patients in high-risk categories—

cancer, fulminant hepatitis, age >65, concurrent renal failure, respirator dependence, portal vein thrombosis, and history of a portacaval

shunt or multiple right upper quadrant operations—survival statistics

fall into the range of 60% at 1 year and 35% at 5 years. Survival after

2640 PART 10 Disorders of the Gastrointestinal System

retransplantation for primary graft nonfunction is ~50%. Causes of

failure of liver transplantation vary with time. Failures within the first

3 months result primarily from technical complications, postoperative

infections, and hemorrhage. Transplant failures after the first 3 months

are more likely to result from infection, rejection, or recurrent disease

(such as malignancy or viral hepatitis).

■ RECURRENCE OF PRIMARY DISEASE

Features of autoimmune hepatitis, primary sclerosing cholangitis, and

primary biliary cholangitis overlap with those of rejection or posttransplantation bile duct injury. Whether autoimmune hepatitis and

sclerosing cholangitis recur after liver transplantation is controversial;

data supporting recurrent autoimmune hepatitis (in up to one-third

of patients in some series) are more convincing than those supporting

recurrent sclerosing cholangitis. Similarly, reports of recurrent primary

biliary cholangitis after liver transplantation have appeared; however,

the histologic features of primary biliary cholangitis and chronic

rejection are virtually indistinguishable and occur as frequently in

patients with primary biliary cholangitis as in patients undergoing

transplantation for other reasons. The presence of a florid inflammatory bile duct lesion is highly suggestive of the recurrence of primary

biliary cholangitis, but even this lesion can be observed in acute rejection. Hereditary disorders such as Wilson’s disease and α1

 antitrypsin

deficiency have not recurred after liver transplantation; however,

recurrence of disordered iron metabolism has been observed in some

patients with hemochromatosis. Hepatic vein thrombosis (BuddChiari syndrome) may recur; this can be minimized by treating underlying myeloproliferative disorders and by anticoagulation. Because

cholangiocarcinoma recurs almost invariably, few centers now offer

transplantation to such patients; however, a few highly selected patients

with operatively confirmed stage I or II cholangiocarcinoma who

undergo liver transplantation combined with neoadjuvant chemoradiation may experience excellent outcomes. In patients with intrahepatic

HCC who meet criteria for transplantation, 1- and 5-year survivals are

similar to those observed in patients undergoing liver transplantation

for nonmalignant disease. Finally, metabolic disorders such as NAFLD

recur frequently, especially if the underlying metabolic predisposition

is not altered. The metabolic syndrome occurs commonly after liver

transplantation as a result of recurrent NAFLD, immunosuppressive

medications, and/or, in patients with hepatitis C related to the impact

of HCV infection on insulin resistance, diabetes and fatty liver.

Hepatitis A can recur after transplantation for fulminant hepatitis

A, but such acute reinfection has no serious clinical sequelae. In fulminant hepatitis B, recurrence is not the rule; however, in the absence

of any prophylactic measures, hepatitis B usually recurs after transplantation for end-stage chronic hepatitis B. Before the introduction of

prophylactic antiviral therapy, immunosuppressive therapy sufficient

to prevent allograft rejection led inevitably to marked increases in

hepatitis B viremia, regardless of pretransplantation levels. Overall

graft and patient survival were poor, and some patients experienced a

rapid recapitulation of severe injury—severe chronic hepatitis or even

fulminant hepatitis—after transplantation. Also recognized in the era

before availability of antiviral regimens was fibrosing cholestatic hepatitis,

rapidly progressive liver injury associated with marked hyperbilirubinemia, substantial prolongation of the prothrombin time (both out

of proportion to relatively modest elevations of aminotransferase activity), and rapidly progressive liver failure. This lesion has been suggested

to represent a “choking off ” of the hepatocyte by an overwhelming

density of HBV proteins. Complications such as sepsis and pancreatitis

were also observed more frequently in patients undergoing liver transplantation for hepatitis B prior to the introduction of antiviral therapy.

The introduction of long-term prophylaxis with HBIg revolutionized

liver transplantation for chronic hepatitis B. Preoperative hepatitis B

vaccination, preoperative or postoperative interferon (IFN) therapy,

or short-term (≤2 months) HBIg prophylaxis has not been shown to

be effective, but a retrospective analysis of data from several hundred

European patients followed for 3 years after transplantation has shown

that long-term (≥6 months) prophylaxis with HBIg is associated with a

lowering of the risk of HBV reinfection from ~75 to 35% and a reduction in mortality from ~50 to 20%.

As a result of long-term HBIg use following liver transplantation

for chronic hepatitis B, similar improvements in outcome have been

observed in the United States, with 1-year survival rates between 75

and 90%. Currently, with HBIg prophylaxis, the outcome of liver transplantation for chronic hepatitis B is indistinguishable from that for

chronic liver disease unassociated with chronic hepatitis B; essentially,

medical concerns regarding liver transplantation for chronic hepatitis B

have been eliminated. Passive immunoprophylaxis with HBIg is begun

during the anhepatic stage of surgery, repeated daily for the first 6

postoperative days, and then continued with infusions that are given

either at regular intervals of 4–6 weeks or, alternatively, when anti–

hepatitis B surface (HBs) levels fall below a threshold of 100 mIU/mL.

The current approach in most centers is to continue HBIg indefinitely,

which can add ~$20,000 per year to the cost of care; some centers are

evaluating regimens that shift to less frequent administration or to IM

administration in the late posttransplantation period or, in low-risk

patients, maintenance with antiviral therapy (see below) alone. Still,

“breakthrough” HBV infection occasionally occurs.

Further improving the outcome of liver transplantation for chronic

hepatitis B is the current availability of such antiviral drugs as entecavir,

tenofovir disoproxil fumarate, and tenofovir alafenamide (Chap. 341).

When these drugs are administered to patients with decompensated

liver disease, a proportion improves sufficiently to postpone imminent liver transplantation. In addition, antiviral therapy can be used

to prevent recurrence of HBV infection when administered prior to

transplantation; to treat hepatitis B that recurs after transplantation,

including in patients who break through HBIg prophylaxis; and to

reverse the course of otherwise fatal fibrosing cholestatic hepatitis.

Clinical trials have shown that entecavir or tenofovir antiviral therapy

reduces the level of HBV replication substantially, sometimes even

resulting in clearance of hepatitis B surface antigen (HBsAg); reduces

alanine aminotransferase (ALT) levels; and improves histologic features of necrosis and inflammation. Currently, most liver transplantation centers combine HBIg plus one of the high-barrier-to-resistance

oral nucleoside (entecavir) or nucleotide analogues (tenofovir). In

low-risk patients with no detectable hepatitis B viremia at the time of

transplantation, a number of clinical trials have suggested that antiviral

prophylaxis can suffice, without HBIg or with a finite duration of HBIg,

to prevent recurrent HBV infection of the allograft. In patients documented at the time of liver transplantation to have undetectable HBV

DNA in serum and covalently closed circular DNA in the liver (i.e.,

with low risk for recurrence of HBV infection), a preliminary clinical

trial suggested that, after receipt of 5 years of combined therapy, both

HBIg and oral-agent therapy can be withdrawn sequentially (over two

6-month periods) with a success rate, as monitored over a median of

6 years after withdrawal, of 90% and an anti-HBs seroconversion rate

of 60% (despite transient reappearance of HBV DNA and/or HBsAg in

some of these patients).

Antiviral prophylactic approaches applied to patients undergoing

liver transplantation for chronic hepatitis B are being used as well

for patients without hepatitis B who receive organs from donors

with antibody to hepatitis B core antigen (anti-HBc) but do not have

HBsAg. Patients who undergo liver transplantation for chronic hepatitis B plus D are less likely to experience recurrent liver injury than

patients undergoing liver transplantation for hepatitis B alone; still, such

co-infected patients would also be offered standard posttransplantation

prophylactic therapy for hepatitis B.

Until recently, the most common indication for liver transplantation

was end-stage liver disease resulting from chronic hepatitis C. For

patients undergoing liver transplantation for hepatitis C, because of

an aggressive natural history of recurrent allograft hepatitis C, graft

and patient survival were diminished substantially compared to other

indications for transplantation.

The approval over the last decade of several DAA agents and of

IFN-free DAA regimens against HCV has had a major impact on the

management and outcome of both pretransplantation and posttransplantation HCV infection. Such therapeutic approaches (1) permit

2641 Diseases of the Gallbladder and Bile Ducts CHAPTER 346

the clearance of viremia in a substantial proportion of decompensated

cirrhotics, thereby preventing recurrent allograft infection and even

improving the clinical status of most 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 and tolerability. Ideally, patients should be treated prior to

liver transplantation. This approach has already reduced the numbers

of patients referred for liver transplantation and led to delisting of

others. A concern, however, is that eradication of HCV infection will

reduce the MELD score and lower the priority for a donor organ in

some patients who still require transplantation because of continued

hepatic decompensation and profound reduction in quality of life. In

addition, elimination of HCV infection prior to transplantation would

disqualify such patients from accepting donor livers from persons

with HCV infection, contracting the potential donor pool and limiting

accessibility to donor organs and timely transplantation. Therefore,

consideration should be given to postponing DAA therapy in patients

with high-MELD HCV-associated end-stage liver disease until after

liver transplantation; however, a distinct threshold at which to treat

pretransplantation or posttransplantation has not yet been established. Regardless, the approach to treatment should be individualized

thoughtfully for each patient, based on such factors as MELD score,

time anticipated prior to availability of a donor organ, relative clinical

stability, and comorbidities.

DAA combinations that have been used successfully against allograft HCV include ledipasvir, sofosbuvir, and ribavirin; velpatasvir,

sofosbuvir, and ribavirin; and grazoprevir and pibrentasvir. (For

updated guidelines, see www.hcvguidelines.org.) In patients with recurrent HCV infection after liver transplantation, each of these regimens

has yielded response rates approaching those seen in compensated

nontransplant patient populations.

A small number of allograft recipients have historically succumbed

to early HCV-associated liver injury, and a syndrome reminiscent of

fibrosing cholestatic hepatitis (see above) has been observed rarely.

Currently, however, the routine use of DAA regimens early after transplantation, before the onset of these variant presentations, has already

had a profound impact on the frequency of severe recurrent allograft

hepatitis C.

Patients who undergo liver transplantation for end-stage alcohol-associated cirrhosis are at risk of resorting to drinking again after

transplantation, a potential source of recurrent alcohol-associated liver

injury. Currently, alcohol-associated liver disease is the most common

indication for liver transplantation, accounting for 30% 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 alcohol-associated 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.

■ POSTTRANSPLANTATION QUALITY OF LIFE

Full rehabilitation is achieved in most 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.

■ FURTHER READING

AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance 2019

update: American Association for the Study of Liver Diseases-Infectious

Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology 71:686,

346 Diseases of the

Gallbladder and Bile Ducts

Norton J. Greenberger*, Gustav Paumgartner,

Daniel S. Pratt

PHYSIOLOGY OF BILE PRODUCTION

AND FLOW

■ BILE SECRETION AND COMPOSITION

Bile formed in hepatocytes 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.

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.

2020. (Updated regularly, available at http://www.hcvguidelines.org.)

Accessed August 24, 2021.

Cotter TG et al: Improved graft survival after liver transplantation

for recipients with hepatitis C virus in the direct-acting antiviral era.

Liver Transpl 25:598, 2019.

European Association for the Study of the Liver: EASL clinical

practice guidelines: Liver transplantation. J Hepatol 64:433, 2016.

Fung J et al: Outcomes including liver histology after liver transplantation for chronic hepatitis B using oral antiviral therapy alone. Liver

Transpl 21:1504, 2015.

Goldberg D et al: Changes in the prevalence of hepatitis C virus

infection, nonalcoholic steatohepatitis, and alcoholic liver disease

among patients with cirrhosis or liver failure on the waitlist for liver

transplantation. Gastroenterology 152:1090, 2017.

Kwo PY et al: An interferon-free antiviral regimen for HCV after liver

transplantation. N Engl J Med 371:2375, 2014.

Lenci I et al: Complete hepatitis B virus prophylaxis withdrawal in

hepatitis B surface antigen-positive liver transplant recipients after

long-term minimal immunosuppression. Liver Transpl 22:1205,

2016.

Lucey MR et al: Long-term management of the successful adult liver

transplant: 2012 practice guideline by the American Association for

the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 19:3, 2013.

Manns M et al: Ledipasvir and sofosbuvir plus ribavirin in patients

with genotype 1 or 4 hepatitis C virus infection and advanced liver

disease: A multicentre, open-label, randomised, phase 2 trial. Lancet

Infect Dis 16:685, 2016.

Martin P et al: Evaluation for liver transplantation in adults: 2013

practice guideline by the American Association for the Study of Liver

Diseases and the American Society of Transplantation. Hepatology

59:1145, 2014.

Reau N et al: Glecaprevir/pibrentasvir treatment in liver or kidney

transplant patients with hepatitis C virus infection. Hepatology

68:1298, 2018.

*

Deceased.

2642 PART 10 Disorders of the Gastrointestinal System

Major solute components of bile by moles percent include bile

acids (80%), phospholipids (lecithins, cephalins, and sphingomyelin)

(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; heavy metals; and, often, drugs and their metabolites.

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

bicarbonate-rich fluid into the bile ducts.

Active vectorial trans-hepatocellular movement of bile acids from

the portal blood into the bile canaliculi is driven by a set of 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 (OATP1B1/1B3), 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 mono- and 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)

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 (ATP8B1) 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 (ABCB11) is defective in PFIC2 and BRIC2. Mutations of MRP2

(ABCC2) cause the Dubin-Johnson syndrome, an inherited form

of conjugated hyperbilirubinemia (Chap. 338). 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 transmembrane 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.

■ THE BILE ACIDS

The primary bile acids, cholic acid and chenodeoxycholic acid

(CDCA), are synthesized in hepatocytes from cholesterol, conjugated

with glycine or taurine, and secreted into the bile canaliculus. 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.

Bile acids are detergent-like molecules that in aqueous solutions

and above a critical concentration of ~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. 325). 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.

Bile acids also function as hormones binding to nuclear (farnesoid X

receptor [FXR]) and G protein–coupled (TGR5) receptors that regulate

bile acid metabolism and their enterohepatic circulation.

■ ENTEROHEPATIC CIRCULATION

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. 325).

The reabsorbed bile acids enter the portal bloodstream and are taken

up rapidly by hepatocytes, reconjugated, and resecreted into bile

(enterohepatic circulation).

The normal bile acid pool size is ~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 ~95% efficient; therefore, daily fecal loss of bile acids is in the

range of 0.2–0.4 g. 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 stimulate

the release of fibroblast growth factor 19 (FGF19), which suppresses

the hepatic synthesis of bile acids from cholesterol by inhibiting the

rate-limiting enzyme cytochrome P450 7A1 (CYP7A1). FGF19 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.

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 FXR 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.

■ GALLBLADDER AND SPHINCTERIC FUNCTIONS

In the fasting state, the sphincter of Oddi (SOD) 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 SOD, and (3) enhanced flow of biliary contents into the duodenum.

Hepatic bile is “concentrated” within the gallbladder by energydependent 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.

2643 Diseases of the Gallbladder and Bile Ducts CHAPTER 346

DISEASES OF THE GALLBLADDER

■ CONGENITAL ANOMALIES

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.

■ GALLSTONES

Epidemiology and Pathogenesis Gallstones are quite prevalent

in most Western countries. Gallstone formation increases after age 50.

In the United States, the prevalence is highest in Native Americans

followed by Hispanics, non-Hispanic whites, and black Americans. The

prevalence is higher in women than men across all ages.

Gallstones form because of abnormal bile composition. They are

divided into two major types: cholesterol stones and pigment stones.

Cholesterol stones account for >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.

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. 346-1).

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, 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 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.

Mutations in the CYP7A1 gene have been described that result 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 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.

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.

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

ABCG5/G8

Cholesterol

Normal bile acids

Normal lecithin

CYP7A1 MDR3 (ABCB4)

Normal cholesterol

Bile acids

Normal lecithin

Normal cholesterol

Normal bile acids

Lecithin

Promote nucleation

Mucous glycoproteins

Heat-labile proteins

Inhibit nucleation

Apolipoproteins

Lecithin vesicles

Gallstone

IV. Microstone

III. Nucleation

II. Supersaturation

I.

FIGURE 346-1 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.

2644 PART 10 Disorders of the Gastrointestinal System

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 monohydrate 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.

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 exhibits abnormalities

of gallbladder emptying. Ultrasonographic studies show that gallstone

patients display an increased gallbladder volume during fasting and

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.

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

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; that is, 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 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 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 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 346-1.

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); cirrhosis, especially related to alcohol; Gilbert’s syndrome;

or cystic fibrosis. Gallbladder stones in patients with ileal diseases,

ileal resection, or ileal bypass generally are also black pigment stones.

TABLE 346-1 Predisposing Factors for Cholesterol and

Pigment Gallstone Formation

Cholesterol Stones

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. Rapid weight loss: Mobilization of tissue cholesterol leads to increased

biliary cholesterol secretion while enterohepatic circulation of bile acids is

decreased

4. Female sex hormones

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. Total parenteral nutrition

b. Fasting

c. Pregnancy

d. Drugs such as octreotide

8. Clofibrate therapy: Increased biliary secretion of cholesterol

9. Decreased bile acid secretion

a. Genetic defect of the CYP7A1 gene

10. Decreased phospholipid secretion: Genetic defect of the MDR3 gene

11. Miscellaneous

a. High-calorie, high-fat diet

b. Spinal cord injury

Pigment Stones

1. Demographic/genetic factors: Asia, rural setting (presumed due to increased

prevalence of parasitic biliary infections; the incidence has been dropping

with time)

2. Chronic hemolysis (example: sickle cell disease)

3. Alcohol related liver cirrhosis

4. Ineffective erythropoiesis (example: pernicious anemia)

5. Cystic fibrosis

6. Chronic biliary tract infection, parasite infections

7. Increasing age

8. Ileal disease, ileal resection or bypass

2645 Diseases of the Gallbladder and Bile Ducts CHAPTER 346

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 mono- and

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 parasitic infections in the gallbladder and biliary

tree (Table 346-1).

Diagnosis Procedures of potential use in the diagnosis of cholelithiasis and other diseases of the gallbladder are detailed in Table 346-2.

Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis and has replaced oral cholecystography (OCG)

(Fig. 346-2A). 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 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.

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.

OCG was historically a useful procedure for the diagnosis of gallstones but has been replaced by ultrasound and is now 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, useful information if medical dissolution is being considered.

Radiopharmaceuticals such as 99mTc-labeled N-substituted iminodiacetic acids (HIDA and DISIDA) 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 application in the

diagnosis of acute cholecystitis and may play a role in the detection of

a postcholecystectomy bile leak.

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.

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, that is, 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 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.

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.

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

TABLE 346-2 Diagnostic Evaluation of the Gallbladder

DIAGNOSTIC

ADVANTAGES

DIAGNOSTIC

LIMITATIONS COMMENT

Ultrasound

Rapid

Accurate identification of

gallstones (>95%)

Simultaneous scanning

of GB, liver, bile ducts,

pancreas

“Real-time” scanning

allows assessment of GB

volume, contractility

Not limited by jaundice,

pregnancy

May detect very small

stones

Bowel gas

Massive obesity

Ascites

Procedure of choice for

detection of stones

Plain Abdominal X-Ray

Low cost

Readily available

Relatively low yield

Contraindicated in

pregnancy

Pathognomonic findings

in: calcified gallstones,

limey bile, porcelain GB,

emphysematous

cholecystitis,

gallstone ileus

Cholescintigraphy (HIDA, DISIDA, etc.)

Accurate identification of

cystic duct obstruction

Simultaneous

assessment of bile ducts

Contraindicated in

pregnancy

Serum bilirubin >103–205

μmol/L (6–12 mg/dL)

Cholecystogram of low

resolution

Indicated for

confirmation of

suspected acute

cholecystitis; less

sensitive and less

specific in chronic

cholecystitis; useful

in the diagnosis

of acalculous

cholecystopathy,

especially if given

with CCK to assess GB

emptying

Abbreviations: CCK, cholecystokinin; DISIDA, diisopropyl iminodiacetic acid; GB,

gallbladder; HIDA, hydroxyl iminodiacetic acid.

2646 PART 10 Disorders of the Gastrointestinal System

A B C D

FIGURE 346-2 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 CBD shows areas that are strictured and narrowed.

may be somewhat more susceptible to septic complications, but the

magnitude of risk of septic biliary complications in diabetic patients is

incompletely defined.

TREATMENT

Gallstones

SURGICAL THERAPY

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; (2) the presence of a prior complication of gallstone disease, that is, history

of acute cholecystitis, pancreatitis, gallstone fistula, etc.; or (3) the

presence of an underlying condition predisposing the patient to

increased risk of gallstone complications (e.g., 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 asymptomatic gallstone patients,

few authorities would now recommend routine cholecystectomy in

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.

From several studies involving >4000 patients undergoing

laparoscopic cholecystectomy, the following key points emerge:

(1) 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.

MEDICAL THERAPY—GALLSTONE DISSOLUTION

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 <5 mm in diameter. The dose of

UDCA should be 10–15 mg/kg per d. Stones >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 a drug for up to 2 years and perhaps indefinitely.

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 develop

recurrent choledocholithiasis after cholecystectomy should be on

long-term treatment with UDCA.

■ 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.

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.

A low-grade fever is characteristically present, but shaking chills

or rigors are not uncommon. The RUQ of the abdomen is almost

2647 Diseases of the Gallbladder and Bile Ducts CHAPTER 346

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.

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.

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. 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. 346-2B), 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 impacted stone. The preoperative

diagnosis of Mirizzi’s syndrome is important to avoid CBD injury.

ACALCULOUS CHOLECYSTITIS In 5–14% 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 prolonged fasting,

with serious trauma or burns, in 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 with a variety of other

systemic disease processes (e.g., sarcoidosis, cardiovascular disease,

tuberculosis, syphilis, actinomycosis).

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.

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. Importantly, it should be noted that SOD dysfunction can also

give rise to recurrent RUQ pain and CCK-scintigraphic abnormalities.

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 C. 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.

Chronic Cholecystitis Chronic inflammation of the gallbladder

wall 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, which may progress to symptomatic gallbladder disease or to acute cholecystitis or may present with complications

(see below).

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.

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.

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

2648 PART 10 Disorders of the Gastrointestinal System

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 decompresses; this is

followed by signs of generalized peritonitis.

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.

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. Most 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 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 [pneumobilia] 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.

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 often performed, 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. In the past,

cholecystectomy was advised in all patients with porcelain gallbladder

because there was felt to be a high incidence of carcinoma of the gallbladder associated with this condition, an association challenged by a

number of studies. Two patterns of gallbladder wall calcification have

now been appreciated: complete intramural calcification and selective

mucosal calcification. The incidence of cancer in those with selective

intramural calcification is higher than those with complete mucosal

wall calcification, but the risk is very small. As such, the need for cholecystectomy for porcelain gallbladder is not absolute; close surveillance

in these patients is also acceptable.

TREATMENT

Acute Cholecystitis

MEDICAL THERAPY

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, extracellular volume depletion and electrolyte abnormalities are repaired, and analgesia is provided. Intravenous antibiotic therapy is 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 including E. coli, Klebsiella, Enterococcus,

Enterobacter, and Streptococcus. Effective antibiotics include piperacillin plus tazobactam, imipenem, meropenem, ceftriaxone plus

metronidazole, and levofloxacin plus metronidazole (Chap. 161).

Postoperative complications of wound infection, abscess formation,

and sepsis are reduced in antibiotic-treated patients.

SURGICAL THERAPY

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 percutaneous 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 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 to

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 long- or short-term complications of gallbladder

disease. Seriously ill or debilitated patients with cholecystitis may

be managed with percutaneous drainage (a cholecystostomy tube),

transpapillary drainage (an endoscopically placed transpapillary

drainage catheter via the cystic duct), or transmural drainage (an

endoscopically placed covered, lumen-apposing stent). Elective

cholecystectomy may then be done at a later date.

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.

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 SOD, or (5) bile

salt–induced diarrhea or gastritis.

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.