Table 61-3 Natural History of Gallstones

An additional therapy, although not commonly employed, is extracorporeal shock wave lithotripsy

(ESWL). This therapy uses energy (“shock”) waves, produced by different methods depending on the

generator technology, to dissolve stones. ESWL can dissolve small calculi or decrease the size of larger

calculi and make them potentially extractable by endoscopic or percutaneous techniques, if in the CBD

or distal cystic duct, or dissolvable by oral therapy if present in the gallbladder. It is a relatively safe

procedure with rare complications, including: hematoma (biliary or otherwise), bowel perforation, and

necrotizing pancreatitis.24

Symptomatic Patients

It is estimated that 2% to 3% per year of those with known gallstones will develop symptoms

11 and 1%

to 2% will develop more complex problems (such as cholecystitis, pancreatitis, or cholangitis) annually

(Table 61-3).12 Those who develop symptoms will most often have biliary colic, or right upper quadrant

(RUQ) pain, which will often recur. Biliary colic will often last for several hours after onset before

subsiding. Biliary colic develops secondary to intermittent impaction of gallstones at the gallbladder

neck as the gallbladder contracts in order to deliver its contents into the CBD. In more than 50% of

patients it occurs following a fatty meal. Biliary colic can be associated with belching, bloating, and

even nausea or emesis. Over time this intermittent obstruction leads to increased tension in the

gallbladder wall and more chronic pain and inflammation known as chronic cholecystitis.

COMPLICATED GALLSTONE-RELATED DISEASE

Complicated gallstone-related disease (acute cholecystitis [AC], choledocholithiasis, and associated

consequences of gallstone pancreatitis or cholangitis) will occur in 0.3% to 3% of patients per year.25

These complications increase the morbidity and potential mortality of patients with gallstones.

Acute Cholecystitis

AC develops when a gallstone(s) lodges in the gallbladder neck (infundibulum) obstructing bile flow

into the CBD. This obstruction leads to biliary stasis, gallbladder wall edema, venous obstruction, and in

extreme cases, eventual arterial obstruction causing necrosis of the gallbladder wall. Its course can

range from mild pain with fevers to frank sepsis secondary to perforation or development of

emphysematous/gangrenous cholecystitis. Clinically, patients present in a similar manner to those with

biliary colic; however the pain is constant, unrelenting, and often associated with fevers, tachycardia,

and a leukocytosis. The diagnosis is typically made with a thorough history and physical examination, in

which the patient may present with midepigastric or RUQ pain, as well as, localized peritoneal

irritation. Murphy’s sign, which is defined by cessation of inspiration secondary to pain, due to the

presence of an inflamed gallbladder during deep abdominal palpation at the midclavicular line of the

RUQ, is pathognomonic for AC.

Imaging and Diagnosis

A variety of imaging tests can be used when evaluating the patient with AC, each of which have

different strengths and weaknesses, and serve as an adjunct to a thorough history and physical

examination.

Ultrasound (US) uses oscillating sound waves to measure differences in tissue densities and interfaces

between liquids and solids and is the backbone of imaging for gallstone disease (Fig. 61-4). The primary

advantages of US are that it is readily available, quickly performed, and avoids ionizing radiation. The

main disadvantage is that it is user-dependent, and technique and experience are therefore quite

important.26 AC can be diagnosed by various US criteria, with the higher number of criteria met on US

examination, the more likely for cholecystitis to be present. These criteria include gallbladder wall

thickening >5 mm, pericholecystic fluid, gallstones, and a positive sonographic Murphy sign

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characterized by pain and cessation of inspiration when the probe is pressed over the gallbladder. A

2012 meta-analysis by Kiewiet et al.27 which included 26 studies with 2,847 patients, evaluated the role

of US as a tool to diagnose AC, and reported a sensitivity of 81% and specificity of 83% with the

comparison being against surgical pathologic findings in the majority of patients.

HIDA scan (biliary scintigraphy) first came into use in the late 1970s.28 The injectable radioactive dye

(derivatives of technetium and iminodiacetic acid) used is preferentially taken up by the liver and

excreted into the bile and should fill both the CBD and gallbladder if there is free flow through the

entire biliary system. A HIDA scan is considered positive for AC if there is lack of visualization of the

gallbladder due to cystic duct occlusion from gallstones which does not allow the radioactive tracer to

enter the gallbladder (Fig. 61-5). The overall sensitivity for AC of a HIDA scan is 95% to 98% with a

specificity of >90%.27,28 A false-positive HIDA scan can occur in various situations, including

consumption of a recent meal (the gallbladder is contracted due to CCK), prolonged fasting (the

gallbladder has concentrated thick bile which acts as a mechanical obstruction to entrance of the tracer),

chronic cholecystitis, or the presence of underlying hepatobiliary disease.

Limitations of HIDA scans are that it is not always readily available, especially after hours, and

require exposure to ionizing radiation; thus, most clinicians will begin with US and then use HIDA to

clarify equivocal US results. Several studies have looked at the utility of adding HIDA to US in the case

of diagnostic dilemma, but the combined modalities do not appear to add sensitivity or specificity for

detection of AC, although they may provide additional morphologic information.29–31

CT scans are typically less helpful for diagnosing uncomplicated gallstone disease, as most gallstones

(85%) are not radiopaque. CT scans are limited in their ability of evaluating the CBD and identifying an

obstruction of the cystic duct, which is a prerequisite for the diagnosis of AC.26,32–34 They have been

shown to be less sensitive and specific than US.32 CT scans can be helpful, however, in evaluating

patients for complications of AC (Fig. 61-4). Gangrenous cholecystitis, which is the most common AC

complication, occurs in up to 38% of patients with AC. Gallbladder perforation and abscess formation

can be seen in up to 8% to 12% of AC cases. A CT scan can detect a defect in the gallbladder wall in

53% of patients with early perforation whereas US cannot easily delineate a mural defect, unless large,

although both will likely help detect the resulting abscess formation (Fig. 61-6).

Figure 61-4. Classic acute cholecystitis seen on US (A) with luminal distention, gallbladder wall thickening >5 mm, and

pericholecystic fluid; CT scan (B) demonstrates similar findings of wall thickening and pericholecystic stranding; MRI T2 fatsaturated sequence (C) demonstrates gallbladder wall edema and pericholecystic fluid, as well as small stones in the gallbladder

neck. (Image courtesy of Aarti Sekhar, MD and David Schuster, MD, Emory University Department of Radiology.)

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MRI has only been evaluated in small studies in the setting of AC. Its sensitivity and specificity are

similar to that of US (approximately 80% to 85% for both). MRI is useful for evaluation of the biliary

tree and to assess for the presence of choledocholithiasis; however, it can overestimate the presence of

gallbladder wall inflammation (Fig. 61-4). Advancements in MRI protocols employing unique tracers

that are taken up and excreted in the biliary tree similar to iminodiacetic acid compounds, such as

Eovist, are currently under investigation.35 Ultimately, the current cost and availability of MRI

machines make it of limited use for the diagnosis of AC.

Treatment

The treatment of AC can consist of medical or surgical therapies and the correct treatment modality will

depend on the individual clinical scenario. The medical treatment of AC involves nothing per os,

parenteral hydration, and antibiotics until the patient’s clinical examination improves and pain resolves.

The diet is then slowly advanced and the patient is kept on a low-fat diet until cholecystectomy is

performed. Despite symptom resolution, the patient should undergo an interval cholecystectomy, as the

likelihood of a second biliary-related complication is high. Surgical therapy consists of either a

laparoscopic or open cholecystectomy, or placement of a cholecystostomy tube in combination with

medical therapy.

5 Cholecystectomy. Cholecystectomy is considered standard therapy for patients with symptomatic

gallstones and AC. With regard to the surgical treatment of AC, the discussion in the literature has been

the timing of the cholecystectomy – early versus delayed. Early cholecystectomy removes the

pathologic source, usually within the first 72 hours of presentation. Certain clinicians advocate for

delayed cholecystectomy to allow the acute inflammatory response to resolve potentially making the

surgery safer with fewer complications and morbidity, such as bile duct injuries, bleeding, and

conversion from laparoscopic to open procedure.

Figure 61-5. HIDA scan (A) demonstrating positive result with uptake of tracer within liver and excretion through the common

bile duct with filling of the duodenum, but absence of filling of gallbladder (arrowhead) even on delayed postmorphine imaging

(B), confirming cystic duct occlusion. Final panel (C), shows normal filling of gallbladder (arrow), or a negative result. (Image

courtesy of Aarti Sekhar, MD and David Schuster, MD, Emory University Department of Radiology.)

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Figure 61-6. Examples from two patients with focal perforations of the gallbladder wall seen on US (A) and CT scan (B). Large

perforations are visible with either modality, but CT is more sensitive for detecting smaller perforations. (Image courtesy of Aarti

Sekhar, MD and David Schuster, MD, Emory University Department of Radiology.)

6 A 2006 meta-analysis showed no significant differences in patient outcomes between early and

delayed surgeries with respect to bile duct injuries, bleeding complications, laparoscopic-to-open

conversion, postoperative infection, and patient death.36 It was noted that over 23% of delayed patients

presented with complications requiring emergent cholecystectomy. Furthermore, total hospital stay,

including the index admission and subsequent admissions for biliary complications and later

cholecystectomy, was significantly shorter for early cholecystectomy, leading to a decreased cost to the

patient and system.

Early has also been somewhat of a misnomer, as traditionally this early approach has consisted of

performing a cholecystectomy within 72 hours of the onset of symptoms. A Cochrane review in 2006,37

which included 6 randomized trials with 488 patients, compared early (within 7 days of presentation) to

late (>6 weeks after initial treatment) cholecystectomy and found similar results to the above metaanalysis with no increase in terms of complications and outcomes. Multiple studies demonstrate that

early should be within the index admission and the 72-hour limit is not as much a steadfast rule given

improved skills of surgeons with laparoscopic surgery and the understanding that surgery delayed to a

different admission could potentially lead to worse complications.

A recent study from Italy seems to confirm these data. Patients (n = 316) were enrolled in a

prospective study38 to assess the benefit of immediate cholecystectomy during the index admission or

delayed surgery after at least 4 weeks. As with the other studies, the complication profiles were no

different between the two groups; however, the subgroup analysis within the early intervention group

showed that immediate surgery on admission or early surgery within 48 hours was associated with

shorter operative time, similar conversion and complication rates, and shorter hospital stay. Within the

delayed group, 26% required rehospitalization and 37% required urgent reevaluation prior to planned

surgery.

Percutaneous Cholecystostomy. In the otherwise healthy patient with AC, laparoscopic

cholecystectomy should be considered the therapy of choice during the index hospitalization. However,

in the elderly patient with poor performance status, multiple comorbidities, or for the extremely ill

patient in the intensive care unit, the underlying medical status may impact increased perioperative risk

and therefore preclude surgical intervention. Percutaneous cholecystostomy (PC) may be employed as a

bridge or final therapy in such patients. This procedure was first described in the 1980s by Radder et

al.39 and involves the placement of a percutaneous transhepatic drain into the gallbladder (Fig. 61-7).

The transhepatic approach has remained the method of choice to reduce intraperitoneal bile leak in case

of tube dislodgement. Use of this approach has grown over 500% since 1994, along with the field of

interventional radiology.40 Typically, rapid patient improvement is seen following decompression in

combination with antibiotics tailored to bacterial isolates. In most patients, an interval cholecystectomy

will be performed 6 weeks or more after the drain is placed. Removing the drain alone is usually not

sufficient, as the cystic duct obstruction is typically still present. If Bile is draining from the catheter,

then it may be possible to remove the catheter after 6 weeks without removing the gallbladder in

patients with questionable fitness for surgery.

Acalculous Cholecystitis

Acute acalculous cholecystitis (AAC) represents 12% of all cases of AC with the incidence being

significantly higher in intensive care unit patients.41 AAC is associated with increased bile stasis and

therefore decreased gallbladder emptying, which typically occurs in the setting of severe illness with

multiple contributing mediators, such as the inflammatory response, total parenteral nutrition, and highdose narcotics. The diagnosis of ACC requires a high index of clinical suspicion, as patients are often

critically ill and unable to communicate symptoms. The potential consequences of late diagnosis are

considerable, with gallbladder ischemia and progression to gangrene and eventual perforation resulting

in a mortality rate of up to 30%.42 Diagnosis may be made using bedside ultrasonography following

similar criteria as used for acute calculous cholecystitis, with the exception of lack of calculi. The

sensitivity of US in this setting ranges from 50% to 100% with a specificity of 90% to 94%. HIDA scan

with morphine amplification can be used to increase bile secretory pressure and allow bile to reflux

through a contracted gallbladder neck, thereby decreasing false-positive rates, providing sensitivity

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understanding of gallstone formation.

Bile Composition and Function

Healthy livers produce between 600 and 750 mL of bile per day. Normal bile is composed of bile acids

(or salts, 61%), fatty acids (12%), cholesterol (9%), proteins (7%), phospholipids (3%), bilirubin (3%),

and other substances (5%).3 Bilirubin is the breakdown product of spent red blood cells and is

conjugated with glucuronic acid prior to being excreted. Bile acid components can be further

subclassified as primary bile acids and secondary bile acids. Primary bile acids (cholic and

chenodeoxycholic acids) are synthesized in the liver and secondary bile acids (deoxycholic and

lithocholic acids) represent primary bile acids that undergo deconjugation in the gut by bacteria.

Cholesterol is produced primarily by the liver with little contribution from dietary sources, and is highly

nonpolar and insoluble in water and thus in bile, as well. Phospholipids (95% phosphatidylcholine in

healthy individuals) are synthesized in the liver in conjunction with bile salt synthesis. Percentages of

biliary phospholipid and cholesterol vary with underlying liver disease.

Bile facilitates the intestinal absorption of lipids, fat-soluble vitamins and various drugs, and promotes

excretion of certain organic solids, such as bilirubin and cholesterol. Bile acids solubilize lipids and

facilitate their absorption and excretion through emulsification of dietary fats. More recent evidence

shows that bile acids regulate their own synthesis, perform various endocrine and autocrine functions,

and serve as ligands for various nuclear receptors involved in carbohydrate, triglyceride, and sterol

metabolism.4 Bile acids also interact with cell surface receptors involved in glucose and lipid

metabolism, energy consumption, and immune response.5

The potency of bile is increased through the process of concentration (5 to 10×) within the

gallbladder, as electrolytes, water, and calcium are reabsorbed (Table 61-1). Sodium chloride channels

actively transport salt across the epithelium efficiently6 and water follows passively in response to the

resultant osmotic force. Calcium absorption is less efficient, resulting in a net increase in calcium

percentage in stored bile. As gallbladder bile becomes concentrated, the capacity of bile to solubilize

cholesterol lessens. Solubility of the micellar fraction is increased; however, solubility of phospholipid–

cholesterol vesicles is reduced. It is the vesicular fraction of vesicular cholesterol combined with the

increased concentration of calcium in the gallbladder lumen that promotes development of cholesterol

crystals and subsequent gallstones.

Table 61-1 Composition of Hepatic and Gallbladder Bile

Enterohepatic Circulation

Bile acids travel in the bile through the liver, biliary tree, intestines, and the portal venous circulation to

return to the liver, thereby recovering 95% of bile acids, with the other 5% passing in stool.

Hepatocytes secrete bile acids through a rate-limiting, ATP-dependent process via a bile salt export

pump. Approximately 600 to 750 mL of bile is produced daily. Hormones, such as secretin,

cholecystokinin (CCK), and gastrin increase bile flow primarily by promoting active secretion of

chloride-rich fluid in the bile ducts.

Gallbladder Function

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The main functions of the gallbladder are to concentrate and store bile during the fasting state and

deliver bile into the duodenum when needed. Bile reenters the distal bile duct and is secreted into the

duodenum in response to a meal. The gallbladder mucosa is unique in that it has the greatest absorptive

capacity per unit of any structure in the body, but the gallbladder itself has a limited storage capacity of

approximately 50 mL; thus the bile it can store is made more effective through the process of

concentration.

The gallbladder’s mucosa secretes mucous glycoproteins and hydrogen ions. Mucous glycoproteins are

actively secreted from the mucosal glands in the gallbladder neck and cystic duct. The resultant mucous

barrier protects the gallbladder epithelium from the detergent effect of concentrated bile salts. The

transport of hydrogen ions by the gallbladder epithelium leads to a decrease in bile pH through an

active sodium-exchange mechanism. Acidification of bile in the gallbladder promotes calcium solubility,

thereby preventing its precipitation as calcium salts and subsequent gallstone formation. The

gallbladder’s normal acidification process lowers the pH of hepatic bile from 7.5 to 7.8 down to 7.1 to

7.3.7

Biliary Motility

Gallbladder filling is facilitated through tonic contraction of the ampullary sphincter, which maintains a

constant pressure in the common bile duct (CBD) (10 to 15 mm Hg). There are periods of gallbladder

filling flanked by brief periods of partial emptying (10% to 15% of its volume) of concentrated bile.

These emptying periods are coordinated with each passage of chyme through the duodenum via the

migrating myoelectric complex (MMC) and the hormone motilin. Following a meal, the release of

stored bile from the gallbladder requires coordination of both gallbladder contraction and sphincter of

Oddi relaxation. CCK is released from the duodenal mucosa in response to a meal, and this hormone

serves as a major stimulus for gallbladder contraction. Following a meal, the gallbladder releases 50%

to 70% of its contents within 30 to 40 minutes. Gallbladder refilling then occurs gradually over the next

60 to 90 minutes. Many other hormonal and neural pathways are also necessary for the coordinated

action of the gallbladder and sphincter of Oddi. Dysmotility of the gallbladder increases the time bile

dwells in the gallbladder, and along with calcium precipitation, plays a central role in the pathogenesis

of gallstones.8

Sphincter of Oddi

The human sphincter of Oddi is a complex structure that is functionally independent from the duodenal

musculature. Endoscopic manometric studies demonstrate that the sphincter of Oddi creates a highpressure zone between the bile duct and the duodenum, which regulates the flow of bile and pancreatic

juice into the duodenum while preventing regurgitation of duodenal contents into the biliary tract.

Through this action, a higher luminal pressure is maintained in the biliary tract than in the duodenal

lumen.

Both neural and hormonal factors influence the sphincter of Oddi. In humans, sphincter of Oddi

pressure and phasic wave activity diminish in response to CCK. Thus, sphincter pressure relaxes after a

meal, allowing the passive flow of bile into the duodenum. During fasting, high-pressure phasic

contractions of the sphincter of Oddi persist through all phases of the MMC. Results of animal studies

demonstrate that sphincter of Oddi phasic waves do vary with the MMC, permitting partial gallbladder

emptying and increasing bile flow during phase III of the MMC; a mechanism which may serve to limit

accumulation of biliary crystals during fasting.9 Neurally mediated reflexes link the sphincter of Oddi

with the gallbladder and stomach to coordinate the flow of bile and pancreatic juice into the duodenum.

The cholecystosphincter of Oddi reflex allows the sphincter to relax as the gallbladder contracts.

Similarly, antral distention causes both gallbladder contraction and sphincter relaxation.

GALLSTONES

Ten to 20% of adults in the United States will be affected by gallstones during their lifetime.10 The vast

majority of people with gallstone will have asymptomatic disease diagnosed incidentally via imaging

(ultrasound [US], computed tomography [CT], or magnetic resonance imaging [MRI]) for other health

problems. It is estimated that 2% to 3% per year of those with known gallstones will develop

symptoms

11 and 1% to 2% will develop more complex problems such as cholecystitis, pancreatitis, or

cholangitis annually.12 Gallstones represent a failure to maintain certain biliary solutes, primarily

1578

cholesterol and calcium salts, in a solubilized state, and can form in the gallbladder and less commonly

in the bile ducts.

Gallstone Formation

1, 2 The gallbladder fills with hepatic bile during tonic contraction of the ampullary sphincter.

Following a meal, the duodenum releases the gut peptide CCK, which stimulates gallbladder emptying.

Fifty to 70% of the gallbladder contents are forced into the duodenum and then refilling gradually

happens within the next 60 to 90 minutes.13 The combination of hepatic bile acidification and

concentration in the gallbladder, by 5 to 10-fold, enhance calcium solubility; however, the secretion of

mucous glycoproteins to protect the mucosa from bile salts serves as a nidus for cholesterol stone

formation. An important biliary precipitate in gallstone pathogenesis is biliary “sludge,” which refers to

a mixture of cholesterol crystals, calcium bilirubinate granules, and a mucin gel matrix. Biliary sludge

has been observed clinically in prolonged fasting states or with the use of long-term total parenteral

nutrition (TPN). Both of these conditions are also associated with gallstone formation. The finding of

macromolecular complexes of mucin and bilirubin, similar to biliary sludge in the central core of most

cholesterol gallstones, suggests that sludge may serve as the nidus for gallstone formation.

Figure 61-1. A: Cholesterol gallstones. B: Black pigment gallstones. C: Brown pigment gallstones.

Gallstone Types

3 Gallstones are classified by their cholesterol content as either cholesterol or pigment stones. Pigment

stones are further classified as either black or brown (Fig. 61-1). In most American populations, 70% to

80% of gallstones are cholesterol stones and the others are black pigment stones.

Cholesterol Gallstones

Pure cholesterol gallstones are uncommon, as most have a core of calcium salts (90%). The

pathogenesis of cholesterol gallstones involves four key factors: (a) cholesterol supersaturation in bile,

(b) crystal nucleation, (c) gallbladder dysmotility, and (d) gallbladder absorption/secretion.

Cholesterol Supersaturation. The key to maintaining cholesterol in solution is the formation of

micelles, a bile salt–phospholipid–cholesterol complex, and cholesterol–phospholipid vesicles (Fig. 61-

2). Present theory suggests that in states of excess cholesterol production, these large vesicles may

1579

exceed their capability to transport cholesterol and crystal precipitation may occur. Cholesterol

solubility depends on the relative concentration of cholesterol, bile salts, and phospholipid. By plotting

the percentages of each component on triangular coordinates, the micellar zone in which cholesterol is

completely soluble can be demonstrated (Fig. 61-3). In the area above the curve, bile is supersaturated

with cholesterol and precipitation of cholesterol crystals can occur.

Figure 61-2. Phases of cholesterol in bile.

Figure 61-3. Equilibrium phase diagram for bile salt–lecithin–cholesterol–water at a concentration of 10% solids, 90% water. The

monomeric phase is not depicted as a phase because it exists at the same concentration throughout. The one-phase zone contains

only micelles. Several other zones exist, but only the two on the left above the one-phase zone apply to human gallbladder bile,

and both contain cholesterol monohydrate crystals at equilibrium.

Cholesterol Crystallization. Cholesterol supersaturation does not always result in stone formation. As

bile is concentrated in the gallbladder, a net transfer of phospholipids and cholesterol from vesicles to

micelles occurs. The phospholipids are transferred more efficiently than cholesterol, leading to

cholesterol enrichment in the vesicles. These cholesterol-rich vesicles aggregate to form large

multilamellar liquid vesicles that then precipitate cholesterol monohydrate crystals. Several

pronucleating factors including mucin glycoproteins, immunoglobulins, and transferrin accelerate the

precipitation of cholesterol in bile.

Gallbladder Motility. For gallstones to cause clinical symptoms, they must obtain a size sufficient to

produce mechanical injury to the gallbladder or obstruction of the biliary tree. Growth of stones may

occur in two ways: (a) progressive enlargement of individual crystals or stones by deposition of

additional insoluble precipitate at the bile–stone interface, or (b) fusion of individual crystals or stones

to form a larger conglomerate. Poor gallbladder motility increases the dwell time of bile in the

gallbladder, further promoting stone formation. Clinical conditions associated with reduced gallbladder

motility include prolonged fasting, long-term TPN administration, surgical vagotomy, diabetes mellitus,

and supratherapeutic levels of somatostatin resulting from either somatostatin-producing tumors or in

patients receiving long-term somatostatin therapy.

Gallbladder Absorption/Secretion. Alterations in sodium, chloride, bicarbonate, and water

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absorption may alter the milieu for cholesterol saturation and crystal formation as well as for calcium

precipitation.14

Pigment Gallstones

Pigment gallstones are classified as either brown or black pigment stones.

Brown Pigment Stones. These stones are composed of calcium bilirubinate, fatty acid soaps (calcium

palmitate and calcium stearate), cholesterol, and mucinous glycoproteins (products of bacterial

biofilms). They are earthy in texture and are typically found in the intrahepatic and extrahepatic bile

ducts (as opposed to the gallbladder) in states of increased bile duct stasis, such as sclerosing

cholangitis, congenital biliary cystic disease, chronic biliary strictures, chronic pancreatitis, duodenal

diverticula, and infections with bacteria or biliary parasites. East Asian populations are particularly at

risk of brown stone formation due to susceptibility to oriental cholangiohepatitis (recurrent pyogenic

cholangitis). In this condition, bacteria produce a biofilm rich in glucuronidase, which hydrolyses

conjugated bilirubin to free bilirubin. Free bilirubin precipitates when mixed with calcium.

In these settings, bacteria-producing slime and bacteria containing the enzyme glucuronidase cause

enzymatic hydrolysis of soluble conjugated bilirubin glucuronide to form free bilirubin, which then

precipitates with calcium leading to stone formation.

Black Pigment Stones. These stones form primarily in the gallbladder in sterile bile and are associated

with advanced age, chronic hemolysis, alcoholism, cirrhosis, pancreatitis, and total parenteral nutrition,

and are typically tarry. These stones are usually not associated with infected bile and are located almost

exclusively in the gallbladder.

INDICATIONS FOR CHOLECYSTECTOMY

Asymptomatic Patients

4 Given that the large majority of individuals with gallstones are asymptomatic and have no associated

complications, most patients can be managed expectantly without surgical intervention. Prophylactic

cholecystectomy may, however, be indicated in certain circumstances (Table 61-2). Patients who have a

higher risk of cancer in the setting of gallbladder disease, such as Native Americans, presence of large

gallstones (>2.5 cm), or calcification of gallbladder wall (“porcelain gallbladder”) are commonly

offered prophylactic cholecystectomy. Patients who are more likely to have recurrent symptoms or

complications secondary to gallstone disease may also undergo prophylactic cholecystectomy; examples

of these conditions include hereditary spherocytosis, sickle cell disease, other hemoglobinopathies, the

bariatric patients, and pediatric patients. Finally, some clinicians argue that organ transplant patients

with gallstones should undergo pretransplant prophylactic cholecystectomy given the possible higher

risk of developing complicated gallstone disease due to chronic immunosuppression.

Patients with asymptomatic gallstones who are not offered a cholecystectomy, or choose not to

undergo an operation, can be managed with other therapies. In patients with small gallstones (<5 mm)

oral dissolution therapy with bile salts may be utilized.22 Ursodeoxycholic acid (ursodiol) appears to

work by dissolving cholesterol crystals and decreasing hepatic secretion of biliary cholesterol thereby

decreasing the number of stones. It is also thought that this would decrease the number of colic attacks.

Unfortunately, the majority of stones recur (>50% at 5 years) and in a prospective randomized study of

177 patients from the Netherlands, a country that has a long waiting list for elective biliary procedures,

ursodiol did not decrease the number of attacks nor gallstone-related complications during the waiting

period for cholecystectomy.23

Table 61-2 Indications for Prophylactic Cholecystectomy

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Chapter 61

Calculous Biliary Disease

David A. Kooby, Joshua H. Winer, and Kenneth Cardona

Key Points

1 Gallstones are classified by their cholesterol content as either cholesterol (70% to 80%) or pigment

(20% to 30%), with pigment stones further classified as black or brown.

2 Biliary sludge refers to a mixture of cholesterol crystals, calcium bilirubinate granules, and a mucin

gel matrix and is thought to serve as the nidus for gallstone growth.

3 The pathogenesis of cholesterol gallstones is clearly multifactorial but essentially involves four

factors: (a) cholesterol supersaturation in bile, (b) crystal nucleation, (c) gallbladder dysmotility,

and (d) gallbladder absorption/secretion.

4 Prophylactic cholecystectomy is generally not indicated in patients with asymptomatic gallstones,

because studies show that under 30% of patients will become symptomatic within 20 years and only

1% to 2% will develop gallstone-related complications, such as cholecystitis, per year.

5 Elective laparoscopic cholecystectomy is associated with a mortality rate of less than 0.3% and an

overall complication rate of 10%, with less than 5% of patients requiring conversion to an open

procedure.

6 Randomized trials have shown that laparoscopic cholecystectomy performed for acute cholecystitis

(AC) during initial hospitalization can be performed safely resulting in a lower morbidity rate and

shorter overall hospital stay when compared to delayed cholecystectomy during a separate

admission.

7 Common bile duct (CBD) stones, similar to gallbladder stones, can have an asymptomatic course and

pass spontaneously without clinical consequence. When symptomatic, the presentation of CBD stones

can vary between mild biliary colic to fulminant sepsis from acute cholangitis, biliary pancreatitis, or

hepatic abscesses.

8 ERCP with stone extraction is effective in removing stones in 85% to 95% of cases but is associated

with postprocedural complications (pancreatitis and cholangitis) in 5% of cases.

9 Endoscopic cholangiography with sphincterotomy allows for the diagnosis of CBD stones in the vast

majority of cases. The primary advantage of endoscopic retrograde cholangiopancreatography

(ERCP) is that it allows for therapeutic intervention if stones are identified.

10 Acute cholangitis results from the combination of significant bacterial concentration in bile and

increased biliary pressure associated with biliary obstruction.

INTRODUCTION

Cholelithiasis (gallbladder stone disease) is both a substantial healthcare problem and financial burden

for the US healthcare system, with more than 20 million Americans afflicted, resulting in expenses of

more than 6 billion dollars annually.1 A recent report demonstrates that cholelithiasis and cholecystitis

were the second most common gastrointestinal problems listed as the discharge diagnosis in 2009 with

approximately 750,000 gallbladders removed.2 Surgeons treating patients with gallstones and their

associated conditions should have an understanding of biliary physiology and of the pathophysiology of

gallstone formation. This chapter reviews the physiology and surgical management of calculous biliary

disease.

BILIARY PHYSIOLOGY

An understanding of normal bile composition, synthesis, and metabolism is pertinent to the

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101. Roskams T. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma.

Oncogene 2006;25:3818–3822.

102. de Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholangiocarcinoma: an international

multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol

2011;29:3140–3145.

103. Almersjo O, Bengmark S, Hafstrom L. Liver metastases found by follow-up of patients operated on

for colorectal cancer. Cancer 1976;37:1454–1457.

104. Bengmark S, Hafstrom L. The natural history of primary and secondary malignant tumors of the

liver. I. The prognosis for patients with hepatic metastases from colonic and rectal carcinoma by

laparotomy. Cancer 1969;23:198–202.

105. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the liver. J Gastrointest Surg

2007;11:1057–1077.

106. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol

1997;15:938–946.

107. Ito H, Are C, Gonen M, et al. Effect of postoperative morbidity on long-term survival after hepatic

resection for metastatic colorectal cancer. Ann Surg 2008;247:994–1002.

108. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of

recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241:715–722, discussion

722–714.

109. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is

associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol

2009;27:3677–3683.

110. Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases. Lancet

2008;371:963–965.

111. Chua TC, Saxena A, Liauw W, et al. Hepatectomy and resection of concomitant extrahepatic disease

for colorectal liver metastases–a systematic review. Eur J Cancer 2012;48:1757–1765.

 

elapsed after PVE) sensitively predicts the risk of postoperative hepatic insufficiency. A kinetic growth

rate >2.0%/week is strongly associated with a low risk of postoperative morbidity and mortality

irrespective of the sFLR volume.125

Figure 60-13. Example of right and segment IV portal vein embolization (PVE). Adequate hypertrophy of future liver remnant is

observed from the standardized future liver remnant (sFLR) volume of 10% to 33% at 4 weeks after PVE.

Recently, a new short-interval, two-stage liver surgery technique was reported which consists of an

initial open right portal vein ligation with in situ splitting of the liver parenchyma followed by

reexploration for right trisectionectomy; this technique is called associating liver partition and portal

vein ligation for staged hepatectomy (ALPPS).137 The combination of portal vein ligation and in situ

splitting of the liver to prevent cross-portal circulation between the lobes of the liver is believed to lead

to profound hypertrophy of the FLR. However, preliminary data suggested a high incidence of major

morbidity and inpatient mortality associated with this new procedure. The true efficacy of ALPPS in

preventing postoperative hepatic insufficiency remains controversial and this procedure is still

investigational.

SURGICAL TECHNIQUE

Exposure

8 Incision and exposure are key components of the quality of the exploration of the liver and the safety

of hepatectomy. Various incisions – including the inverted-T (Mercedes) incision, bilateral subcostal

(chevron) incision, right/left subcostal (Kocher/Kehr) incisions, J-shaped (Makuuchi) incision with or

without thoracotomy, and inverted L-shaped (modified Makuuchi) incision (Fig. 60-14) – have been

used to achieve these objectives. Recently evolved laparoscopic approaches may reduce the

disadvantage of a large incision for hepatectomy. However, most hepatobiliary malignancies require

complex surgical manipulations, including handling of the vena cava or major vessels just beneath the

right atrium. Thus, hepatobiliary surgeons should be familiar with the traditional approaches for safe

handling of the liver.

1563

Figure 60-14. Inverted L-shaped incision and exposure. The inverted L-shaped (modified Makuuchi) incision. The incision begins

cephalad to the xiphoid, extends to 1 cm above the umbilicus, and then extends laterally to the right. This incision achieves a

superb en face view of critical structures, including the hepatocaval junction. (Adapted from Chang SB, Palavecino M, Wray CJ, et

al. Modified Makuuchi incision for foregut procedures. Arch Surg 2010;145:281–284.)

Principles of Parenchymal Transection

The routine use of intraoperative ultrasonography has contributed to major improvements in liver

resection techniques.138 Intraoperative ultrasonography allows confirmation of the location of the

tumors, the sites of intrahepatic anatomic structures, and the direction of transection. For anatomic

resection of Couinaud segments, a segmental staining method with ultrasound guidance has been used

to confirm the segmental border on the liver surface.

The key point in anatomic resection of the liver is exposure of the landmark vein on the cut surface of

the liver. The three-dimensional shape of the intersegmental plane is not always flat and it varies

considerably among individuals.36,139 However, the specific landmark vein for each intersegmental

plane of the liver is consistent. Because the actual shape of the intersegmental plane is difficult to

recognize during parenchymal transection without a special staining technique such as the ICG

fluorescent technique140 or contrast medium for ultrasound,141 the identification and exposure of the

landmark vein on the cut surface of the liver is the only convincing technique that allows precise

anatomic resection of the liver (Fig. 60-15).

For hepatic parenchymal transection, multiple techniques and devices are available to hepatobiliary

surgeons, including clamps, staplers, jet cutters, ultrasonic aspirators (e.g., CUSA), saline-linked cautery

(e.g., TissueLink), bipolar electrocoagulation devices, radiofrequency transection devices, harmonic

scalpels, and microwave coagulators.142–145

Control of Bleeding

Inflow occlusion at the hepatic hilum (Pringle maneuver) is widely used to reduce blood loss during

hepatic parenchymal transection. Intermittent inflow occlusion (15 minutes of clamping and 5 minutes

of release) has been proven to be a safe procedure even for living-donor surgery for liver

transplantation.146,147 Under inflow occlusion, the amount of bleeding depends on the central venous

pressure and the height of the manipulating point from the level of the inferior vena cava. Therefore,

controlling central venous pressure by limiting the tidal volume and infusions in cooperation with

anesthesiologists is important. In addition, adequate lifting of the hepatic parenchyma with the

surgeon’s left hand decreases back-bleeding during hepatic parenchymal transection.

1564

Figure 60-15. Anatomic resection of Segments I + II + III + IV + VIII. This patient was found to have a huge HCC generated in

the left hemiliver on underlying steatohepatitis. Because the tumor also extended to Segments I and VIII, compressing the right

hepatic vein and hepatic hilum, left trisectionectomy was considered to be the most optimal approach. However, due to impaired

hepatic functional reserve (ICG-R15, 17%), the future liver remnant (i.e., right lateral sector) was considered too small (<30% vs.

standard liver volume). Therefore, Segment V was preserved with a staining technique. Top left: Puncture of Segment VIII portal

pedicle under ultrasound guidance and injection of indigocarmine (arrow). Top right: Segment VIII was clearly stained on the

surface of the liver (arrowheads). Bottom left: transection line for anatomic Segments I + II + III + IV + VIII resection was

marked by cautery. Bottom right: completion of anatomic resection fully preserving Segments V, VI, and VII. The right hepatic

vein is exposed on the cut surface of the liver (arrows).

Figure 60-16. Retrohepatic dissection and hanging maneuver during anterior approach. Left: The avascular plane between the

liver and the inferior vena cava is dissected and a tape is placed. Right: Traction of the tape during parenchymal transection

allows adequate control of bleeding from the deeper transection plane of the liver. (Adapted from Donadon M, Abdalla EK and

1565

Vauthey JN. J. Am Coll Surg 2007;204:329–333.)

When conventional mobilization of the liver is difficult prior to parenchymal transection due to tumor

invasion of the diaphragm on the right side of the liver, parenchymal transection needs to be preceded

by mobilization of the right lobe (anterior approach). To control bleeding at the deeper part of the liver

parenchyma in such cases, the hanging maneuver proposed by Belghiti et al.148 is widely used. This

maneuver involves dissecting the retrohepatic avascular space between the liver and the inferior vena

cava and placing a tape for lifting the liver. By retracting the tape during parenchymal transection,

squeezing pressure can be applied on the deep transection plane and may reduce bleeding (Fig. 60-16).

Bile Leak Test

Bile leak from the cut surface of the liver is a frequent major complication observed after liver resection

and requires postoperative drainage according to the degree of leakage (Table 60-3).149 Even though

various intraoperative tests have been tried, bile leaks are still reported in up to 8% of patients who

have undergone liver resection. Although it can be treated with adequate drainage, bile leak increases

the risk of sepsis and hepatic insufficiency. One group recently assessed the efficacy of transcystic

injection of air into the biliary system to test the patency of the biliary tract and to detect any air leak

from the major ducts of the parenchymal transection surface (Fig. 60-17) and found that postoperative

bile leak decreased from 10.8% to 1.0% (p = 0.008) with adequate use of a bile leak test after

completion of hepatectomy.150

Staged Surgery

When the liver tumor burden is limited, including small tumors and anatomically favorably positioned

bilateral metastases, a one-stage strategy involving one or more simultaneous partial hepatectomies in

lobar hepatic resection is safe and effective.151–156 In contrast, when extensive bilobar metastases are

present, different surgical strategies are required.

Figure 60-17. Air leak test for detection of bile leak. Left: With injection of air into the biliary tract, the point of bile leak can be

sensitively detected as an air leak point (arrows). Right: Patency of the bile duct can be confirmed as pneumobilia on ultrasound

image. (Adapted from Zimmitti G. Systematic use of an intraoperative air leak test at the time of major liver resection reduces the

rate of postoperative biliary complications. J Am Coll Surg 217;1028–1037, with permission.)

Table 60-3 Definition and Grades of Bile Leak After Liver Resection by

International Study Group of Liver Surgery (ISGLS)

1566

Two-stage liver resection is a reasonable approach for patients with advanced bilateral CLM who

responded to chemotherapy and in whom limited resection could clear the less affected side of the liver

before a planned extended contralateral liver resection. Patients undergo first-stage limited resection of

metastases in the left lobe that is followed by right PVE with or without Segment IV embolization to

allow hypertrophy of the FLR. Then, extended right hepatectomy is completed after the sFLR meets the

volume criteria. A previous study reported that 72.3% of the patients with planned two-stage liver

resection completed the second-stage resection and the 5-year survival of these patients was 51% but

15% in the cases treated with chemotherapy alone.157

The ALPPS procedure is a similar approach in which right portal vein ligation and parenchymal

transection at the time of first resection is performed instead of PVE. This procedure seems to offer

rapid growth of the FLR compared with conventional PVE. However, because the safety of this new

approach and the detailed techniques are still under investigation, clinical application should be limited

to highly selected patients at high-volume hepatobiliary centers.

Laparoscopic Liver Resection

9 The laparoscopic approach for liver resection has evolved since the early 1990s

158–161 and its

feasibility has since been established, especially for patients undergoing partial hepatectomy or left

lateral segmentectomy.162–165 Although this approach has benefits, including less postoperative pain,

earlier recovery, and shorter length of hospital stay compared to the conventional open approach,166–169

it requires experience with an open approach and advanced techniques in laparoscopic surgery. Because

the liver is a large, heavy organ, mobilization and parenchymal transection require advanced skill in a

limited surgical field. Recently, several centers have reported on the feasibility of the laparoscopic

approach for major hepatectomy or graft procurement of living donors for liver transplantation;

however, these complex laparoscopic procedures should not be approached by surgeons without

significant laparoscopic liver surgery experience. In addition, for patients with hepatic malignancies,

oncologic curability should be secured if the laparoscopic liver resection is adopted. Therefore, the

indication for laparoscopic approach should be determined according to the technical feasibility, the

surgeon’s surgical skill, and the oncologic curability of the tumors.

Liver Transplantation

Liver transplantation is a reasonable approach with a theoretically higher chance of eradication of

tumors, especially for patients with severe hepatic dysfunction. However, because of the negative

impact of posttransplant immunosuppression on tumor recurrence or progression, liver transplantation

was originally thought to be a contraindication for hepatic malignancy. More recent experience with

liver transplantation for hepatoblastoma in children170 or early-stage HCC77 has led to cautious

application of liver transplantation for hepatic malignancies. As we mentioned previously, several highvolume transplant centers have used their original expanded criteria for liver transplantation for

HCC,86–97,171 although these criteria have not yet been standardized and HCC meeting the Milan criteria

remains a standard indication for liver transplantation.

Liver transplantation has also been used in selected patients with other hepatobiliary malignancies,

such as NET,172–174 epithelioid hemangioendothelioma,175 colorectal cancer,176 and hilar

cholangiocarcinoma.177,178 However, the clinical evidence remains limited and true efficacy over other

nonsurgical treatments has not yet been proven.

1567

SUMMARY

Despite recent advances in the nonsurgical treatment of hepatic neoplasms, surgical resection still plays

a pivotal role. In the era of effective chemotherapy and interventional radiology, primary unresectable

tumor can become resectable during the treatment course, especially for CLM. However, oncologic

curability and surgical safety are, by nature, conflicting factors. Comprehensive assessment of the

oncologic characteristics, the hepatic lesions, and the status of the underlying liver is essential for

proper risk management and for selecting candidates with the greatest survival benefit from surgical

resection.

References

1. Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatectomies without mortality in

8 years. Arch Surg 2003;138:1198–1206; discussion 1206.

2. Zimmitti G, Roses RE, Andreou A, et al. Greater complexity of liver surgery is not associated with

an increased incidence of liver-related complications except for bile leak: an experience with 2,628

consecutive resections. J Gastrointest Surg 2013;17:57–64; discussion 64–55.

3. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic

resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002;236:397–406;

discussion 406–397.

4. Kishi Y, Abdalla EK, Chun YS, et al. Three hundred and one consecutive extended right

hepatectomies: evaluation of outcome based on systematic liver volumetry. Ann Surg

2009;250:540–548.

5. Adam R, Laurent A, Azoulay D, et al. Two-stage hepatectomy: A planned strategy to treat

irresectable liver tumors. Ann Surg 2000;232:777–785.

6. Jaeck D, Bachellier P, Nakano H, et al. One or two-stage hepatectomy combined with portal vein

embolization for initially nonresectable colorectal liver metastases. Am J Surg 2003;185:221–229.

7. World Health Organization. Hepatitis B and C fact sheets. 2014.

8. Yeh MM, Brunt EM. Pathologic features of fatty liver disease. Gastroenterology 2014;6(8):3303–

3325.

9. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for

hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10:1342–

1359.e2.

10. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with

oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol

2004;15:460–466.

11. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an

increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol

2006;24:2065–2072.

12. Kishi Y, Zorzi D, Contreras CM, et al. Extended preoperative chemotherapy does not improve

pathologic response and increases postoperative liver insufficiency after hepatic resection for

colorectal liver metastases. Ann Surg Oncol 2010;17:2870–2876.

13. Azoulay D, Castaing D, Krissat J, et al. Percutaneous portal vein embolization increases the

feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Ann Surg

2000;232:665–672.

14. Shindoh J, Tzeng CW, Aloia TA, et al. Optimal future liver remnant in patients treated with

extensive preoperative chemotherapy for colorectal liver metastases. Ann Surg Oncol 2013;20:2493–

2500.

 

Colorectal Liver Metastases

5 Colorectal cancer is the second-leading cause of cancer-related deaths in the United States. About 20%

to 25% of colorectal cancer patients are found to have synchronous CLM,103,104 and 35% to 55%

develop CLM during the course of the disease.105 The 5-year survival rate after curative resection of

CLM has been reported to be up to 58%,106–108 while the median survival duration for patients with

CLM without any treatment is approximately 6 months.104 Therefore, adequate assessment and

preoperative management are important in selecting patients with resectable or potentially resectable

CLM who are candidates for liver resection.

CLMs are classified as stage IV colorectal cancer. However, with recent advancements in

chemotherapy and surgical management, the resectability of CLM has dramatically increased and longterm survival after resection of CLM has significantly improved.109 The practical keys to the initial

management of CLM include precise assessment of the extension of disease and the proper selection of

the initial therapeutic options. Although surgical resection is potentially the most curative strategy for

CLM, a multidisciplinary approach by surgeons, medical oncologists, radiologists, and pathologists is

essential for selecting the patients who would benefit from surgery and to determine the optimal timing

of surgery (Algorithm 60-3).110

Table 60-2 Published Results of Expanded Liver Transplant Eligibility Criteria for

Hepatocellular Carcinoma

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1558

In imaging evaluation, the choice of imaging technique for pretreatment assessment of CLM depends

on the local expertise and the availability of imaging modalities. However, at least CT of the chest,

abdomen (including three-phase liver protocol CT), and pelvis should be performed routinely to

evaluate patients with CLM, with selective use of MRI and PET to further evaluate small hepatic

nodules or extrahepatic disease.

Algorithm 60-3. Multidisciplinary treatment approach for colorectal liver metastasis. (Adapted from Kopetz S, Vauthey JN.

Perioperative chemotherapy for resectable hepatic metastases. Lancet 2008;371:964–965 with permission.)

The surgical indication for CLM should be considered from two standpoints: oncologic resectability

and technical resectability. From an oncologic standpoint, complete resection of all viable disease is

crucial if the patient is to derive the most benefit from surgery. The presence of extrahepatic disease

does not necessarily represent an absolute contraindication for surgery. Isolated lung metastases have

reportedly been associated with a high 5-year survival rate (30% to 40%) when complete resection is

feasible. Localized peritoneal disease correlates with an intermediate 5-year survival rate (15% to 30%),

whereas para-aortic adenopathy and evidence of multiple sites of extrahepatic disease are rarely

associated with favorable survival after resection of CLM (5-year survival rate <15%).111 These data

suggest that patients harboring limited extrahepatic disease are amenable to surgical resection with a

reasonable expectation for long-term control with adjuvant therapies.112 However, when the

extrahepatic disease is unresectable or uncontrollable with systemic chemotherapy, hepatic resection for

CLM is contraindicated.

Another oncologically important factor in determining resectability is response to chemotherapy.

With modern effective chemotherapy, disease progression during neoadjuvant systemic therapy is

relatively rare. However, some patients present with tumor progression during preoperative systemic

therapy. Growth of pre-existing intrahepatic metastases does not seem to be associated with poor

outcomes. However, development of a new lesion is reportedly associated with a poor prognosis after

resection of CLM.113 Therefore, the oncologic behavior of the tumor during preoperative chemotherapy

1559

offers useful information to adequately stratify patients who would benefit from surgical resection.

From a technical standpoint, the resectability of CLM relies on anatomic considerations and

underlying hepatic function. Because a safety limit for the extent of liver resection exists according to

individual hepatic functional reserve, assessment of hepatic function and systematic volumetry of FLR

are mandatory to estimate the risk of postoperative hepatic insufficiency and preoperative intervention

to reduce the risk of surgery, as described later in this chapter. When the estimated FLR volume is

smaller than the minimal FLR volume, to avoid postoperative hepatic insufficiency PVE or another

approach, including two-stage resection, is considered.

Neuroendocrine Liver Metastases

Neuroendocrine tumors grow indolently and metastasize primarily to the liver. In the majority of the

cases, these tumors are nonfunctioning and patients with a significant tumor burden can remain

asymptomatic for years, while patients with minimal lesions can suffer various symptoms caused by

excessive production of hormones by the tumor. Although the best treatment strategy has not yet been

established, resection of functioning NETs reduces symptoms and prolongs survival. The survival rate of

patients undergoing liver resection is relatively high, reaching 91% at 3 years

114 and 61% at 5

years,115,116 even though the curative resection rate is relatively low. NETs are basically incurable in

most advanced-stage cases. However, cytoreduction of >90% of the tumor volume is reportedly

superior to other treatment options, such as transarterial embolization or systemic therapy.117,118 To

maximize the treatment outcomes, a multidisciplinary approach that includes surgery, transarterial

embolization, systemic chemotherapy, and radiation is needed.

PREOPERATIVE SURGICAL MANAGEMENT

When surgical resection is selected as an initial treatment for hepatic malignancy, secondary

assessments for surgical planning and preoperative management are required.

Review of Vascular Anatomy

6 For surgical planning, precise anatomic interpretations of the intrahepatic vascular structures are

needed. This step specifies the ramification pattern of each vascular structure based on the imaging

studies and knowledge of anatomic variations.

Important variations in the portal venous system include its ramification patterns at the hepatic

hilum. In approximately 80% of patients, the main portal vein bifurcates into the left and right portal

branches at the hepatic hilum (bifurcation type). However, trifurcation into the left paramedian, right

paramedian, and right lateral portal trunks at the hilum (10%) or early branching of the right lateral

pedicle (10%) (trifurcation type) is frequently encountered in major hepatectomy. In addition,

anomalies such as right-sided ligamentum teres (0.6% to 1.2%), lack of left portal trunk (0.9%), or lack

of intrahepatic portal vein (<0.1%) are sometimes encountered. Because the portal ramification pattern

defines the segmental anatomy of an individual liver, precise confirmation of the anatomy in the portal

venous system is of primary importance.

As for the hepatic veins, attention should be paid to the drainage pattern of the right lateral sector

(i.e., Segments VI + VII) because thick accessory right hepatic veins, such as the middle right hepatic

vein or the inferior right hepatic vein,119 are observed in nearly 70% of cases. Care must be taken when

these veins are thick and drain a large portion of Segment VI or VII because ligation of these veins may

cause congestion of the right lateral sector and because careless handling of the right hemiliver during

mobilization may cause incidental injury of these veins, resulting in massive bleeding (Fig. 60-11).

Regarding the hepatic arteries, the presence or lack of a “replaced” or “accessory” hepatic artery is

important. Typically, both right and left hepatic arteries are derived from the proper hepatic artery.

However, there are two frequent variations in the ramification patterns of the left and right hepatic

arteries: the left hepatic artery sometimes branches from the left gastric artery, running in the lesser

omentum and feeding Segments II and III, and the right hepatic artery sometimes originates from the

superior mesenteric artery, running behind the portal vein and reaching the right hemiliver on the right

side of the hepatic hilum. When the total arterial supply for the left lateral section (Segments II + III)

or right hemiliver comes from these aberrant arteries, these arteries are called “replaced” arteries, while

they are called “accessory” arteries when the other arterial flow from the proper hepatic artery is also

present. Because of the presence of a typical arterial route derived from the proper hepatic artery,

1560

accessory arteries can be ligated. In contrast, due to a lack of compensatory arterial supply from the

proper hepatic artery, the replaced arteries should be preserved when the corresponding part of the

liver is not resected. Therefore, preoperative review of the arterial anomalies in the early arterial phase

in dynamic CT is essential, and a routine clamp test with Doppler ultrasound is needed before these

aberrant arteries are ligated.

Figure 60-11. Multiple accessory right hepatic veins during liver mobilization. Intraoperative photo of the exposed right wall of

the inferior vena cava during mobilization of the right lobe of the liver. IVC, inferior vena cava; RHV, right hepatic vein; MRHV,

middle right hepatic vein; IRHV, inferior right hepatic vein. (Adapted from Shindoh J, Aoki T, Hasegawa K, et al. Donor

hepatectomy using hanging maneuvers: Tokyo University experiences in 300 donors. Hepatogastroenterology 2012;59:1939–1943

with permission.)

Aside from the blood vessels, precise preoperative assessment of the biliary anatomy is difficult.

There are considerable variations in the ramification pattern of the right-side biliary branches, while the

anatomy of the left hepatic duct is rather simple and constant. Thus, right or extended right

hepatectomy can be performed safely without any unnecessary injury to the biliary branches to be

preserved. However, when left-side major hepatectomy is being performed, care should be paid not to

injure the biliary branches for the right side. Magnetic resonance cholangiopancreatography may clarify

the ramification pattern of the biliary tree. However, its imaging quality is not always satisfactory

unless the intrahepatic bile duct is obstructed or dilated.

Based on this anatomic information and the tumor distribution, oncologically adequate types of

resection can be planned and a safe vascular handling approach adopted. Conventionally, the quality of

such meticulous anatomic assessments was highly dependent on the surgeon’s knowledge or experience.

However, with recent advancements in imaging modalities, three-dimensional reconstruction of CT

images is easy and the three-dimensional liver simulation technique has provided ready access to the

information on a patient’s precise individual vascular anatomy (Fig. 60-12).120

Assessment of the Minimal Requirement of FLR and CT Volumetry

The functional reserve of the liver depends on the quality of the liver parenchyma. The volume of the

FLR4,14,121–123 and the regenerative capacity of the liver124,125 are important predictors of postoperative

morbidity and mortality after extended hepatectomy. The minimal requirement of the FLR volume is

determined by the balance between the hepatic functional capacity per volume and the actual volume of

the FLR. The ICG clearance test is widely used to measure the hepatic functional reserve and to

determine an adequate extent of surgery, especially for patients with cirrhosis. The landmark criteria

for the maximum extent of resection proposed by Makuuchi et al.82 offer a simple algorithm to safely

perform hepatic resection according to the ICG retention rate at 15 minutes (ICG-R15) (Algorithm 60-

2), and the clinical relevance of this algorithm was validated in a large prospective cohort treated under

the constant resection policy.1 However, ICG-R15 has several limitations. First, it is used mainly to

determine the extent of minor resection for patients with cirrhotic livers, and it does not offer a safety

limit for major hepatectomy. Second, ICG-R15 is influenced by hepatic blood flow and measures

performed after a meal, after exercise, or with patients with portosystemic shunts are not reliable.

Third, because ICG is exclusively excreted in bile, the ICG test cannot be used for patients with

obstructive jaundice or inherited hyperbilirubinemia. 99mTc-GSA, a scintigraphy agent that binds

specifically to asialoglycoprotein receptors on hepatocytes, can be used to evaluate hepatic functional

reserve. Because 99mTc-GSA scintigraphy is not influenced by the hepatic blood flow or biliary

obstruction, it can be used to evaluate the hepatic functional reserve when the ICG clearance test is not

1561

appropriate.

Figure 60-12. Three-dimensional evaluation of venous drainage areas. Three-dimensional volume assessment of venous drainage

area predicts venous congestion area after deprivation of the corresponding hepatic venous branches or hepatic veins at surgery.

Evaluating the volume of the FLR is the most reliable approach to predicting outcome in patients who

are candidates for major liver resection. Several methods have been described to evaluate the volume of

the FLR. At The University of Texas MD Anderson Cancer Center, the standard liver volume (SLV) is

estimated with a formula that relies on the linear correlation between the SLV and body surface area

(BSA), as follows:

SLV (cm3) = −794.41 + 1,267.28 × BSA (m2)

The standardized FLR (sFLR) is calculated as the ratio of the FLR volume divided by the SLV. In a

series of 301 patients without chronic liver disease or hepatic injury who were undergoing extended

right hepatectomy, an sFLR of <20% was a risk factor for postoperative liver insufficiency and 90-day

postoperative mortality.4 Patients with chemotherapy-induced liver injury require an sFLR of

approximately 30% and those with cirrhosis require at least 40% residual volume.13,14,121

Of note, these volume criteria are based on the volume of the fully functioning hepatic parenchyma;

in other words, the hepatic parenchyma with patent blood flow and intact biliary drainage. If combined

resection of a hepatic vein is needed, the area with deprived venous drainage develops venous

congestion and represents impaired hepatic function,126,127 resulting in atrophy of the corresponding

area.128,129

Portal Flow Modulation to Expand the Surgical Indication

7 PVE is a safe and minimally invasive procedure for inducing ipsilateral atrophy and compensatory

contralateral hypertrophy of the FLR.130–133 When the sFLR volume is considered insufficient according

to the baseline status of the underlying liver, PVE is considered to expand the surgical indication and to

improve the safety of major hepatectomy (Fig. 60-13).

Several studies have demonstrated the efficacy of PVE in terms of hepatic functional shift from the

embolized liver to the FLR and reduced surgical risk. First, a dynamic functional shift from the

embolized liver to the FLR after PVE was confirmed in three studies using the ICG excretion rate,134

99mTc-GSA scintigraphy,135 or bile clearance.136 All of those studies indicated that PVE produced a clear

functional shift from the embolized liver to the nonembolized FLR with a concomitant increase in FLR

volume. Another study showed that when a patient achieved sufficient growth of the FLR to meet the

minimum criteria for FLR volume, the operative risk was significantly reduced compared to the risk for

patients who did not meet the minimum FLR volume criteria after PVE.4

sFLR after PVE sensitively predicts the risk of postoperative hepatic insufficiency. However, recent

studies have indicated that the regeneration capacity or speed of regeneration independently predicts

short-term surgical outcomes in patients undergoing PVE for a small FLR. Ribero et al.124 reported that

the degree of hypertrophy in sFLR volume after PVE is significantly associated with surgical outcomes.

A degree of hypertrophy >5% after PVE along with sFLR >20% predicted good postoperative

outcomes with high specificity and sensitivity in patients with normal liver function. The kinetic growth

rate (defined as the degree of hypertrophy at initial volume assessment divided by the number of weeks

1562