Diseases of the Liver and Biliary System - part 9 pptx

Endoscopic ultrasound to look for tiny bile duct stones and for pancreatic disease may be clinically indicated in combination with endoscopic biliary manometry.. They consist of polycyst

tumour (93%) than CT (53%) [52] Endoscopic

ultra-sound may also be used to stage pancreatic cancer but its

accuracy needs further evaluation [2] This technique is

also highly accurate for localizing pancreatic

neuroen-docrine tumours which are often not well seen by other

methods (fig 32.8) [6]

Endoscopic ultrasound-guided fine-needle aspiration

biopsy is possible from lymph nodes and pancreatic

lesions and in experienced hands is safe [75]

With the increased availability of this technique it is

being used more frequently for the evaluation of patients

with pancreatic tumours, in particular for biopsy and

assessing resectability It may also be valuable for patients

with problematic biliary tract pain where MRCP and

other scanning has been negative and ERCP unhelpful

Endoscopic ultrasound to look for tiny bile duct stones

and for pancreatic disease may be clinically indicated in

combination with endoscopic biliary manometry

Biliary scintigraphy

The technetium-labelled iminodiacetic acid derivative

(IDA) is cleared from the plasma by hepato-cellular

organic anion transport and excreted in the bile (fig

32.9a) Biliary radiopharmaceuticals have so improved

that one of the newest, Iodida, is easily prepared and is

taken up by the liver and excreted into bile efficiently

with only 5% of the injected dose excreted in the urine

Effective concentration in the bile duct is achieved in

patients with total serum bilirubin levels exceeding

340 mmol/l (20 mg/dl) Resolution is much less than with

other forms of bile duct visualization and the role of cholescintigraphy is therefore limited

The method may be used to determine patency of the

cystic duct in suspected acute cholecystitis (fig 32.9b) The

radio-activity is followed until it reaches the duodenum

If the gallbladder fails to visualize, despite common bileduct patency and intestinal visualization, the probability

of acute cholecystitis is 99%

The gallbladder ejection fraction can be calculatedfrom the loss of isotope from the gallbladder after a stan-dard infusion of sincalide (the C-terminal octapeptide ofCCK) [78] This technique can help to identify gallblad-der disease in some patients who have gallbladder-likepain but a normal ultrasound

Cholescintigraphy can show whether the bile duct isobstructed, but in most units US serves this role

In the more complicated patient, analysis of the pattern

of uptake and hepatic clearance of radio-activity, or thecombination of scintigraphy with US, can differentiateintra-hepatic cholestasis from bile duct obstruction —useful, for example, in the patient with a biliary stricture,who remains cholestatic despite insertion of a biliaryendoprosthesis Scintigraphy is also useful in assessingthe patency of biliary-enteric anastomoses, and mayshow biliary leaks after cholecystectomy (fig 32.9c) orliver transplantation [44]

Choledochal cysts can be diagnosed although

ultra-sound CT and MRI scanning are just as satisfactory (see fig 33.13)

In the neonate, IDA scanning is used to differentiate

between biliary atresia and neonatal hepatitis (fig.32.9d) It may be combined with ultrasound

Functional obstruction of the sphincter of Oddi after

cholecystectomy may be suggested by delayed andreduced excretion of activity with slower emptying ofthe biliary tree

Oral cholecystography

Although oral cholecystography shows gallbladderstones with an accuracy of 85–90%, it is now rarely usedbecause of the greater sensitivity and wide availability oftransabdominal ultrasonography In recent years it had alimited role in the evaluation of the gallbladder beforeoral bile acid therapy but this treatment has also becomemuch less frequent with the development of laparo-scopic cholecystectomy

The contrast agents used were iodine containing, jugated with glucuronic acid by the liver, and excreted inbile In the fasting patient contrast enters the gallbladder

con-if the cystic duct is patent There is reabsorption of water

by the lining mucosa, concentration of contrast and bladder opacification (fig 32.10) Complications includ-ing hypersensitivity are extremely rare

gall-Fig 32.8 Endoscopic ultrasound in a patient with suspected

neuroendocrine tumour in whom CT scan had shown no

abnormality 2.5 cm diameter mass shown in head of pancreas

PD, pancreatic duct; SV, superior mesenteric vein (Courtesy of

Dr Steve Pereira.)

When this method is used three X-ray films are

necessary; control, fasting after oral contrast, and after

gallbladder contraction by fat stimulation or CCK

The gallbladder is seen in 85% of patients Films are

taken erect and prone Normal visualization without

stones gives a 95% probability that the gallbladder is

normal The technique is not valuable if the bilirubin

is greater than twice the upper limit of normal

be-cause of failure of efficient secretion of contrast by the

liver

Oral cholecystography is of value in showing lesions

of the gallbladder wall, for example adenomyomatosis

[47] This is seen as small fundal outpouchings

Rokitan-sky–Aschoff sinuses are seen as a dotted second contour

around the gallbladder lumen Anomalies of the

gall-bladder may be visualized by oral cholecystography

Intravenous cholangiography

The contrast (meglumine iotroxate; biliscopin) is

concen-trated by the liver so that hepatic and common bile ducts

are demonstrated Tomography is used

However, intravenous cholangiography had become

obsolete because of its poor diagnostic accuracy, its

mor-bidity and the advent of MRCP

Endoscopic retrograde

The ampulla of Vater is visualized endoscopically, thecommon bile duct or pancreatic duct is cannulated andcontrast material injected (fig 32.11)

Patients with suspected biliary obstruction, a history

of cholangitis or a pancreatic pseudocyst are at risk

of procedure-related sepsis, and require antibiotic premedication [66] The elderly are also at greater risk.Micro-organisms responsible include colonic flora

(Escherichia coli, Klebsiella, Proteus, Pseudomonas, coccus faecalis) and the antibiotic choice should reflect

Strepto-this and the hospital antimicrobial policy Oralciprofloxacin is as effective as intravenous cefuroxime,and more cost-effective [66]

The patient is starved for 6 h The procedure is doneunder sedation with a benzodiazepine (diazepam, midazolam) with an opiate as necessary

At ERCP, diseases of the oesophagus, stomach, num, pancreas and biliary tract including duodenaldiverticula and fistulae may be diagnosed Manometry

duode-of the sphincter area is possible Immediate treatmentmay be instituted, for example sphincterotomy forcommon duct stones However, endoscopes are costlyand the technique demands an experienced team.Usually the patient must be under observation for 24 h

Fig 32.9 Cholescintigraphy (99m Tc Iodida) (a) Normal scan At 30 min the gallbladder (g) has filled Isotope has already entered the bowel (B)

(b) Acute cholecystitis Gallbladder has not filled by 60 min (c) Post-

cholecystectomy bile leak Isotope tracks laterally from gallbladder bed (short arrow) and T-tube track (long arrow) (d) Two-week-old infant with severe jaundice Radio-activity is concentrated in the liver (L) and did not enter the bowel Biliary atresia was confirmed B, bladder.

(a)

(c)

(b)

(d)

after the procedure However, outpatient ERCP may bedone for selected patients, although around 25% mayneed admission for complications or observation after atherapeutic procedure [36] After sphincterotomy obser-vation for 6 h or overnight may reduce the need for readmission [30].

The side-viewing duodenoscope is passed Thestomach and duodenum are inspected and biopsy andcytology specimens taken if indicated The papilla is identified Duodenal ileus is maintained by intermittent

intravenous hyoscine N-butylbromide (Buscopan) or

glucagon The cannula is then introduced under directvision into the papilla and contrast (e.g iopromide)injected under fluoroscopic control Preferential catheter-ization of bile duct and pancreatic duct is helped bydirecting the catheter towards 11 and 12 o’clock, respec-

tively, with the ampullary area en face seen as a clock face.

Use of a dual channel sphincterotome allows selectivebile duct cannulation or cannulation after failure with astandard catheter

The intra-hepatic biliary tree, cystic and common bileducts and gallbladder are filled (fig 32.11) Changes inthe position of the patient and tilting of the screeningtable after injection encourage distribution of contrastmaterial throughout the duct system In difficult cases,such as after sphincterotomy, a balloon catheter in theduct may be used to prevent reflux of contrast into theduodenum and so obtain better bile duct filling Thepancreatic duct is similarly cannulated and X-ray filmstaken

An aseptic technique is maintained throughout scopes are thoroughly cleansed with soap and water anddisinfected with activated glutaraldehyde The danger

Endo-of introducing infection is shown by a single endoscopewhich, although cleaned in an automatic machine,

remained contaminated with Pseudomonas aeruginosa so

resulting in biliary infection in 10 patients, with onefatality [3]

A history of minor reactions to intravenous contrast isnot important but those who have had a major allergicreaction to iodinated contrast should be premedicatedwith corticosteroids and antihistamines [25]

The success rate for ERCP is 80–90% but depends onexperience Anatomical causes of failure include a peri-ampullary diverticulum or an ampullary tumour orstricture Billroth II gastrectomy poses difficulties whichmay be overcome by an experienced endoscopist if necessary using a forward-viewing endoscope

Interpretation of the cholangiogram is not alwayseasy Contrast may obscure small stones Air bubblesmay cause confusion Failure to fully fill the biliary tree, particularly in non-dependent parts, may add to the difficulty

Fig 32.10 Oral cholecystogram showing gallbladder packed

with stones.

Fig 32.11 ERCP, normal appearances C, common bile duct;

G, gallbladder; PD, pancreatic duct.

The complication rate is 2–3% and mortality 0.1–0.2%

Complications are directly related to the skill and

experi-ence of the operator and to the presexperi-ence of underlying

pancreatic or biliary disease

Serum amylase levels rise considerably after ERCP

and acute pancreatitis is the commonest complication It

almost always follows successful pancreatic cannulation

and injection The volume of contrast injected should be

kept to a minimum Non-ionic lower osmolarity contrast

media have not been proven to carry a lower risk of acute

pancreatitis In most cases pancreatitis is clinically mild

with recovery over a few days For this and other reasons

(duration of infusion required, cost-effectiveness)

somatostatin or gabexate, both shown in randomized

studies to reduce post-ERCP pancreatic injury, are not

routinely used [4] Pancreatic pseudocyst is a relative

contraindication to ERCP

Cholangitis is the second most common

compli-cation but the commonest cause of death Bacteraemia

is reported in 0–14% [66] Pre-existing biliary infection

and obstruction are important risk factors

Prophy-lactic antibiotics are important in prevention,

together with early decompression of any biliary

obstruction

In patients with primary sclerosing cholangitis and

advanced disease, there may be deterioration after ERCP

[10]

Indications

ERCP adds to the speed of diagnosis of the jaundiced

patient as it can be performed irrespective of depth of

jaundice or state of liver function It outlines the site of

any biliary obstruction and in many instances indicates

the cause

It can be used to show duct strictures, and gallbladder

and common bile duct stones (figs 32.12, 32.13) It is of

particular value in those with biliary disease and

undi-lated intra-hepatic ducts Diagnoses include primary

sclerosing cholangitis, Caroli’s disease and other

con-genital anomalies

ERCP may be performed after biliary surgery in the

investigation of benign post-cholecystectomy symptoms

or to define and treat more serious sequelae such as

residual calculi, leaks and biliary strictures [22]

ERCP may be used to diagnose pancreatic disease,

particularly in those with coincident hepato-biliary

problems such as carcinoma of the pancreas and

alco-holic pancreatitis with biliary obstruction

ERCP is occasionally used in the investigation of the

patient with obscure epigastric pain It allows

visualiza-tion of stomach and duodenum as well as pancreatic and

biliary ducts, all at one sitting

Pure bile or pancreatic juice may be obtained forculture, aspiration cytology or chemical analysis

Strictures may be brushed for cytology or biopsied[43]

Endoscopic sphincterotomy[18]

Normal coagulation is a prerequisite for endoscopic

Fig 32.12 ERCP showing: (a) dilated bile duct above a

stricture The pancreatic duct comes to an abrupt halt in the head of the pancreas Appearances are characteristic of carcinoma of the pancreas; (b) common bile duct filling as far

as a hilar stricture due to a cholangiocarcinoma.

(a)

(b)

sphincterotomy and the result of platelet count and

pro-thrombin time as well as haemoglobin should be known

Serum is taken for blood group analysis and saved in

case transfusion is necessary Premedication with

anti-biotic is routine in most units A skilled team is required

with adequate equipment, in a hospital with facilities to

treat any complication

After the diagnostic ERCP has shown a stone, the

ampulla is catheterized with a dual-channel

sphinctero-tome appropriate in length and design to the anatomy

found Fluoroscopy is used to establish that this has

entered the bile duct A guide-wire is usually passed into

the bile duct to stabilise the sphincterotome position

during sphincterotomy The sphincterotome is

with-drawn leaving approximately 1 cm of the wire within

the ampulla, the wire is bowed and, under direct vision,

a cut is made using a blend or cutting current from the

cautery unit (fig 32.14) The length of cut depends upon

the anatomy of the ampulla and the supra-ampullary

area, and the size of the stone If sphincterotomy is being

done as a preliminary to endoprosthesis insertion only a

small cut is needed For stones, the aim is to make a cut of

sufficient length to allow removal It may be necessary to

cut through the biliary sphincter, shown by the release

of bile Air refluxes up the bile duct For larger stones

it is necessary to decide when to use a mechanicallithotripter and a moderate cut, rather than risk a larger,possibly complicated sphincterotomy

The success rate is above 90% [37], reaching 97% in anexpert unit [70] Causes of failure include a large peri-ampullary diverticulum, a Billroth II partial gastrectomyand an impacted stone at the ampulla

Related techniques which may be helpful includeneedle knife papillotomy [29], but this should only beused by experienced endoscopists

Complications[20, 31]

These occur in about 10% and include haemorrhage,cholangitis, pancreatitis, duodenal perforation, Dormiabasket impaction and Gram-negative shock They arelife threatening in 2–3% Mortality is 0.4–0.6%

Prospective studies show pancreatitis in 8–10% ofpatients having an endoscopic sphincterotomy The rate will be influenced by the technique used includingselective catheterization of the biliary system using asphinctertome Pure cut electrocautery may reduce therisk [27] Post-sphincterotomy pancreatitis is usuallymild

Bleeding, usually from the retro-duodenal artery, isthe most serious potential problem It usually settles but,

if not, surgery can be difficult Treatment by arterialembolization may be successful Bleeding is not alwaysimmediate and may be delayed several days after theprocedure [30]

Fig 32.13 ERCP showing common bile duct stone A

sphincterotome has been passed into the lower end of the bile

duct.

Fig 32.14 Sphincterotome inserted into ampulla of Vater The

wire has been bowed and the sphincterotomy cut has begun.

Cholangitis occurs if biliary decompression (stone

removal) is unsuccessful Prevention is by insertion of a

naso-biliary tube or endoprosthesis

Late results of sphincterotomy show that two-thirds

of patients have air in the biliary tract and free reflux

of duodenal juice Bacterial colonization of the bile is

present whether or not there are symptoms; the

signifi-cance of this is unknown Late complications (5–10%

over 5 years) include sphincter stenosis [13] and

recur-rent stones The long-term effects of loss of sphincter

function are unresolved

In cirrhotic patients with choledocholithiasis

endo-scopic sphincterotomy is effective and safe although

coagulopathy must be corrected beforehand [58]

Indications

Choledocholithiasis is the commonest indication

Emer-gency ERCP with endoscopic sphincterotomy is the

treatment of choice for patients with acute suppurative

obstructive cholangitis [45] which is almost always caused

by a stone Where there is acute cholangitis of lesser

sever-ity elective ERCP is done after a period of antibiotic

treatment Whether or not the gallbladder is in place,

sphincterotomy is the treatment of choice

In patients with common duct stones without cholangitis

the choice depends on the clinical situation For

post-Fig 32.15 (a) ERCP showing trawling of bile duct with balloon catheter to remove stones (b) Removal of duct stone with basket (c)

Naso-biliary tube with stones in the common bile duct.

(c)

(a)

(b)

cholecystectomy retained bile duct stones sphincterotomy is

clearly the best treatment in elderly frail patients andthose with other medical problems In this group ofpatients it is also the accepted treatment even when the

gallbladder is still in situ After removal of the common

duct stone(s), the decision whether to proceed to cystectomy depends upon clinical data, although whenthe patient is unfit for surgery conservative therapywithout cholecystectomy is an option (Chapter 34)

chole-In younger, fit patients with retained stones aftercholecystectomy, sphincterotomy is preferred to surgicalbile duct exploration With the gallbladder in place,however, it is not clear whether cholecystectomy should

be preceded by endoscopic sphincterotomy or nied by duct exploration and stone removal at the time

accompa-of surgery

The evolution of laparoscopic cholecystectomy andduct exploration adds to the therapeutic choice

Acute gallstone pancreatitis, particularly if severe and

unresolving, is an indication for emergency ERCP andsphincterotomy if a stone is found (Chapter 34)

Stone extraction is done with wire baskets or ballooncatheters (fig 32.15a,b) In 90% the common bile duct issuccessfully cleared of stones If all the stones cannot beextracted from a patient with cholangitis a naso-biliarycatheter or endoprosthesis must be left to drain the duct(fig 32.15c) Stones larger than 15 mm may be difficult to

extract Mechanical lithotripsy may be used to crush

stones with success in 92% of patients [63] Alternatively,

an endoprosthesis may be inserted [50] This prevents

the stone obstructing the bile duct, and is a quicker

pro-cedure than lithotripsy Endoprosthesis insertion may

be temporary until another attempt at stone removal,

or used for long-term drainage Administration of oral

ursodeoxycholic acid while the endoprosthesis is in

place appears to make later clearance of stones from the

duct more successful [41]

Extracorporeal shock wave lithotripsy of common bile

duct stones fragments them and allows them to pass

through the sphincterotomy [26] Laser lithotripsy is

available in some specialist centres

Sphincterotomy is often done before endoscopic

endo-prosthesis insertion This was originally recommended

to reduce the risk of pancreatic duct obstruction and

pancreatitis, but carries the risk of bleeding and is not

essential unless the os is particularly small or tight

Sphincterotomy at the main papilla may be used to

treat the rare sump syndrome following

choledocho-duodenostomy [14] Papillary stenosis (Chapter 34) can

also be treated by sphincterotomy

Stone removal without sphincterotomy

Small stones (< 8 mm) may be removed through an intact

ampulla, with or without balloon dilatation [51] Larger

stones have been removed using the combination of

mechanical lithotripsy and balloon dilatation of the

sphincter of Oddi Pancreatitis is a complication in about

7%, but in a randomized trial was as frequent as with

endoscopic sphincterotomy [9]

Naso-biliary drainage

A sphincterotomy is not usually necessary After ERCP,

the common bile duct is cannulated and a guide-wire

passed deep into an intra-hepatic duct The cannula is

removed and a 300-cm 5 French (Fr) pigtail catheter with

multiple side holes is threaded over the wire which is

then removed (fig 32.15c) The catheter is re-routed

through the nose This technique allows decompression

of the biliary tree

There are fewer complications than with percutaneous

biliary drainage in terms of infection, bile leak and

bleeding

Naso-biliary drainage can be used as a preliminary to

later sphincterotomy in poor risk patients with

choledo-cholithiasis and acute suppurative cholangitis,

espe-cially if coagulation is abnormal

A naso-biliary drain may be left in position when, after

sphincterotomy, it has been impossible to clear all the

stones from the common bile duct Later

cholangiogra-phy through the tube shows whether the stones havepassed Naso-biliary drainage may also be used to treatbile leaks after cholecystectomy or liver transplantation,although stent insertion is the first method of choice forboth leaks and residual duct stones

Endoscopic biliary endoprostheses

After catheterization of the ampulla and demonstration

of the stricture by contrast, a guide-wire is passedthrough the catheter and an attempt is made to pass itthrough the stricture At the first session this is possible

in 60–70% of patients Using a combination of an innertube and pushing tube, an endoprosthesis is railroadedinto position across the stricture A 3.3-mm diameter(10Fr) tube requires an endoscope with a 4.2-mm chan-nel and provides effective decompression (fig 32.16).Barbs on the endoprosthesis prevent it passing all theway up into the bile duct or subsequently back into the duodenum Two endoprostheses may be used

if necessary, for example to left and right hepatic ductswhen there is a hilar stricture Overall success rate ofendoprosthesis insertion is 85–90% in skilled hands.Early complications include cholangitis and pancre-atitis Sphincterotomy is not necessary before 10Fr stent insertion and may cause haemorrhage [48] Sphinc-

Fig 32.16 ERCP: polyethylene stent inserted to relieve

obstruction due to peri-ampullary tumour.

terotomy may be needed if the ampulla is too tight to

admit the stent or if catherization of the biliary system

has been difficult so as to allow easy access on a

subse-quent ERCP

Late complications include cholangitis and recurrent

jaundice due to blockage of the tube, which can easily

be removed and replaced endoscopically Mesh

metal endoprostheses are now available which, after

insertion in compressed form, expand when released

to a diameter of up to 1 cm and remain patent for

a longer period than conventional plastic stents

(figs 32.17, 32.18) However, blockage still eventually

occurs Coated metal shunts may delay this [39]

Results and indications

Endoscopic plastic endoprostheses successfully

decom-press the bile duct and relieve symptoms in about

70–80% of patients The method carries fewer

complica-tions than the percutaneous route [65], and has a

lower morbidity and mortality than surgical palliative

bypass in patients with peri-ampullary carcinoma [64]

Blockage of polyethylene endoprostheses occurs in

25–30% at 3–6 months due to biliary sludge, containing

bacteria Antibiotic and ursodeoxycholic acid

adminis-tration do not prevent this [33] Tannenbaum stentsmade of Teflon do not have longer patency rates [28].When expandable metal mesh endoprostheses block, obstruction is relieved by insertion of a plasticstent or another metal stent within the occluded endo-prosthesis [67] However, the patency of expandablemetal mesh endoprostheses is significantly longer thanplastic types (fig 32.18) [19, 42], but the metal type ismore expensive Present experience suggests that aplastic type be placed first, and when it blocks, a metalendoprosthesis is inserted in those patients who are progressing more slowly and are expected to survivelonger [53]

Inoperable malignant biliary obstruction from carcinoma

of pancreas, ampulla and hilum can be relieved For amalignant hilar obstruction, drainage of only one lobeprovides good palliation A second endoprosthesis isonly needed if cholestasis is not relieved sufficiently orthere is sepsis in the undrained side [56]

Benign strictures, whether due to primary sclerosing

cholangitis or post-cholecystectomy, can be treated

in this way, although balloon dilatation is an alternative

Failed endoscopic removal of common duct stones A stent

may be introduced into the common bile duct where it

Fig 32.17 (a) ERCP showing

malignant stricture (arrows) at lower end of bile duct (b) Mesh metal stent (Wallstent) placed across the stricture (Courtesy of Dr Kees Huibregtse.)

has been impossible to remove all stones and when the

patient is unfit for surgery

External biliary fistulas Post-operative leaks from the

cystic duct or gallbladder bed may be treated by

intro-duction of a biliary stent The leak usually seals making

re-operation unnecessary The stent is removed after a

few weeks

Balloon dilatation

Following endoscopic cholangiography, a ballooncatheter may be introduced into the common bile ductand inflated This may be used to dilate a benign stricture (fig 32.19), whether traumatic or secondary

to primary sclerosing cholangitis It may be a useful preliminary step before insertion of an endoprosthesis

Per-oral cholangioscopy

The bile duct interior can be inspected using a ‘baby’endoscope introduced via a large channel (‘mother’)

Polyethylene Metal

100

80

Fig 32.18 Kaplan–Meier life table

analysis of stent patency: randomized

trial of metal vs polyethylene stents.

(From [19] with permission.)

Fig 32.19 Endoscopic balloon dilatation of bile duct stricture

following liver transplantation (a) Cholangiogram showing

stricture (b) Wire passed into intra-hepatic ducts (c) Balloon

dilatation to 8 mm diameter (d) Final cholangiogram with

good result.

six needle ‘passes’ are allowed before the procedure isabandoned.

After successful injection into obstructed and dilatedducts the patient may need to be tilted so that thecommon bile duct has an opportunity to fill If hilarobstruction prevents communication between the rightand left hepatic duct, a percutaneous cholangiogramfrom both sides should be done The technique is rela-tively safe so that surgery need not inevitably followimmediately If dilated ducts are encountered, theyshould be catheterized and external or internal biliarydrainage established Trans-hepatically aspirated bileshould be cultured The patient must be observed care-fully in hospital

The technique is easy and the success rate is 100%

if intra-hepatic bile ducts are dilated With undilatedducts, such as in primary sclerosing cholangitis or withsome cases of choledocholithiasis, the success rate drops

to 90% but can rise to 95% in specially skilled hands

Complications

The complication rate is less than 5% and includes ing, bile peritonitis and septicaemia (usually Gram-negative) in those with cholangitis or unsuspected bacteria in the bile

bleed-Indications

For the majority of patients needing direct

cholangiogra-phy, the percutaneous approach is the second choice

used only after ERCP has failed This practice is basedless on the relative complication rates of the two diag-nostic procedures, and more on the greater therapeuticpotential of ERCP, with a lower risk Thus the endo-scopic approach allows sphincterotomy for stones, andsafer stent insertion Percutaneous cholangiographycomes into its own, however, when endoscopic access is

difficult or impossible (hepatico-enterostomy, Billroth II) It

is also important in the work-up of hilar noma, where detail of both right- and left-sided ductsystems is needed Brush cytology and biliary biopsymay be performed by the percutaneous as well as endoscopic route

cholangiocarci-Percutaneous bile drainage

Bile duct catheterization

A sheathed needle is directed under antero-posteriorand lateral fluoroscopy into a selected intra-hepatic ductalready opacified by the ‘skinny’ needle cholangiogram.The needle is withdrawn and a guide-wire passedthrough the sheath into common bile duct or peripheralintra-hepatic duct

duodenoscope This may provide additional

informa-tion [61], but the thin scopes are fragile, the system

expensive, and the technique requires two endoscopists

Percutaneous trans-hepatic

cholangiography[74]

Contrast is injected percutaneously into a bile duct

within the liver (fig 32.20) The procedure is done in the

radiology department with intravenous sedation and

under local anaesthesia Antibiotic is given 0.5–1 h before

the procedure The ‘skinny’ Chiba needle is 0.7 mm (22

gauge) outside diameter It is very flexible so that the

patient is able to breathe normally with it in situ.

The needle is introduced in the 7th, 8th or 9th right

intercostal space at the point of maximal dullness to

per-cussion in the mid-axillary line Ultrasound guidance

adds to the success It is advanced parallel to the table

top to about 2.5 cm from the spine, bisecting a sagittal

line between the dome of the diaphragm and the

duode-nal cap identified by its gas shadow Contrast is injected

continuously as the needle is withdrawn Bile ducts are

identified by the persistence of contrast in tube-like

branching structures Portal and hepatic veins are

recognized by the peripheral direction of flow and rapid

disappearance of contrast medium Lymphatics can be

filled and the contrast takes 5–10 min to be cleared Up to

Fig 32.20 Diagnostic percutaneous trans-hepatic

cholangiogram showing normal right and left intra-hepatic

ducts and common bile duct, and free flow of contrast into

duodenum The gallbladder is beginning to fill.

External biliary drainage

A drainage catheter is exchanged for the sheath over the

guide-wire, secured to skin and connected to a drainage

bag Theoretically, external bile drainage would be

expected to bring the patient with biliary obstruction,

particularly malignant, to surgery in better condition

and so lessen the incidence of post-operative renal

failure There are, however, many complications

includ-ing fluid and electrolyte loss, sepsis and dislodgement

of the drainage tube [46] Several randomized control

trials have now shown that short-term (1–2 weeks)

pre-operative external bile drainage does not reduce

the post-operative mortality and morbidity in patients

having surgery for malignant bile duct obstruction [35,

46, 54] Long-term external drainage should be avoided,

having both physical and psychological side-effects It is

now rarely necessary, since either endoscopic or

percuta-neous stenting, or surgical bypass is possible

Internal/external biliary drainage

After bile duct catheterization, a guide-wire can usually

be manipulated through the stricture and into low bile

duct or bowel A catheter (8–9Fr) can then be placed

across the stricture with side holes above and below Bile

can then drain into bowel, or, if the external limb is not

spigotted, into an external bag This technique is usually

used as the first stage before endoprosthesis insertion a

few days later It is occasionally used in its own right for

long-term relief of obstruction but commits the patient to

a permanent external tube even if closed off

Percutaneous biliary endoprosthesis

Following percutaneous cholangiography, bile duct

catheterization and manipulation of a guide-wire

through the stricture, an endoprosthesis (10–14Fr) is

inserted over the guide-wire across the stricture

allowing free drainage of bile into bowel (fig 32.21)

Sometimes an external drain is left temporarily above

the endoprosthesis for 24–48 h to guarantee biliary

decompression and to allow check cholangiography The

external tube is then removed Endoprostheses made of

polyethylene and other plastics have been used for many

years [21, 23] As with endoscopic stents, these also block

with time Metal stents have been developed including

the metal wire zigzag (Gianturco) and metal mesh

(Wallstent) types [34, 38] The longer patency of mesh

metal stents is based on endoscopic trials (see above)

Results and complications

Success rate for endoprosthesis insertion is 85% Failures

are due to inability to find the lumen of the stricture with

the guide-wire Hilar strictures are more difficult thanlow common duct obstruction [23] There is completerelief of bile duct obstruction in 65–70% of patients, afurther 15% having partial decompression Major com-plications (haemorrhage and bile leakage with peritoni-tis) occur in 3% of patients Deaths due to the procedureare reported rarely Other early complications includesepticaemia and right-sided pleural effusion with atelec-tasis Late complications are stent blockage with cholan-gitis and recurrent jaundice, and passage of the stent out

of the bile duct

Indications

When endoscopic access to the biliary tree is possible,ERCP and endoscopic stent insertion is the first choice torelieve irresectable malignant biliary obstruction Whenthis fails or endoscopic access is impossible, percuta-

neous insertion is indicated An alternative is a combined approach with percutaneous catheterization of the stric-

ture, placement of the guide-wire tip in the duodenum,and endoscopic retrograde insertion of the stent over thewire This approach still carries an appreciable mortalityand morbidity [24] Since percutaneous metal mesh

Fig 32.21 Percutaneous trans-hepatic insertion of

Carey–Coons stent.

stents can be inserted on a 7Fr catheter, this technique

may replace the more complicated combined approach

[49]

Re-stenosis of hepatico-enteric anastomoses may be

treated by percutaneous stenting or balloon dilatation if

surgical revision is not appropriate

Percutaneous balloon dilatation

Benign strictures of the bile duct have been successfully

treated by percutaneous trans-hepatic balloon dilatation

(see fig 35.4) [17]

Resectability of tumours

Pancreatic carcinomas and hilar cholangiocarcinomas

are rarely resectable, but this possibility should be

assessed particularly in the middle-aged and younger

patient

For pancreatic carcinoma, US and spiral CT are

capable of predicting irresectability with a high degree

of accuracy [11] based on hepatic metastases, local

extension, vascular encasement or invasion, and

lymphadenopathy (Chapter 36), but both depend on

good technique and experience Laparoscopy may show

hepatic metastases or peritoneal seedlings Each unit

will have its preferred approach Angiography is

worth-while but may not provide extra information on

resectability It gives a road map which some surgeons

value greatly

For cholangiocarcinoma, many imaging techniques

have a place in the assessment of resectability, including

US, CT, MRCP, direct cholangiography hepatic

arteriog-raphy and portogarteriog-raphy (Chapter 37)

With ampullary carcinomas, the treatment is surgical

resection if there is no medical contraindication

Choice between surgical and

non-surgical palliation of

malignant obstruction

Randomized control trials have shown that

percutaneous stenting has a similar outcome to bypass

surgery [12] Endoscopic insertion has a lower morbidity

and mortality than either the percutaneous route [65]

or palliative bypass surgery [64] The disadvantage of

plastic stents is that they block, but many patients

die from their malignant disease before this problem

occurs

Clinical features influence the choice of treatment and

in general it is the older, poorer risk patient who receives

the non-surgical endoprosthesis and the younger, fitter

patient who may still have surgery, especially if a tissue

diagnosis has not been made Exfoliative bile cytology,

brush cytology and percutaneous aspiration cytology

should be done in an attempt to establish a tissue diagnosis

Choice between endoscopic and percutaneous approach (table 32.1)Using ERCP or PTC the biliary tree can be visualized invirtually every patient in whom mechanical cholestasishas to be excluded Any large hospital should have both techniques available and a surgeon should alwayshave a cholangiogram to view when exploring the biliarytract MRCP will be useful but ERCP is the first choice fordirect cholangiography PTC is used after failed ERCP orwhen the ampulla is inaccessible Both techniques may

be necessary, for example when ERCP has shown a hilarstricture but the intra-hepatic ducts have not filled PTC

is indicated, left and right sided if necessary, to show thedetailed anatomy The techniques are complementaryrather than competitive Intervention by both routes isnow used widely ERCP offers sphincterotomy and is thesafer method for duct drainage

Percutaneous cholecystostomy

The gallbladder is punctured percutaneously under time ultrasound or fluoroscopic control, and drained.This technique has been used successfully as an emer-gency for high-risk patients with acute calculous andacalculous cholecystitis [73] Access is either direct

real-Table 32.1 Comparison of percutaneous trans-hepatic

cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP)

Time taken (min)* 15–30 15–60 Anatomical difficulties Few Many

Biliary leak Pancreatitis Cholangitis Cholangitis Haemorrhage

across the peritoneal cavity or trans-hepatic The latter is

generally safer since the point of gallbladder puncture

is sealed by adjacent liver The trans-peritoneal route is

preferred if gallstones are to be removed [16] The

trans-hepatic approach is best for drainage of empyema

(Chapter 34)

Operative and post-operative

cholangiography

Routine operative cholangiography is not necessary at

cholecystectomy unless there are indications suggesting

that stones are present in the common bile duct [8]

These include a history of jaundice, dilated bile

ducts, palpable gallstones or a raised serum bilirubin,

alkaline phosphatase or g-glutamyl transpeptidase

(g-GT) level After exploration of the common bile

duct, cholangiography should always be performed

using high kilovolt peak technique and full strength

contrast [68]

Debris may cause filling defects less sharply defined

than those caused by gallstones Air bubbles may

simu-late stones Small stones may be obliterated by the

con-trast medium

During laparoscopic cholecystectomy, laparoscopic

ultrasound successfully detects duct stones [62] and may

obviate the need for intra-operative cholangiography

Post-operative cholangiography, using contrast

injected gently, should be undertaken routinely before

final removal of a T-tube draining the biliary tree During

the injection, bile duct contents, including bacteria,

probably regurgitate into the blood This is particularly

marked in the presence of biliary obstruction

A surprising number of operative and post-operative

cholangiograms are technically unsatisfactory, through

failure to visualize intra-hepatic bile ducts or the

trans-duodenal or sphincteric segment of the ducts It is

essen-tial not to use too dense contrast to fill the biliary tree and

to ensure correct positioning and exposure

T-tube extraction of gallstones

See Chapter 34

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Fibropolycystic disease

Cystic lesions of the liver and bile ducts are increasingly

being diagnosed This can be related to the improved

methods of imaging the liver and bile ducts, and of liver

biopsy Application of such methods makes it clear that

the fibropolycystic diseases do not exist as single entities,

but as members of a family [40]

The members are found in various combinations

(fig 33.1) They consist of polycystic liver disease,

micro-hamartoma, congenital hepatic fibrosis, congenital

intra-hepatic biliary dilatation (Caroli’s disease) and

choledochal cysts (fig 33.2)

Clinically, fibropolycystic diseases have three effects,

again present in different proportions: those of a

space-occupying lesion, of portal hypertension and of

cholan-gitis They are usually inherited Fibrocystic disease of

the kidneys is associated to a variable extent Malignantchange may complicate congenital hepatic fibrosis, bileduct cysts and Caroli’s syndrome

Embryologically the hepato-biliary abnormalities arethought to stem from ductal plate maldevelopment indifferent parts of the biliary tree [11]

The ductal plate is a sleeve of epithelium, one and thentwo cells thick, that forms in the mesenchyme surround-ing portal vein branches from bipotential liver progeni-tor cells — that is cells that may form either hepatocytes

or bile duct epithelium During hepato-biliary ment ductal plates are remodelled into mature tubularducts that eventually form (in descending size interhep-atically from the hilum) hepatic ducts, segmental ducts,area ducts, interlobular ducts and the smallest bile ductbranches

develop-583

Chapter 33 Cysts and Congenital Biliary Abnormalities

27

20 3

12

Congenital

hepatic fibrosis

Choledochal cyst

Caroli's disease

Polycystic liver

Microhamartoma (10) 12

Fig 33.1 Venn diagram showing one series of 51 patients in

which many had more than one fibropolycystic disease The

combination of congenital hepatic fibrosis and Caroli’s disease

was most striking Microhamartomas, although reported in

only 10 patients in this series, are common [40].

Polycystic (space-occupying)

Gallbladder

Choledochal cyst (infection, obstruction)

Microhamartoma

Congenital hepatic fibrosis

(portal hypertension)

Caroli's (cholangitis)

Fig 33.2 Fibropolycystic disease: spectrum of pathology.

Ductal plate malformations include conditions where

the intra-hepatic bile ducts are destroyed, as in biliary

atresia, and conditions in which excess epithelial

compo-nents do not disappear as normal but persist with some

degree of dilatation and fibrosis (fibropolycystic

dis-eases) [11] The resulting disorder depends upon the

level within the biliary tree of ductal plate malformation

(table 33.1), and the degree of associated fibrosis

Childhood fibropolycystic diseases

These are recessively inherited and may be perinatal,

neonatal or infantile (table 33.2) Morphometry shows

that the neonatal and infantile forms represent one

dis-order [26] Prognosis depends on the extent of renal

involvement The association is with autosomal recessive

polycystic kidney disease which usually presents shortly

after birth and generally is more serious than the

auto-somal dominant form The gene responsible has been

mapped to chromosome 6p21 Patients may die in the

perinatal period from renal failure This recessive form of

polycystic kidney disease is usually associated with

con-genital hepatic fibrosis Choledochal cysts may coexist

Adult polycystic disease

The liver cysts are probably developmental and quently associated with autosomal dominant polycystickidney disease Understanding of polycystic kidneydisease is more advanced than of the liver cysts At least

fre-three different genes appear to be responsible PKD-1 on

chromosome 16p13.3 expresses polycystin 1 which isthought to have a role in epithelial cell differentiationand maturation, and in cell–cell interactions [19, 20].Loss of function of this protein may be one prerequisitefor cyst formation but a further somatic event is thoughtnecessary

A second gene implicated in autosomal dominant

polycystic kidney disease is PKD-2 on chromosome

4q21–23 which expresses polycystin 2 Polycystin 1 and 2interact through their C-terminal cytoplasmic tails sug-gesting that they function together through a commonsignal link pathway Polycystic kidney disease type 2 isclinically milder than type 1

Polycystic liver disease is most often associated withautosomal dominant polycystic kidney disease althoughpolycystic liver may be an isolated finding and is geneti-cally linked to chromosome 19p13.2–13.1 [34]

The molecular mechanism for the formation of cysts isnot clear They may arise from the failure of supernumer-ary intra-hepatic bile ducts within the hepatic embryonicanlage to involute when the biliary system forms Whenthe original segment of blind bile ducts is replaced by asecond generation of highly active proliferating ducts,redundant ducts may become distorted and form cysts.The second-generation bile ducts are normal so there is

no biliary dysfunction

Pathology

Depending on the number and size of the cysts, the livermay be normal or greatly enlarged Cysts may be scat-tered diffusely or restricted to one lobe, usually the left

Table 33.1 The association of ductal plate malformations

(DPM) with fibropolycystic disease

Level in bile duct of DPM Disease

Small interlobular Childhood fibropolycystic disease

(association autosomal recessive polycystic disease)

Congenital hepatic fibrosis (fibrotic element ++)

Von Meyenberg complexes (dilatation = polycystic liver disease) Large interlobular Caroli’s disease

Both Caroli’s syndrome

Table 33.2 Hepatic fibropolycystic disease

Subtype Inheritance Presentation Hepatic Portal hypertension Renal* Childhood fibropolycystic

Ducts dilated +

Intra-hepatic biliary dilatation (Caroli’s) See text Cholangitis any age Dilated ducts only — —

* Percentage of tubules with cystic change.

The outer surface may be considerably deformed A cyst

may vary in size from a pin’s head to a child’s head, the

largest having a capacity of over 1 litre They are rarely

greater than 10 cm in diameter The larger ones are

prob-ably formed by rupture of septa between adjacent

cysts, and the cut liver may display a honeycomb

appearance The cavities are thin walled and contain

clear or brown fluid due to altered blood They never

contain bile because they are not in continuity with the

biliary tract They may be complicated by haemorrhage

or infection

Histologically (fig 33.3) the lobular architecture is

unchanged and the liver cells are normal The cystic

areas are related to the bile ducts and to biliary

micro-hamartomas in the portal areas They are surrounded

by a fibrous tissue capsule and lined by columnar or

cuboidal epithelium

Frequently, there is cystic disease of other organs,

including kidneys, spleen, pancreas, ovary and lungs

About half the patients with polycystic disease of the

liver have polycystic kidneys The majority (50–88%) of

patients with polycystic kidneys have a polycystic liver

[16] The prevalance of hepatic cysts increases with age,

being approximately 20% in the third decade rising to

75% in the seventh decade

Cyst fluid

Fluid has been obtained using needle aspiration under

ultrasound guidance [13] The constituents and sponse to secretin support the concept that cyst fluid isformed by functioning bile duct epithelium lining thecysts

re-Clinical features

In many patients the liver lesion is diagnosed tally during scanning or at autopsy Sometimes thepatient presents with some other disease or with poly-cystic kidneys

inciden-Patients with symptoms and signs are usually in the fourth or fifth decade The patient complains ofabdominal distension and dull abdominal pain Pressure

on the stomach and duodenum causes epigastric comfort, nausea, flatulence and occasional vomiting.Acute pain may be due to rupture of, or haemorrhageinto, a cyst

dis-Cysts tend to be larger in women who have been nant [17] Hormone replacement therapy is associatedwith an approximate 5% enlargement of the liver over ayear [37] There is no increase in symptoms On the basis

preg-of these data hormone replacement therapy is not held when clinically indicated [37]

with-Ascites, obstructive jaundice and hepatic venousoutflow obstruction [48] are rare

On examination the liver may be impalpable or solarge that it seems to fill the whole abdomen The edge isfirm and nodules can be palpated There may be diffi-culty in distinguishing cysts from other types of livernodule The spleen is not enlarged

Bilaterally enlarged irregular kidneys may suggest

associated renal cysts which may be symptomatic

Hepatic function is excellent because the liver cells are

preserved Serum alkaline phosphatase and g-GT may beincreased but bilirubin is normal

Portal venous obstruction rarely may result in phageal varices which bleed [39]

oeso-Imaging

Ultrasound is the most satisfactory method of diagnosis(fig 33.4) CT scanning (fig 33.5) is also useful in symp-tomatic patients with multiple cysts to show how muchnormal liver remains This helps with planning surgicaloptions

Differential diagnosis

Polycystic liver should be suspected in an apparentlywell person, often over 33 years of age, with nodularhepatomegaly, but no evidence of hepatic dysfunction,associated with polycystic kidney or a family history ofthis condition

Polycystic liver may be confused with hydatid disease

(Chapter 29)

Fig 33.3 Polycystic disease of the liver The cysts vary in size

and are lined by flattened epithelium (H & E, ¥ 63.)

Metastases are accompanied by malaise, weight loss,

rapid increase in size of the liver, and, possibly, evidence

of a primary neoplasm

Cirrhosis may be accompanied by signs of

hepato-cellular disease and the spleen is usually enlarged

Prognosis and treatment

Polycystic disease of the liver is compatible with long

life

The prognosis is determined by the extent of

associ-ated renal cystic disease Carcinoma is very rare Surgery

is rarely necessary and aspiration under ultrasoundcontrol is easy and effective in controlling acute symp-toms However, the fluid returns

There are several surgical techniques, the choice pending upon the extent of disease [18] Patients with

de-a limited number of lde-arge cysts mde-ay be trede-ated by stration which can be performed laparoscopically [23] Where there is localized involvement of the liverparenchyma by multiple medium-sized cysts but withadjacent large areas of normal parenchyma shown by

fene-CT, operative fenestration with or without hepatic tion produces symptomatic improvement in the major-ity [14, 33] In patients with massive diffuse involvement

resec-of the majority resec-of liver parenchyma by all sizes resec-of livercysts with only a small amount of normal parenchymabetween them, fenestration may be useful but carries ahigh morbidity and mortality In patients with severelimitation of daily activity and failed previous treatment,liver transplantation can be done (combined with kidneytransplantation if necessary) and has a 1-year survival of89% [41]

Successful liver transplantation has been reportedusing a donor liver with polycystic change [4]

Congenital hepatic fibrosis

This condition consists, histologically, of broad, denselycollagenous fibrous bands surrounding otherwisenormal hepatic lobules (fig 33.6) The bands containlarge numbers of microscopic, well-formed bile ducts(fig 33.7), some containing bile Arterial branches are normal or hypoplastic, while the veins appearreduced in size Inflammatory infiltration is not seen.Caroli’s syndrome may be associated, also choledochalcyst

The disease appears both sporadically and in a ial form It is inherited as autosomal recessive A ductalplate malformation of interlobular bile ducts has beensuggested as the pathogenetic mechanism [11]

famil-Portal hypertension is common Occasionally this may

be due to defects in the main portal veins More often it iscaused by hypoplasia or fibrous compression of portalvein radicles in the fibrous bands surrounding thenodules

Associated renal conditions include renal dysplasia,adult-type polycystic kidneys [6] and nephronophthisis(medullary cystic disease)

Fig 33.4 Adult polycystic liver: ultrasound shows numerous

echo-free space-occupying lesions.

Fig 33.5 CT scan (contrast enhanced) showing a polycystic

liver.

from oesophageal varices, a symptomless, large, very

hard liver or splenomegaly (fig 33.8)

There may be other congenital anomalies, especially of

the biliary system, with cholangitis [10]

Carcinoma, both hepato-cellular and

cholangiocarci-noma, may be a complication [2, 49] as may

adenoma-tous hyperplasia [3]

Congenital hepatic fibrosis is part of the rare disorder

reported with phosphomannose isomerase deficiency[15]

Investigations

Serum protein, bilirubin and transaminase levels areusually normal, but serum alkaline phosphatase valuesare sometimes increased

Liver biopsy is essential for diagnosis Because of the

tough consistency of the liver this may be difficult

Ultrasound shows very bright areas of echogenicity

due to the dense bands of fibrous tissue Direct giography in patients with congenital hepatic fibrosisalone shows tapered intra-hepatic radicals suggestingfibrosis MR cholangiography shows duct abnormalitiesincluding biliary cysts in some patients and this associa-tion with congenital hepatic fibrosis has been termedCaroli’s syndrome Choledochal cysts may also be seen[12]

cholan-Portal venography reveals the collateral circulation and

a normal or distorted intra-hepatic portal tree

Ultrasound, CT, MRI and intravenous pyelography may

show cystic renal changes or medullary sponge kidney

Prognosis and treatment

Congenital hepatic fibrosis must be distinguished from

Fig 33.6 Congenital hepatic fibrosis Broad bands of fibrous

tissue containing bile ducts separate and surround liver

lobules (Silver impregnation, ¥ 36).

Fig 33.7 Congenital hepatic fibrosis Portal area shows dense

mature fibrous tissue with a number of abnormal bile ducts

(H & E, ¥ 40.)

Fig 33.8 Girl of 8 years with hepatosplenomegaly discovered

at routine examination Liver biopsy showed congenital hepatic fibrosis Note normal development.

cirrhosis since hepato-cellular function is preserved and

the prognosis is considerably better

Following haemorrhage these patients are excellent

candidates for porta-caval anastomosis

Death can be due to renal failure, but renal

transplan-tation has been successful

Congenital intra-hepatic biliary dilatation

(Caroli’s disease) [42]

This rare disease is characterized by congenital,

seg-mental, saccular dilatations of the intra-hepatic bile

ducts without other hepatic histological abnormalities

The dilated ducts connect with the main duct system

and are liable to become infected and contain stones

(fig 33.9)

The inheritance of Caroli’s disease is uncertain [45]

Kidney lesions are usually absent, but renal tubular

ectasia and larger cysts have been associated

Clinical features

The condition presents at any age, but usually in childhood or early adult life, as abdominal pain,hepatomegaly, and fever with Gram-negative septi-caemia [8] About 75% are male

Jaundice is mild or absent but may increase during theepisodes of cholangitis Portal hypertension is absent

If the cyst is drained bile volumes may be high, andflow increased by an infusion of secretin which stimu-lates ductular secretion It is likely that the high restingflow arises from the cysts [46]

Imaging

Ultrasound may be helpful as may CT scanning (fig.33.10) where portal vein radicles can be seen afterenhancement within dilated intra-hepatic bile ducts (the

‘central dot’ sign) [5] MR cholangiography is diagnostic[1] as is more invasive endoscopic or percutaneouscholangiography (fig 33.9) The common bile duct isnormal, but the intra-hepatic ducts are marked bybulbous dilatations with normal ducts between Theabnormality may be unilateral [30] The appearancescontrast with those of primary sclerosing cholangitiswhere the common bile duct is irregular with stricturesand the intra-hepatic ducts show irregularities withdilatations

Cholangiocarcinoma may be a complication, reported

in about 7% of patients [9]

Prognosis

The prognosis is poor with survival varying between

a mean survival of 9 months [45] in one report to a

Fig 33.9 Caroli’s disease Endoscopic cholangiography

shows bulbous dilatations of the intra-hepatic bile ducts, some

of which contain multiple gallstones.

Fig 33.10 Caroli’s disease CT scan after intravenous contrast

shows dilated intra-hepatic bile ducts with adjacent enhanced radicles of the portal vein.

mortality over 5 years of 20% [8] Death is related to

septicaemia, liver abscess, liver failure and portal

hypertension

Treatment

Antibiotics are given to treat cholangitis Drainage of

the common bile duct, whether endoscopic or surgical,

may be required to remove calculi Intra-hepatic stones

have been successfully treated with ursodeoxycholic

acid [36]

Unilateral involvement may be treated by hepatic

resection [30] Hepatic transplantation must be

consid-ered, but infection is a relative contraindication

The prognosis is poor but episodes of cholangitis can

extend over many years

Death from renal failure is very unusual

Congenital hepatic fibrosis and Caroli’s disease

Caroli’s disease often coexists with congenital hepatic

fibrosis [40] and is then designated Caroli’s syndrome.

Both result from malformations of the embryonic ductal

plate at different levels of the biliary tree Inheritance

is autosomal recessive Presentation may be as

ab-dominal pain and cholangitis or as haemorrhage from

oesophageal varices (fig 33.11)

Choledochal cyst

This describes cystic dilatation of all or part of the

extra-hepatic biliary tree with or without associated

cystic change of intra-hepatic bile ducts When the

common duct itself is involved, the gallbladder, cystic

duct and proximal hepatic ducts are not dilated, as

distinct from the pattern of dilatation of the whole

biliary tree above an obstructing lesion Caroli’s

disease may coexist Histologically the cyst wall

consists of fibrotic tissue with acute and chronic

inflammation

No unifying pathological process explains all cysts

Some are associated with a long common channel

between the pancreatic duct and the bile duct which

pre-disposes to the reflux of pancreatic enzymes [24] Many

patients, however, do not have this anomaly There may

be infective and molecular genetic factors Reovirus

RNA was detected in tissue taken from eight out of

nine infants and children with choledochal cysts [47]

Choledochal cysts may be found in patients with other

fibropolycystic disease raising the possibility of a

devel-opmental anomaly

Choledochal cysts are classified as follows (fig 33.12)

[27, 28]

Type I: cystic (Ia), segmental (Ib) or fusiform (Ic)

dilata-tion of the extra-hepatic bile duct A further group (Id)has been suggested with multiple extra-hepatic cysts.Differentiation between the fusiform type and dilata-tion of the bile duct secondary to obstruction is based

on the absence of a previous history of gallstones orbiliary surgery, a common bile duct diameter greaterthan 30 mm, and the presence of an anomalous bileduct junction shown on cholangiography [27]

Type II: the cyst forms a diverticulum from the

extra-hepatic bile duct

Type III: there is cystic dilatation (choledochocele) of the

distal common bile duct lying mostly within the denal wall

duo-Type IV: this comprises type I anatomy together with

intra-hepatic bile duct cysts It has been proposed thatIVa, IVb and IVc describe this picture with cystic, seg-mental or fusiform change of the extra-hepatic biliarytree [27]

When used, type V denotes Caroli’s disease

The commonest types are I and IV [27, 28] Whethercholedochocele (type III) should be classified as a chole-dochal cyst has been questioned [38]

Rarely a solitary cystic dilatation of an intra-hepaticbile duct is seen [43]

The type I lesion presents as a partially

30 20

10 0

Age (years)

Fig 33.11 The evolution of symptoms in five patients (I–V)

with coexistent congenital hepatic fibrosis and Caroli’s disease who had both variceal haemorrhages and cholangitis.

Haemorrhage always occurred first, followed, a mean of 10 years later, by cholangitis PCS, porta-caval shunt [40].

toneal, cystic tumour varying from 2 to 3 cm in size, to a

capacity of 8 litre The cyst contains thin, dark brown

fluid It is sterile but may become secondarily infected

The cyst can burst

Biliary cirrhosis is a late complication Choledochal

cysts may obstruct the portal vein leading to portal

hypertension Malignant tumours in the cyst or bile

ducts may develop [28]

Clinical features

The infantile form presents as prolonged cholestasis In

infancy the cyst may perforate causing bile peritonitis

Later the classical symptoms are intermittent jaundice,

pain and an abdominal tumour Children are more likely

to have two or more of this ‘classical’ triad than adults

(82 vs 25%) [28] Although formerly regarded as a

child-hood disease, the diagnosis is now more often made in

adult life One-quarter of individuals affected present

with symptoms and signs of pancreatitis [28]

Chole-dochal cysts appear more frequently in the Japanese and

other Oriental races

The jaundice is intermittent, of cholestatic type, and

associated with fever The pain is colicky and mainly

experienced in the right upper abdomen The tumour is

cystic and in the right upper quadrant of the abdomen It

characteristically varies in size and in tenseness

Choledochal cysts may be associated with

congenit-al hepatic fibrosis or Caroli’s disease Anomcongenit-alous

pancreatico-biliary drainage is important particularly if

the duct junction is right-angular or acute [32]

Imaging

Plain X-ray of the abdomen may show a soft-tissue mass

HIDA scanning, ultrasound and CT can show the cysticlesion but magnetic resonance cholangiography (MRCP)

is an effective approach and is the first choice imagingtechnique for examining these cysts (fig 33.13) [21, 25]

It does not, however, remove the need for other proaches including endoscopic retrograde cholangio-pancreatography (ERCP) in some patients [21]

of the common bile duct

Type III: Diverticulum within duodenal wall

Type IV: Type I with intra-hepatic bile duct cysts

Fig 33.12 Classification of congenital biliary dilatation

(choledochal cyst) (IVb is type I plus III).

Fig 33.13 MR cholangiogram in a 40-year-old woman with a

type Ia choledochal cyst The patient presented with acute pancreatitis.

choice [22, 28] Biliary tract continuity is maintained by

choledocho-jejunostomy with Roux-en-Y anastomosis

Anastomosis of the cyst to the intestinal tract without

excision is simpler but post-operative cholangitis and

subsequent biliary stricturing and stone formation are

frequent The risk of carcinoma remains, perhaps related

to dysplasia and metaplasia of the epithelium [44]

Microhamartoma (von Meyenberg complexes)

These are usually asymptomatic, diagnosed incidentally

or found at autopsy Rarely, they may be associated with

portal hypertension Kidneys may show medullary

sponge change Microhamartomas can be associated

with polycystic disease

Histologically, microhamartomas consist of groups of

rounded biliary channels, lined by cuboidal epithelium

and often containing inspissated bile (fig 33.14) These

biliary structures are embedded in mature collagenous

stroma They are usually located in, or near, portal tracts

The appearances suggest congenital hepatic fibrosis, but

in a localized form

Imaging

In a hepatic arteriogram, multiple microhamartomas

lead to stretching of the arteries and blushing in the

venous phase

Carcinoma secondary to fibropolycystic disease

Tumours may arise in association with

microhamar-tomas, congenital hepatic fibrosis, Caroli’s disease [9],

and choledochal cyst [28] Carcinoma is rare in

associa-tion with non-parasitic cysts [31] or polycystic liver

disease Malignant change is more likely where lium is exposed to bile

epithe-Solitary non-parasitic liver cyst

This is being increasingly diagnosed due to the increase

in various scanning techniques It is probably a variant

of polycystic disease

The lining wall has partitions, which suggest an originfrom conglomerate polycystic disease The fibrouscapsule contains aberrant bile ducts and blood vessels.The contents vary from colourless to brown alteredblood The tension is low in contrast to the high pressure

of hydatid cysts

Symptoms are rare and related to abdominal sion, or pressure effects on adjacent organs including thebile ducts, causing intermittent jaundice The patientshould be reassured

disten-Symptoms follow rupture or haemorrhage into thecyst These events are extremely rare Surgical excision isindicated only for complications

Other cysts

These are all very rare, small and superficial Their tents vary with the cause Bile cysts may follow pro-longed extra-hepatic biliary obstruction of all types.Blood cysts follow haemorrhage into a simple cyst.They can also follow trauma to the liver Small cysticspaces containing blood may follow needle biopsy.Lymphatic cysts are due to obstruction or congenitaldilatation of liver lymphatics They are usually on thesurface of the liver

con-Biliary cystadenoma and cystadenocarcinoma are rare(Chapter 31) Malignant pseudocysts from degeneration

Fig 33.14 Microhamartoma of the liver.

Groups of biliary channels are lined by

cuboidal epithelium and are embedded in

mature fibrous tissue [40] (H & E, ¥ 180.)

and softening of secondary malignant growths also

occur

Congenital anomalies of the biliary tract

The liver and biliary tract develop from a bud-like

out-pouching of the ventral wall of the primitive foregut just

cranial to the yolk sac Two solid buds of cells form the

right and left lobes of the liver while the original

elon-gated diverticulum forms the hepatic and common bile

duct The gallbladder arises as a smaller bud of cells

from this same diverticulum The biliary tract is patent

in early intra-uterine life but becomes solid later by

epi-thelial proliferation within the lumen Eventually

re-vacuolization takes place, starting simultaneously in

different parts of the solid gallbladder bud and

spread-ing until the whole system is recanalized At 5 weeks the

ductal communications of gallbladder, cystic duct and

hepatic ducts are completed and at 3 months the fetal

liver begins to secrete bile

The majority of the congenital anomalies can be

related to alterations in the original budding from the

foregut or to failure of vacuolization of the solid

gall-bladder and bile diverticulum (table 33.3)

These congenital defects are usually of no importance

and cannot be related to symptoms Occasionally bile

duct anomalies lead to bile stasis, inflammation and

gall-stones [7] They are of importance to the radiologist and

to the biliary and hepatic transplant surgeon

Anomalies of the biliary tree and liver may be

associ-ated with congenital lesions elsewhere, including

cardiac defects, polydactyly and polycystic kidneys

They can also be related to maternal virus infections,

such as rubella

Absence of the gallbladder[35]

This is a rare congenital anomaly Two types can be

recognized

Type I is the failure of the gallbladder and cystic duct to

develop as an outgrowth from the hepatic

diverticu-lum of the foregut This type is often found with other

anomalies of the biliary passages

Type II is the failure of the gallbladder to vacuolize from

its solid state This is usually associated with atresia

of the extra-hepatic ducts The gallbladder is not

absent but rudimentary This type is therefore found in

infants who present the picture of congenital biliary

atresia

Most cases occur in infants with other major

congeni-tal anomalies Adults are usually healthy and without

other anomalies Some have right upper quadrant pain

or jaundice The inability to show the gallbladder on

ultrasound may be interpreted as gallbladder disease

and lead to surgery The possibility of agenesis or an

ectopic location must be considered Cholangiographyshould be diagnostic Failure to identify the gallbladder

at operation is not proof of its absence The gallbladdermay be intra-hepatic, buried in extensive adhesions, oratrophied following previous cholecystitis

An intraoperative cholangiogram should be done

Double gallbladder

Double gallbladder is very rare In embryonic life, littlepockets often arise from the hepatic or common bileducts Occasionally these persist and form a second gall-bladder having its own cystic duct (fig 33.15) This mayenter the hepatic substance directly If the pouch formsfrom the cystic duct the two gallbladders share a Y-shaped cystic duct

Double gallbladder can be recognized by imaging.The accessory organ is frequently diseased

Bilobed gallbladder is an extremely rare congenital

anomaly Embryologically, the single bud forming the

Table 33.3 Classification of congenital anomalies of the

biliary tract

Anomalies of the primitive foregut bud

Failure of bud absent bile ducts absent gallbladder Accessory buds or splitting of bud accessory gallbladder

bilobed gallbladder accessory bile ducts Bud migrates to left instead of right left-sided gallbladder

Anomalies of vacuolization of the solid biliary bud

Defective bile duct vacuolization Congenital obliteration of bile ducts Congenital obliteration of cystic duct Choledochal cyst

Defective gallbladder vacuolization rudimentary gallbladder Fundal diverticulum Serosal type of Phrygian cap Hour-glass gallbladder

Persistent cysto-hepatic duct

Diverticulum of body or neck of gallbladder

Persistence of intra-hepatic gallbladder

Aberrant folding of gallbladder anlage

Retroserosal type of Phrygian cap

Accessory peritoneal folds

Congenital adhesions Floating gallbladder

Anomalies of hepatic and cystic arteries

Accessory arteries Abnormal relation of hepatic artery to cystic duct

gallbladder becomes paired but primary connection is

maintained, thus forming two separate and distinct

fundi with a single cystic duct

The anomaly is of no clinical significance

Accessory bile ducts

These are rare The extra duct is usually a subdivision of

the right hepatic system and joins the common hepatic

duct somewhere between the junction of the main right

and left hepatic ducts and the entry of the cystic duct

(fig 35.1c) It may, however, join the cystic duct, the bladder or the common bile duct

gall-Cholecysto-hepatic ducts are due to persistence of fetal

connections between the gallbladder and the liverparenchyma with failure of re-canalization of the rightand left hepatic ducts Continuity is maintained by thecystic duct entering a remaining hepatic duct or commonhepatic duct or the duodenum directly

Accessory ducts are of importance to the biliary andtransplant surgeon as they may be inadvertently ligated

or cut with resultant biliary stricture or fistula

Two cystic ducts

Diverticula

Folded gallbladder

Hour-glass gallbladder

Intra-hepatic gallbladder Retroserosal

Infundibulum

Body

Serosa

Phrygian cap Neck

Floating gallbladder

Fig 33.15 Congenital anomalies of the

gallbladder.

Left-sided gallbladder

In this rare anomaly the gallbladder lies under the left

lobe of the liver, to the left of the falciform ligament

This may be caused by the gallbladder migrating to a

position under the left lobe of the liver (to the left of the

round ligament) The path of the cystic duct is normal

Alternatively a second gallbladder may develop directly

from the left hepatic duct with failure of development or

regression of the normal structure on the right side A

left-sided gallbladder formed in this way is of little

clini-cal significance

In some cases however, a left-sided gallbladder may

be described as such because of its relationship to the

round ligament (‘a right-sided round ligament’) In these

cases the gallbladder is in its normal site The right-sided

round ligament anomaly is important because it is

associated with abnormal intra-hepatic portal venous

branching This is important to recognize when

perform-ing hepatectomy [29]

Rokitansky–Aschoff sinuses of the gallbladder

These consist of hernia-like protrusions of the

gall-bladder mucosa through the muscular layer

(intra-mural diverticulosis) Although potentially congenital

they are particularly prominent with chronic

cholecysti-tis when intraluminal pressure rises They may be seen

in an oral cholecystogram as a halo-like stippling

sur-rounding the gallbladder

Folded gallbladder

The gallbladder is deformed so that the fundus appears

folded ‘bent down to the breaking point after the manner

of a Phrygian cap’ A Phrygian cap is a conical cap or

bonnet, with the peak bent or turned over in front, worn

by the ancient Phrygians, and identified with the Cap of

Liberty (Oxford English Dictionary).

Two varieties are recognized:

1 Kinking between body and fundus (retroserosal Phrygian

cap) (fig 33.15) This is due to aberrant folding of the

gall-bladder within the embryonic fossa

2 Kinking between body and infundibulum (serosal Phrygian

cap) (fig 33.15) This is due to aberrant folding of the

fossa itself in the early stages of development The bend

in the gallbladder is fixed by development of fetal

liga-ments, vestigial septa or constrictions of the lumen

fol-lowing delayed vacuolization of the solid epithelial

anlage

These kinked gallbladders empty at a normal rate and

are of no clinical significance The importance lies in the

correct interpretation of the cholecystograms

Hour-glass gallbladder (fig 33.15) This probably

repre-sents an exaggerated form of Phrygian cap, presumably

of the serosal type The constancy of position of thefundus during contraction and the small size of theopening between the two parts indicate that this is probably a fixed, congenital malformation

Diverticula of the gallbladder and ducts

Diverticula of the body and neck may arise from persistent

cysto-hepatic ducts which run in embryonic life betweenthe gallbladder and the liver

The fundal variety arises from incomplete vacuolization

of the solid gallbladder of embryonic life An incompleteseptum pinches off a small cavity at the tip of the gall-bladder (fig 33.15)

These diverticula are rare and of no clinical cance The congenital variety should be distinguished

signifi-from pseudo-diverticula developing in the diseased

gall-bladder as a result of partial perforation The diverticulum in these cases usually contains a largegallstone

pseudo-Intra-hepatic gallbladder

The gallbladder is included and buried in hepatic tissue

up to the second month of intra-uterine life, thereafterassuming an extra-hepatic position In some instancesthe intra-hepatic condition may persist (fig 33.15) Thegallbladder is higher than normal and more or lessburied but never entirely covered by liver tissue It is fre-quently diseased, for the embedded organ has difficulty

in contracting and so becomes infected, with subsequentgallstone formation

Congenital adhesions to the gallbladder

These are very frequent Developmentally these toneal sheets are due to an extension of the anteriormesentery, which forms the lesser omentum The sheetmay run from the common bile duct laterally over thegallbladder down to the duodenum, to the hepaticflexure of the colon and even to the right lobe of the liver,perhaps closing the foramen of Winslow In a milderform, a band of tissue runs from the lesser omentumacross to the cystic duct and anterior to the gallbladder;

peri-or a loose veil fperi-orms a mesentery to the gallbladder(‘floating gallbladder’) (fig 33.15)

These adhesions are of no clinical importance cally, their presence should be remembered, so that theyare not mistaken for inflammatory adhesions

Surgi-Floating gallbladder and torsion of the gallbladder

The gallbladder possesses a supporting membrane in4–5% of specimens The peritoneal coat surrounding thegallbladder continues as two approximated leaves to

form a fold or mesentery to support the gallbladder from

under the surface of the liver This fold may allow the

gallbladder to hang as much as 2–3 cm below the inferior

hepatic surface

The mobile gallbladder is apt to twist, and torsion

results The blood supply is impaired in the small pedicle

and infarction follows

The condition usually occurs in thin, elderly women

With ageing, omental fat lessens and there is a great

caudal displacement of abdominal viscera due to loss

of tone in the abdominal and pelvic muscles The

gall-bladder with mesentery becomes more pendulous and

can twist It can affect all ages, including children

Torsion is followed by sudden, severe, constant

epi-gastric and right costal margin pain passing through to

the back with vomiting and collapse Characteristically a

palpable tumour appears, having the features of an

enlarged gallbladder Within a few hours it may

disap-pear The treatment is cholecystectomy

Recurrent partial torsion leads to acute episodes

Ultra-sound or CT shows a gallbladder situated low in the

abdomen and even in the pelvis It is suspended by

a very long, down-curved cystic duct Early

cholecystec-tomy is indicated

Anomalies of the cystic duct and cystic artery

In 20% of subjects the cystic duct does not join the

common hepatic duct directly but first runs parallel to it,

lying in the same sheath of connective tissue

Occasion-ally it makes a spiral turn around the duct

These variations are extremely important to the

sur-geon Unless the cystic duct is carefully dissected and its

union with the common hepatic duct identified, the

common hepatic duct may be ligated, with disastrous

consequences

The cystic artery can arise not, as normally, from the

right hepatic artery but from the left hepatic artery or

even from the gastroduodenal artery Accessory cystic

arteries usually arise from the right hepatic artery

Again, the surgeon must be careful to identify the cystic

artery precisely

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Composition of gallstones

There are three major types of gallstone: cholesterol,

black pigment and brown pigment (fig 34.1, table 34.1)

In the Western world most are cholesterol stones

Although these consist predominantly of cholesterol

(51–99%) they, along with all types, have a complex

content and contain a variable proportion of other

com-ponents including calcium carbonate, phosphate,

biliru-binate and palmitate, phospholipids, glycoproteins and

mucopolysaccharides Crystallography confirms that

the cholesterol is in monohydrate and anhydrous forms

The nature of the nucleus of the stone is uncertain —

pigment, glycoprotein and amorphous material have all

been suggested

The problem is to explain how in normal individuals

insoluble cholesterol is kept in solution in bile, and what

in other people leads to its precipitation to form

gallstones

Composition of bile

Biliary cholesterol is in the free unesterified form

Concen-tration is unrelated to serum cholesterol level and

depends only to a limited extent on the bile acid pool size

and bile acid secretory rate

Biliary phospholipids These are insoluble in water

and include lecithin (90%) with small quantities of

lysolecithin (3%) and phosphatidyl ethanolamine (1%).Entry of phospholipid into bile depends upon a canalic-ular protein that acts as a ‘flippase’ which is encoded by

the MDR3 gene (Chapter 13) Transgenic knockout mice

in which the analogous gene has been deleted are pable of secreting phospholipid (and cholesterol) intobile [173] Bile acid secretion remains normal

inca-Phospholipids are hydrolysed in the gut and there is

no entero-hepatic circulation Bile acids determine tion and enhance synthesis

excre-Bile acids The primary bile acids are the trihydroxy,

cholic acid and the dihydroxy, chenodeoxycholic acid.These are conjugated with glycine and taurine They areconverted by bacterial action, usually in the colon, to thesecondary bile acids, deoxycholic acid and lithocholicacid Cholic, cheno- and deoxycholic acids are absorbedand undergo an entero-hepatic circulation which takesplace 6–10 times daily [48] Lithocholic acid is poorlyabsorbed and there is little to be found in the bile Thetotal bile acid pool is normally 2.5 g and the averagedaily production of cholic acid is about 330 mg and chenodeoxycholic acid 280 mg

The control of bile acid synthesis is complex; it is probably a negative feedback mechanism through theamount of bile salts and cholesterol reaching the liverfrom the gut Bile acid synthesis is decreased by adminis-tration of bile salts and increased by interruption of theentero-hepatic circulation

597

Chapter 34 Gallstones and Inflammatory Gallbladder Diseases

Table 34.1 Classification of gallstones

Cholesterol Black pigment Brown pigment Location Gallbladder, ducts Gallbladder, ducts Ducts

Major constituents Cholesterol Bilirubin pigment Calcium bilirubinate

polymer Consistency Crystalline with Hard Soft, friable

nucleus

Associations

Other diseases See fig 34.2 Haemolysis, cirrhosis Chronic partial biliary

obstruction

Factors in cholesterol gallstone

formation[47, 49]

Three major factors determine the formation of

choles-terol gallstones These are: altered composition of

hepatic bile, nucleation of cholesterol crystals and

impaired gallbladder function (fig 34.2) Hepatic bile

supersaturated with cholesterol and with an increasedproportion of deoxycholic acid favours stone formation

Altered hepatic bile composition

Bile is 85–95% water Cholesterol, which is insoluble inwater and must be maintained in solution, is secretedfrom the canalicular membrane in unilamellar phospho-

lipid vesicles (fig 34.3) Whether cholesterol remains in

solution depends upon the concentration of lipids and bile acids in bile, and also the type of phos-pholipid and bile acid present

Fig 34.1 (a) Two faceted cholesterol gallstones The fragment

above shows the concentric structure formed as layer upon

layer of cholesterol crystals aggregate (b) Stones removed

from the common bile duct (ch, cholesterol gallstone; p, brown

pigment stone) (c) Black pigment gallstones.

SUPERSATURATED BILE Age Sex Genetics Obesity Drugs Diet Liver disease

ABSORPTION/

ENTERO-HEPATIC CIRCULATION

OF BILE ACIDS Deoxycholate Bowel transit time Faecal flora Ileal resection Cholestyramine

Fig 34.2 Major factors in cholesterol

gallstone formation are supersaturation

of the bile with cholesterol, increased deoxycholate formation and absorption, cholesterol crystal nucleation and impaired gallbladder function.

Vesicle

Cholesterol Lecithin

Fig 34.3 Structure of mixed micelles and

cholesterol/phospholipid vesicles.

Nucleation

Biliary cholesterol

Unilamellar vesicles (unstable)

Multilamellar vesicle

Cholesterol ++

Bile acid ±

Fig 34.4 Pathway for cholesterol crystallization in bile.

In hepatic bile unsaturated with cholesterol and

con-taining sufficient bile acid, the vesicles are solubilized

into mixed lipid micelles These have a hydrophilic

exter-nal surface and a hydrophobic interior Cholesterol is

incorporated into the hydrophobic interior

Phospho-lipids are inserted into the walls of the micelles so that

they grow These ‘mixed micelles’ are thus able to hold

cholesterol in a stable thermodynamic state This is

the situation with a low cholesterol saturation index

(derived from the molar ratio of cholesterol, bile acid and

phospholipids)

When bile is supersaturated with cholesterol, or bile

acid concentrations are low (a high cholesterol

satura-tion index), the excess cholesterol cannot be transported

in mixed micelles and unilamellar phospholipid vesicles

remain (fig 34.4) These are not stable and can aggregate

Large multilamellar vesicles form from which

choles-terol crystals may nucleate This process involves a

sequence of complex events involving several different

types of vesicle, micelle and disc [96] Cholesterol

pre-cipitates in many forms including filaments, helices and

tubules of non-hydrated cholesterol as well as

character-istic plates of monohydrate cholesterol [145]

The type of bile acid present in bile influences

gall-stone formation A higher proportion of deoxycholate isfound in gallstone patients This is a more hydrophobicbile salt and when secreted into bile extracts more chol-esterol from the canalicular membrane increasing cholesterol saturation It also accelerates cholesterolcrystallization

Deoxycholate is derived from dehydroxylation ofcholic acid in the colon by faecal bacteria There is anentero-hepatic circulation The amount of deoxycholatepresent in the bile acid pool depends upon the largebowel transit time, which when increased (as in patientswith acromegaly treated with octreotide) correlates withincreased serum deoxycholic acid [196] Other factorsaffect the amount of deoxycholate formed Gallstonepatients have significantly prolonged small boweltransit times [6] and increased bacterial dehydroxylatingactivity in faeces [203]

Thus many factors affect the concentration and type

of bile acid and phospholipid in bile, and the amount

of cholesterol The process of gallstone formation is

complex and many areas remain unclear [137] The

com-plexity is demonstrated by the finding that although

cholesterol supersaturation is a prerequisite for gallstone

formation, it does not alone explain the pathogenesis

Other factors must be important since bile

supersatu-rated with cholesterol is frequently found in individuals

without cholesterol gallstones [76].

Nevertheless, in most gallstone sufferers in the

Western world, gallstone formation can be related to

supersaturation of bile with cholesterol There is

hyper-secretion of biliary cholesterol Bile acid output is normal

despite a reduced total body pool of bile acids,

presum-ably because of a more rapid intra-hepatic cycling than

normal Increased biliary cholesterol leads to

gallblad-der hypomotility with increased mucin secretion by the

epithelial lining To what extent cholesterol

hypersecre-tion influences other factors in gallstone formahypersecre-tion is

conjectural [3]

Cholesterol nucleation

Nucleation of cholesterol monohydrate crystals from

multilamellar vesicles is a crucial step in the process

leading to gallstone formation The distinguishing

feature between those who form gallstones and those

who do not, is the ability of the bile to promote or inhibit

nucleation rather than the degree of cholesterol

super-saturation The time taken for this process (‘nucleation

time’) is significantly shorter in those with gallstones

than in those without and in those with multiple as

opposed to solitary stones [87] The interactions

result-ing in nucleation are complex Biliary protein

concentra-tion is increased in lithogenic bile [91, 178] Proteins

which accelerate nucleation (pro-nucleators) are

gall-bladder mucin [201], amino-peptidase-N [134], an a1

acid glycoprotein [1], immunoglobulin and

phospholi-pase C [137] Some studies suggest that mucin gel rather

than soluble biliary glycoproteins promote cholesterol

crystallization [201] Aspirin reduces mucus

biosynthe-sis by gallbladder mucosa [152] which explains why this

drug and other non-steroidal anti-inflammatory drugs

inhibit gallstone formation [77]

Factors that slow nucleation (inhibitors) include

apolipoprotein A1 and A2 [92] and a 120-kDa

glycopro-tein [136] The interplay of pH and calcium iron

con-centration in stone formation in vivo remains to be

established [142]

Ursodeoxycholic acid, as well as decreasing

choles-terol saturation, also prolongs the nucleating time,

which may have implications in the prevention of

gall-stone recurrence [145]

Fatty acid/bile acid conjugates inhibit cholesterol

crystallization in bile experimentally [66] because of the

cholesterol solubilizing activity of long-chain-free fattyacids Conjugation with bile acid subserves hepaticuptake and biliary secretion

Cholesterol gallstones have bilirubin at their centre,and a protein pigment complex might provide thesurface for nucleation of cholesterol crystals from gallbladder bile

Gallbladder function

The gallbladder fills with hepatic bile during fasting,concentrates the bile and injects the concentrated bileinto the duodenum during a meal It must be capable ofemptying so as to clear itself of sludge and debris thatmight initiate stone formation, particularly in the patientwith bile supersaturated with cholesterol and a shortnucleation time

Hepatic bile is stored in the gallbladder and trated by the absorption of Na+, Cl–and HCO3 with anearly isotonic amount of water Active transport ofsodium and chloride by the mucosa is coupled toosmotic water absorption via intercellular and paracel-lular routes The concentration of bile salts, bilirubin andcholesterol, for which the gallbladder wall is essentiallyimpermeable, may rise 10-fold or more The concentra-tion of these constituents does not, however, rise in par-allel and the cholesterol saturation index may decreasewith concentration of bile because of the absorption

concen-of some cholesterol The calcium carbonate saturationindex also falls because of acidification [170]

Gallbladder contraction is under cholinergic and

hor-monal control Cholecystokinin (CCK), derived from the

intestine, contracts and empties the gallbladder andincreases mucosal fluid secretion with dilution of gall-

bladder contents Atropine reduces the contractile response of the gallbladder to CCK [79] Loxiglumide, a

selective CCK antagonist, inhibits both post-prandialgallbladder emptying and gallbladder contractioninduced by the CCK analogue ceruletide Other hor-mones found to have an influence on the gallbladderinclude motilin (stimulatory) and somatostatin

(inhibitory)

The relationship between impaired gallbladder tying and the increased incidence of gallstones inpatients on long-term parenteral nutrition and in preg-nant women has suggested that gallbladder stasis has arole in the formation of gallstones [191] Studies of gall-bladder motor function in patients with cholesterolstones have been conflicting This probably relates to the technique used (ultrasound vs scintigraphy) andpatient variation In general, patients with gallbladderstones have increased fasting and post-prandial gall-bladder volumes [143] Detailed analysis using simulta-neous ultrasound and scintigraphy has challenged theconventional view of gallbladder function and shown adifference between normal and gallstone patients [85]

emp-The concept of the gallbladder emptying after eating

and then subsequently refilling to await the next meal

appears oversimplified Calculations from ultrasound

and scintigraphic studies suggest continuous turnover

of bile due to concurrent filling and emptying of the

gall-bladder This turnover of gallbladder bile is reduced in

patients with gallbladder disease [85] encouraging bile

stasis and an environment in which nucleation and

crys-tallization of cholesterol is likely to occur Whether these

changes are due to an alteration in gallbladder wall

contractility and tone, or cystic duct resistance, is not

clear

Gallbladder muscle strips exposed to bile containing

excess cholesterol have a reduced contractile response to

CCK [12] Reduced contraction may relate to a reduction

in the number of receptors for CCK in the muscle of the

gallbladder wall [204]

Cholesterol crystallization and the formation of biliary

sludge predate gallstone formation and therefore

what-ever the mechanism may be, impaired gallbladder

emptying will encourage stone formation

Biliary sludge

Biliary sludge is a viscous suspension of a precipitate

which includes cholesterol monohydrate crystals,

calcium bilirubinate granules and other calcium

salts/sludge [95] It usually forms as a result of reduced

gallbladder motility related to decreased food intake or

parenteral nutrition It may also occur when the

sympa-thetic nerve supply is interrupted [182] After formation,

sludge disappears in 70% of patients [84] Twenty per cent

of patients develop complications of gallstones or acute

cholecystitis Whether treatment of sludge would reduce

the incidence of complications is not known

Role of infection

Although infection is thought to be of little importance

in cholesterol stone formation, bacterial DNA is found in

these stones [181] Conceivably, bacteria might

deconju-gate bile salts, allowing their absorption and reducing

cholesterol solubility

Biliary infection plays a role in brown pigment stone

formation, the majority containing bacteria on electron

microscopy [105]

Age

There is a steady increase in gallstone prevalence with

advancing years, probably due to the increased

choles-terol content in bile By age 75, 20% of men and 35% of

women have gallstones Clinical problems present most

frequently between the age of 50 and 70

Gallstones of both pigment and cholesterol type are

in patients undergoing cholecystectomy than thosewithout gallstones [18] The presence of apoE4 predictsrapid stone recurrence after extracorporeal shock-wavelithotripsy [144] The mechanism is unclear althoughapolipoprotein E may play a role in dietary lipid absorp-tion, transport and tissue distribution ApoE4 is notrelated to the development of new gallstones duringpregnancy [94]

In animals genes conferring susceptibility to stones are known and studies of human homologues areawaited [100]

gall-Sex and oestrogens

Gallstones are twice as common in women as in men,and this is particularly so before the age of 50

The incidence is higher in multiparous than in parous women Incomplete emptying of the gallbladder

nulli-in late pregnancy leaves a large residual volume and thusretention of cholesterol crystals Biliary sludge occurs fre-quently in pregnancy but is generally asymptomatic anddisappears spontaneously after delivery in two-thirds[119] In the post-partum period gallstones are present in8–12% of women (nine times that in a matched group)[190] One-third of those with a functional gallbladderare symptomatic Small stones disappear spontaneously

in 30%

The bile becomes more lithogenic when women areplaced on birth control pills [13] Women on long-termoral contraceptives have a two-fold increased incidence

of gallbladder disease over controls [20] menopausal women taking oestrogen-containing drugshave a highly significant (2.5 times) increase in gallblad-der disease [21] In men given oestrogen for prostatic carcinoma the bile becomes saturated with cholesteroland gallstones may form [73]

Post-Obesity

This seems to be more common among gallstone ferers than in the general population [111] and is a partic-ular risk factor in women less than 50 years old Obesity

suf-is associated with increased cholesterol synthessuf-is [175].There are no consistent changes in post-prandial gall-bladder volume 50% of markedly obese patients havegallstones at surgery

Dieting (2100 kJ/day) can result in biliary sludge andthe formation of symptomatic gallstones in obese indi-viduals [107] The addition of a small amount of fat in the

diet to maintain gallbladder emptying may reduce the

risk of gallstone formation [63]

Gallstone formation during weight loss following

gastric bypass surgery for obesity is prevented by giving

ursodeoxycholic acid [180]

Dietary factors

In Western countries, gallstones have been linked to

dietary fibre deficiency and a longer intestinal transit

time [71] This increases deoxycholic acid in bile, and

renders it more lithogenic [196] A diet low in

carbohy-drate and a shorter overnight fasting period protects

against gallstones, as does a moderate alcohol intake in

males [5] Vegetarians get fewer gallstones irrespective

of their tendency to be slim [141]

Increasing dietary cholesterol increases biliary

choles-terol but there is no epidemiological or dietary data to

link cholesterol intake with gallstones Indeed, newly

synthesized cholesterol is probably a more important

source of biliary cholesterol

Serum factors

The highest risk of gallstones (both cholesterol and

pigment) is associated with low HDL levels and high

triglyceride levels which may be more important than

body mass [4, 185] High serum cholesterol is not a

deter-minant of gallstone risk

Epidemiology(table 34.2)

In the Western world the prevalence of gallbladder

stones is about 10% In the United States more than 20

million people are estimated to have gallbladder disease

The prevalence in non-Hispanic white men is greater

than in non-Hispanic black men (8.6 vs 5.3%) [56] The

prevalence in women is twice that in men Black Africans

and the Eastern world are largely free of stones The

prevalence, however, is rising as lifestyles change In

Japan, the change from traditional to Western diets has

been associated with a change from bilirubin to

choles-terol gallstones

American Indians have the highest known prevalence

This is related to supersaturation of the bile with

choles-terol [199] In Chile, the prevalence of gallstones is

great-est (35%) in Mapuches This relates to their strong

Amerindian ancestry [126]

Cirrhosis of the liver

About 30% of patients with cirrhosis have gallstones

The risk of developing stones is most strongly associated

with Child’s grade C and alcoholic cirrhosis with a

yearly incidence of about 5% [58] The mechanisms

are uncertain All patients with hepato-cellular diseaseshow a variable degree of haemolysis Although bile acidsecretion is reduced, the stones are usually of the blackpigment type Phospholipid and cholesterol secretionare also lowered so that the bile is not supersaturated.Cholecystectomy and bile duct exploration are poorlytolerated, liver failure being frequently precipitated.Such operations should be done only for life-threateningcomplications of biliary tract disease, such as empyema

or perforation Endoscopic sphincterotomy is indicatedfor bile duct stones

Other factors

Diabetes mellitus is more frequent in individuals with

gallstone disease [41] Diabetics have a higher lence of gallstones (or a history of cholecystectomy) thannon-diabetics [27] Hyperinsulinaemia may play a role ingallstone formation [127, 157]

preva-Ileal resection breaks the entero-hepatic circulation of

bile salts, reduces the total bile salt pool and is followed

by gallstone formation The same is found in subtotal ortotal colectomy [117]

Gastrectomy increases the incidence of gallstones [82] Long-term cholestyramine therapy increases bile salt

loss with a reduced bile acid pool size and gallstone formation

Cholesterol-lowering diets high in unsaturated fat and

plant sterols but low in saturated fats and cholesterolresult in increased gallstone formation

Clofibrate enhances biliary cholesterol excretion and

makes the bile more lithogenic

Parenteral nutrition leads to a dilated, sluggish

gall-bladder containing stones

Long-term octreotide treatment induces

cholesterol-rich gallbladder stones in 13–60% of acromegalicpatients The bile is supersaturated with cholesterol, thenucleation time is abnormally rapid and gallbladderemptying is impaired Serum deoxycholic acid isincreased, due to a prolonged large bowel transit time[196]

Endoscopic sphincterotomy improves gallbladderemptying and decreases the lithogenicity of bile in

Table 34.2 Comparison of gallstone prevalence between

countries and races [10]

Very high High Moderate Low North American Indians USA whites USA blacks Greece Chile Great Britain Japan Egypt

Czechoslovakia Australia

Italy