Diseases of the Liver and Biliary System - part 10 docx

Scanning may also show dilatation of bile ducts and pancreatic duct, hepatic metastases and local spread of the primary lesion.. Glandular enlargement in the reticuloses does, very rarel

found in the pancreatic juice of patients with chronic

pancreatitis This may relate to K-ras mutations in areas

of duct hyperplasia [41] Over a 2-year follow-up a

minority develop pancreatic carcinoma [40].

Pathology

Histologically, the tumour is an adenocarcinoma,

whether arising from pancreatic duct, acinus or

bile duct The ampullary tumours have a papillary

arrangement and are often of low-grade malignancy;

fibrosis is prominent They tend to be polypoid and

soft, whereas the acinar tumours are infiltrative, large

and firm.

Obstruction of common bile duct

This results from direct invasion causing a scirrhous

reaction, from annular stenosis, and from tumour tissue

filling the lumen The duct may also be compressed by

the tumour mass.

The bile ducts dilate and the gallbladder enlarges An

ascending cholangitis in the obstructed duct is rare The

liver shows the changes of cholestasis.

Pancreatic changes

The main pancreatic duct may be obstructed as it enters

the ampulla The ducts and acini distal to the obstruction

dilate and later rupture, causing focal areas of

pancreati-tis and fat necrosis Later all the acinar pancreati-tissue is replaced

by fibrous tissue Occasionally, particularly in the acinar

type, fat necrosis and suppuration may occur in and

around the pancreas.

Diabetes mellitus or impaired glucose tolerance is

found in 60–80% of patients Apart from destruction of

insulin-producing cells by the tumour, this may be due

to production of islet amyloid polypeptide (IAPP) by

islet cells adjacent to the tumour [36].

Spread of the tumour

Direct extension in the wall of the bile duct and

infiltra-tion through the head of the pancreas is common with

the acinar although not with the ampullary type The

second part of the duodenum may be invaded, with

ulceration of the mucosa and secondary haemorrhage.

The splenic and portal veins may be invaded and may

thrombose with resultant splenomegaly.

Involvement of regional nodes is found in

approxi-mately a third of operated cases Perineural lymphatic

spread is common Blood-borne metastases, with

secon-daries in liver and lungs, follow invasion of the splenic

or portal veins There may also be peritoneal and

omental metastases.

Clinical features

Both sexes are affected, but males more frequently than females in a ratio of 2 : 1 The sufferer is usually between

50 and 69 years old.

The clinical picture is a composite one of cholestasis with pancreatic insufficiency, and the general and local effects of a malignant tumour (fig 36.1).

Jaundice is of gradual onset, progressively deepening,

but ampullary neoplasms can cause mild and

intermit-tent jaundice Itching is a common but not invariable

feature, and when present comes after jaundice gitis is unusual.

Cholan-Cancer of the head of the pancreas is not always less Pain may be experienced in the back, the epigas- trium and right upper quadrant, usually as a continuous distress worse at night and sometimes ameliorated by crouching It may be aggravated by eating.

pain-Weakness and weight loss are progressive and have usually continued for at least 3 months before jaundice develops.

Although frank steatorrhoea is rare, the patient often complains of a change in bowel habit, usually diarrhoea Vomiting and intestinal obstruction follows invasion

of the second part of the duodenum in 15–20% of patients Ulceration of the duodenum can erode a vessel with haematemesis or, more commonly, occult bleeding Difficulty in making a diagnosis may make the patient depressed It then becomes easy to believe mistakenly, that the patient is psychoneurotic.

Examination The patient is jaundiced and shows

evi-dence of recent weight loss Theoretically, the

gallblad-der should be enlarged and palpable (Courvoisier’s law).

In practice, the gallbladder is only felt in about half the patients, although at subsequent laparotomy a dilated gallbladder is found in three-quarters The liver is enlarged with a sharp, smooth, firm edge The pancreatic tumour is usually impalpable.

The spleen is palpable if involvement of the splenic vein has caused thrombosis Peritoneal invasion is fol- lowed by ascites.

Lymphatic metastases are more usual with cancer

of the body rather than head of the pancreas [51] sionally, however, axillary, cervical and inguinal glands may be enlarged and Virchow’s gland in the left supra- clavicular fossa may be palpable.

Occa-Sometimes, widespread venous thromboses simulate thrombophlebitis migrans.

Investigations

Glycosuria occurs in 60–80% and with it there is an impaired oral glucose tolerance test.

Blood biochemistry The serum alkaline phosphatase

level is raised The serum amylase and lipase

concentra-tions are sometimes persistently elevated in carcinoma

of the ampullary region Hypoproteinaemia with, later,

peripheral oedema may be found.

There is no reliable serum tumour marker with

suffi-cient specificity or sensitivity Using a cut-off of 70 U/ml

(almost twice the upper limit of normal), CA 19-9 has

the greatest sensitivity (around 70%) and specificity

(90%) of current markers for carcinoma of the pancreas

[14] However its sensitivity in the detection of early

tumour is lower [22] It can be elevated in benign biliary

obstruction.

Haematology Anaemia is mild or absent The leucocyte

count may be normal or raised with a relative increase

in neutrophils The erythrocyte sedimentation rate is

usually raised.

Differential diagnosis

The diagnosis must be considered in any patient over

40 years with progressive or even intermittent

cholesta-sis The suspicion is strengthened by persistent or

unexplained abdominal pain, weakness and weight

loss, diarrhoea, glycosuria, positive faecal occult blood,

hepatomegaly, a palpable spleen or thrombophlebitis

migrans.

Radiology

Most scanning techniques can detect pancreatic masses

with high accuracy in specialist units There are data

supporting transabdominal ultrasound, spiral (helical)

CT, dual-phase (arterial and venous) spiral CT, MRI,

endoscopic ultrasound and PET scanning The most

effective initial technique is helical, dual-phase CT (see

fig 32.5) which has an accuracy of over 90% for tumours

greater than 1.5 cm and 70% for smaller tumours [24].

This technique is widely available with expertise in

interpretation [19] MRI with angiography (gadolinium

enhancement) and endoscopic ultrasound have a similar

accuracy in some centres [2, 4, 16], but these techniques

and expertise are not as widely available as spiral CT

Scanning may also show dilatation of bile ducts and

pancreatic duct, hepatic metastases and local spread of

the primary lesion.

Percutaneous ultrasound or CT-guided fine-needle

aspiration of the pancreatic mass is safe and has a

sensi-tivity of over 90% in some units There is a small risk of

seeding of tumour cells along the needle track.

ERCP can usually demonstrate the pancreatic and bile

ducts, allow biopsy of any ampullary lesion (fig 36.2),

and provide bile or pancreatic juice or brushings from

the stricture for cytological examination (fig 36.3) The

appearance of the bile duct and/or pancreatic duct

stric-ture (double duct sign) gives a good indication of the

underlying malignant cause of the stricture (see fig.

32.12a) but occasionally appearances are deceptive [31] and tissue diagnosis should be sought Biliary brush cytology has a sensitivity of around 60% for pancreatic carcinoma [23, 46] Unusual tumours such as lymphoma need to be identified since they may respond to specific therapy.

In the patient with vomiting, barium meal and/or endoscopy will show the extent of duodenal invasion and obstruction.

Tumour staging

This gives an indication of whether the tumour is resectable or not Clinical evidence, chest X ray, ultra- sound or CT will show obvious metastatic disease Dual or triple-phase spiral CT is highly accurate in predicting irresectability (approximately 90%) [24] but

Diseases of the Ampulla of Vater and Pancreas 641

Fig 36.2 Abnormal ampulla at ERCP Note irregular surface

with nodularity Biopsy showed adenocarcinoma

Fig 36.3 Brush cytology taken from a low common bile duct

stricture There is a sheet of benign biliary epithelial cells andabove this a small group of large polymorphic cells

characteristic of adenocarcinoma

is less accurate in predicting resectability Features

suggesting irresectability are local extension of tumour,

encasement of extra-pancreatic arteries or veins,

inva-sion of adjacent organs and lymph node metastases

(more than an isolated solitary node) Most irresectable

lesions (70%) have three or four of these features — the

minority having only one or two Spiral CT may also

show hepatic metastases but the detection rate is higher

when combined with arterioportography.

Endoscopic ultrasound has a similar accuracy as dual

phase helical CT in assessing irresectability, but expertise

is not as widely available [24].

Experience with MRI is growing but it remains second

choice to helical dual-phase CT.

For vascular involvement these techniques can give

the same information as digital subtraction angiography

(DSA) which is now used only when the data from

scan-ning is inconclusive or conflicting.

Laparoscopy is valuable to show and biopsy minute

hepatic metastases and peritoneal and omental seedings.

Negative results from laparoscopy, CT and angiography

correspond to a 78% resectability rate [51].

Prognosis

The prognosis of pancreatic carcinoma is grave After

biliary bypass surgery the mean survival is about 6

months The acinar type carries a worse prognosis than

the ductal type because regional lymph glands are

involved earlier Only the minority of tumours, between

5 and 20%, are resectable.

Resection has had an operative mortality of

approxi-mately 15–20%, but recent reports have shown this to fall

to 5% and less in specialist centres with a few expert

surgeons performing more operations [14] A recent

report from a superspecialist unit of zero mortality after

145 consecutive pancreatico-duodenal resections is

exceptional [10].

Coincident with reduced operative mortality has been

a rise in reported 5-year survival to around 20% This

may reflect earlier detection of disease through the

newer scanning techniques, or selection of patients with

less extensive spread of disease Disease recurrence,

however, remains a problem [14] Total pancreatectomy

does not lead to longer survival than the less extensive

Whipple’s procedure and produces exocrine

insuffi-ciency and brittle diabetes.

The overall outlook for carcinoma of the pancreas

however, is grim with only 23 of 912 patients with

carci-noma of the pancreas in one series surviving 3 years and

only two of these being considered cures [11].

Prognosis for carcinoma of the ampulla is better 85%

or more of patients survive 5 years after resection if the

tumour has not spread beyond the margins of the

sphincter of Oddi With more extensive tumour the 5-year survival falls to 11–35% [15, 52].

Treatment

Resection

A decision to attempt resection depends on the clinical state of the patient and the staging of the tumour derived from radiological imaging Difficulties in removal arise because of the inaccessibility of the pancreas on the pos- terior wall of the abdomen in the vicinity of vital struc- tures The resectability rate is therefore low.

The classical procedure is pancreatico-duodenectomy (Whipple’s operation) which is performed in one stage

with removal of related regional lymph nodes, the entire duodenum and the distal third of the stomach This operation was modified in 1978 [49] to preserve antral and pyloric function (pylorus-preserving pancreatico- duodenectomy) This reduces post-gastrectomy symp- toms and marginal ulceration, and improves nutrition Survival is the same as those having the classical proce- dure The continuity of the biliary passages is restored by anastomosis of the common bile duct with the jejunum Pancreatico-jejunostomy drains the duct of the remain- ing pancreas The continuity of the intestinal tract is restored by duodeno-jejunostomy.

Frozen section examination of the resection margins is mandatory.

Prognostic factors are tumour size, resection margin and lymph node status [14] The best indicator is lymph node histology If negative at resection, 5-year survival is 40–50%, compared with 8% in those with nodes positive for metastasis [9] Prognosis is also related to whether or not there is histological evidence of vascular invasion (median survival 11 vs 39 months).

Carcinoma of the ampulla is also treated by atico-duodenectomy Local resection (ampullectomy) is

pancre-an alternative in selected patients with premalignpancre-ant or malignant ampullary lesions [5] Endoscopic photody- namic therapy has produced remission or reduced tumour bulk in a series of patients with ampullary carci- noma unsuitable for surgery [1] This technique uses endoscopic delivery of red light (630 nm) to tumour sen- sitized with haematoporphyrin given intravenously.

Palliative procedures

The choice lies between surgical bypass and endoscopic

or percutaneous trans-hepatic insertion of an thesis (stent).

endopros-Palliative surgical biliary bypass is an option in

irre-sectable patients with a predicted longer survival For the jaundiced patient with vomiting due to duodenal

obstruction, choledocho-jejunostomy with

gastroen-terostomy is necessary Gastric outlet and duodenal

stenosis can be treated by endoscopically or

radiologi-cally placed expandable mesh metal stents [33, 43]

although experience with this technique is limited For

the patient with bile duct obstruction alone, some argue

for prophylactic gastric bypass surgery at the time of

biliary bypass but most would make this decision at the

time of operation, according to the size of the tumour.

Endoscopic stent insertion (fig 36.4) is successful in up

to 95% of patients (60% after the first session) and has a

lower 30-day mortality than surgical bypass [42] When

the endoscopic approach fails, the percutaneous, or

com-bined percutaneous/endoscopic approach can be used

(Chapter 32).

Percutaneous stent insertion (see fig 32.21) has a similar

mortality, early morbidity and mean survival time (19

vs 15 weeks) to palliative surgery partly due to the

com-plications of the trans-hepatic approach (haemorrhage, bile leakage) [7] Endoscopic stent insertion has a lower complication rate and mortality than the percutaneous route [44].

Within 3 months of insertion 20–30% of plastic stents need to be replaced because of obstruction by biliary

sludge Metal mesh expandable stents can be inserted

endoscopically or percutaneously (see fig 32.17) They remain patent significantly longer than plastic stents (mean 273 vs 126 days) [12] However, because of their cost, they are best restricted to those patients with irre- sectable peri-ampullary carcinoma who at the time of first stent exchange because of blockage are judged likely

to have slower progression and a longer survival [35] This may be predicted to some extent by tumour size and weight loss [39] If plastic stents are used, elective exchange of the stent every 3 months gives patients a longer complication-free interval than those having stent exchange only once blockage occurs [38].

The choice between surgical and non-surgical relief of biliary obstruction depends upon the expertise available and the clinical status of the patient.

The non-surgical insertion of a stent is particularly applicable to older, poor-risk patients especially when a large, clearly inoperable pancreatic mass has been imaged or where there is extensive metastatic disease For the younger patient with irresectable disease, surgi- cal bypass should still be considered if longer than average survival is expected.

With all the approaches now available, no patient with carcinoma of the pancreas should die jaundiced or with intolerable itching.

Chemotherapy: radiotherapy

Pre-operative adjuvant chemotherapy and radiotherapy have produced disappointing results Selected patients may benefit from adjuvant combined radiotherapy and chemotherapy after radical resection [20] For patients with irresectable tumour many chemotherapeutic regimes have been studied in randomized trials [14] 5- fluorouracil (5-FU) has been used widely Recent data suggest that treatment with gemcitabine may have some benefit on survival and the alleviation of disease-related symptoms [8] Ideally all patients should participate in comparative studies Otherwise gemcitabine may be considered for patients with advanced pancreatic car- cinoma with or without metastases, who are still self- caring [14, 32] For localized disease, radiotherapy and concomitant 5-FU is an alternative [14] In patients who are no longer self-caring, management should focus on palliative measures rather than aggressive chemoradia- tion or chemotherapy.

For patients with pain, coeliac plexus block may be

Diseases of the Ampulla of Vater and Pancreas 643

Fig 36.4 Polyethylene 10 French endoprosthesis inserted

across low common bile duct stricture by the endoscopic route

Note good flow of contrast into duodenum and decompressed

biliary system

more effective than oral or parenteral analgesia Benefit

is more immediate [37] However, although coeliac

plexus block either done percutaneously under X-ray

screening or at operation can reduce pain for a few

months, pain may return in over half of patients [27].

Benign villous adenoma of the ampulla of Vater

This leads to biliary colic and obstructive jaundice The

ampullary tumour is seen and biopsied at ERCP.

Dysplasia may be present on biopsy

Carcinoembry-onic antigen (CEA) and CA19-9 are found on

immuno-histochemistry [53] These lesions should be regarded as

potentially premalignant Local resection or

pancreatico-duodenectomy is indicated [5] In patients unfit for

surgery, stenting is palliative Endoscopic ablation may

be successful using laser, monopolar or bipolar

coagula-tion, or photodynamic therapy [1, 34].

Cystic tumours of the pancreas [18]

These may be benign or malignant and include cystic

adenocarcinoma, cystic adenoma (serous and mucinous)

and papillary cystic tumours They may be

misdiag-nosed as pseudocysts 40% of patients are asymptomatic.

Work-up is by CT, endoscopic ultrasound, angiography

and ERCP Cyst fluid analysis (cytology, tumour

markers) may be valuable in differentiating the type of

tumour [26] Around 40% of lesions are malignant In

general, resection should be attempted Frozen and even

routine histology may be misleading Mucinous cystic

neoplasm should be considered potentially malignant.

Endocrine tumours of the pancreas [3, 47]

These include insulinoma (70%), gastrinoma (20%),

vaso-active intestinal polypeptide-secreting tumour

(VIPoma), glucagonoma, polypeptide-secreting tumour

(PPoma) and somatostatinoma Some may be

non-func-tioning [6] They present with either the systemic effects

of the hormone released or a mass effect with pain or

jaundice as with pancreatic carcinoma A variable

pro-portion are malignant, depending on the endocrine type.

Treatment is by surgical resection or debulking, and

medical measures to counter the effect of any hormone

released Survival depends on the tumour type and

stage.

Chronic pancreatitis

Pancreatitis, usually of alcoholic aetiology, can cause

narrowing of the intra-pancreatic portion of the common

bile duct The resultant cholestasis may be transient

during exacerbations of acute pancreatitis It is

presum-ably related to oedema and swelling of the pancreas.

More persistent cholestasis follows encasement of the intra- and peri-pancreatic bile duct in a progressively fibrotic pancreatitis Pseudocysts of the head of the pan- creas and abscesses can also cause biliary obstruction and persistent cholestasis.

Bile duct stenosis affects about 8% of patients with chronic alcoholic pancreatitis and this figure would be higher if more cholangiograms were done It should be suspected if the serum alkaline phosphatase is more than twice elevated for longer than 1 month ERCP shows a smooth narrowing of the lower end of the common bile duct, sometimes adopting a ‘rat tail’ configuration (fig 36.5) The main pancreatic duct may be tortuous, irregu- lar and dilated Pancreatic calcification may be present Liver biopsy shows portal fibrosis, features of biliary obstruction, and sometimes biliary cirrhosis Features of alcoholic liver disease are unusual Hepatic fibrosis regresses after biliary decompression [21].

Splenic vein thrombosis is a complication of chronic pancreatitis.

Management

Early diagnosis of a biliary stricture due to pancreatitis is essential as biliary cirrhosis and acute cholangitis can develop in the absence of clinical jaundice.

If alcohol is responsible for the pancreatitis the patient must abstain completely.

The place of surgery is controversial Clinical, tory and imaging data do not necessarily distinguish

labora-Fig 36.5 ERCP in a patient with alcoholic chronic

pancreatitis Note the ‘rat tail’ narrowing of the distal commonbile duct (arrow)

those patients with significant bile duct obstruction from

those with alcoholic liver disease or normal liver

histol-ogy [25] Liver biopsy is valuable in deciding whether

surgical decompression of the bile duct is necessary.

Plastic and metal mesh stents successfully relieve bile

duct obstruction due to chronic pancreatitis [13], but

longer-term data are needed to judge whether this is an

appropriate method of treatment Acute cholangitis,

biliary cirrhosis and protracted jaundice are strong

indi-cations for surgery [45] Choledocho-enterostomy is the

usual procedure.

Obstruction of the common bile duct by

enlarged lymph glands

This is rare The enlarged glands are nearly always

metastatic, frequently from a primary in the alimentary

tract, lung or breast, or from a hepato-cellular carcinoma.

Malignant glands in the porta hepatis are associated

with deep jaundice, the main bile ducts usually being

invaded rather than compressed Secondary deposits in

the hepatic parenchyma may also invade the bile ducts,

causing segmental obstruction.

Glands along the common duct may be enlarged in

non-malignant conditions, but the bile duct usually

escapes compression Jaundice in infections such as

tuberculosis, sarcoidosis or infectious mononucleosis is

not obstructive but due to direct hepatic involvement or

haemolysis.

Glandular enlargement in the reticuloses does, very

rarely, cause obstruction to the common bile duct, but

jaundice complicating these diseases is more often

due to hepatic parenchymal involvement, to increased

haemolysis or loss of intra-hepatic bile ducts (Chapter

13).

Other causes of extrinsic pressure on the

common bile duct

Duodenal ulceration

This is an extremely rare cause of obstructive jaundice.

Perforation, so that the ulcer impinges against the bile

duct or causes adhesive peritonitis, may rarely result in

biliary obstruction This can also follow scarring as the

ulcer heals or endoscopic sclerosis for bleeding.

Duodenal diverticulum

Diverticula of the duodenum are often found near the

ampulla of Vater, but rarely cause obstruction of the bile

duct They are associated with an increased rate of

gall-bladder and common bile duct stones, and the

recur-rence of duct stones [54].

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staging and assessment of resectability of pancreatic cancer

Arch Surg 1990; 125: 230.

52 Yamaguchi K, Enjoji M Carcinoma of the ampulla of Vater

A clinico-pathologic study and pathologic staging of 109

cases of carcinoma and five cases of adenoma Cancer 1987;

59: 506.

53 Yamaguchi K, Enjoji M Adenoma of the ampulla of Vater:

putative precancerous lesion Gut 1991; 32: 1558.

54 Zoepf T, Zoepf D-S, Arnold JC et al The relationship

between juxtapapillary duodenal diverticula and disorders

of the biliopancreatic system: analysis of 350 patients

Gas-trointest Endosc 2001; 54: 56.

Benign lesions of the gallbladder

At ultrasound, polypoid lesions of the gallbladder are

occasionally seen and there is usually concern as to their

nature and how to manage them The vast majority are

benign They may be true tumours or pseudo-tumours.

True tumours comprise adenoma, lipoma and

leiomy-oma Pseudo-tumours include cholesterol polyps,

inflammatory polyps and adenomyomatosis.

These lesions are seen most often as an echogeneic

focus that projects into the gallbladder lumen, does not

cast an acoustic shadow, and does not move when the

patient is moved (unlike a stone) The diagnostic

accu-racy of ultrasound for the commonest lesions is 50–90%

depending on the pathology [34].

Cholesterol polyps are usually multiple, with a higher

echogenicity than liver, a pedicle and a mulberry-like

surface [34] They may contain a hyperechoic spot.

Pathologically they consist of hypertrophied villi laden

with cholesterol.

Adenoma is seen as a polypoid lesion which on

ultra-sound has an echogenicity similar to the liver, a smooth

surface and usually no pedicle [34].

80%–90% of gallbladder polypoid lesions do not

change in size on follow-up scans [41, 57] However, they

cause concern because of the low chance of malignancy

in adenomas Cholecystectomy will be done for the

symptomatic patient This is also appropriate for the

lesion greater than 10 mm in diameter, where the risk of

malignancy is greater [34] Other features of malignant

tumour are a sessile lesion, isoechoic with the liver,

growing rapidly on serial ultrasounds.

Patients with a smaller lesion without these features

should undergo a second scan Some lesions disappear

but the majority remain, and these patients may be

offered a cholecystectomy for peace of mind

Alterna-tively, a repeat scan is done at 6-monthly intervals to

detect any change in size [39] In practice ultrasound

lesions less than 10 mm in diameter with benign

appear-ances in an asymptomatic patient tend to be treated

con-servatively but follow-up scanning is important If the

result of trans-abdominal ultrasound is inconclusive,

endoscopic ultrasound if available is useful with a

diag-nostic accuracy for neoplastic lesions of 80% [10].

Carcinoma of the gallbladder [1]

This is an uncommon neoplasm Gallstones coexist in about 75% of cases and chronic cholecystitis is a frequent association There is a clear association with large, multi- ple gallbladder stones [62], but a causal relationship is unproven.

The calcified (porcelain) gallbladder is particularly likely to become cancerous [51] An anomalous pancre- atico-biliary ductal union, greater than 15 mm from the papilla of Vater, is associated with congenital cystic dilatation of the common bile duct and with gallbladder carcinoma [40] Regurgitation of pancreatic juice may

be tumorigenic The common gallbladder cholesterol polyps are not precancerous.

Chronic typhoid infection of the gallbladder increases the risk of gallbladder carcinoma by 167-fold [6], empha- sizing the need for antibiotic treatment to eradicate the chronic typhoid and paratyphoid carrier state, or for elective cholecystectomy.

Papillary adenocarcinoma starts as a wart-like

excres-cence It grows slowly into, rather than through, the wall until a fungating mass fills the gallbladder Mucoid change is associated with more rapid growth, early metastasis and gelatinous peritoneal carcinomatosis.

Squamous cell carcinoma and scirrhous forms are

recog-nized The anaplastic type is particularly malignant The

most common tumour is a differentiated noma [1, 16] which may be papillary.

adenocarci-The tumour usually arises in the fundus or neck, but rapid spread may make the original site difficult to locate The rich lymphatic and venous drainage of the gallbladder leads to early spread to related lymph nodes, causing cholestatic jaundice and widespread dissemina- tion The liver bed is invaded and there may also be local spread to the duodenum, stomach and colon resulting in fistulae or external compression.

Clinical The patient is usually an elderly, white

female, complaining of pain in the right upper quadrant, nausea, vomiting, weight loss and jaundice Sometimes an unsuspected carcinoma is found in a cholecystectomy specimen at histology These small lesions may not even be recognized at the time of operation [13].

647

Chapter 37 Tumours of the Gallbladder and Bile Ducts

Examination may reveal a hard and sometimes tender

mass in the gallbladder area.

Serum, urine and faeces show the changes of cholestatic

jaundice if the bile duct is compressed.

Ultrasound scanning shows a mass in the gallbladder

lumen or totally replacing the gallbladder With early

lesions the differentiation between gallbladder

carci-noma and a thickened wall due to acute or chronic

chole-cystitis is difficult.

CT may also show a mass in the area of the

der Ultrasound and CT detect carcinoma of the

gallblad-der in 60–70% of cases [45].

By the time an abnormality is shown by ultrasound or

CT, extension is likely and the chance of total removal

low Endoscopic ultrasound images correlate with

histo-logical depth of invasion and are useful in staging [23].

ERCP shows external compression of the bile duct in

the jaundiced patient Angiography shows displacement

of hepatic and portal blood vessels by the mass.

In only 50% of patients is a correct pre-operative

diag-nosis made [12].

Prognosis

This is generally hopeless because the majority are

inop-erable at the time of diagnosis Distant metastases are

already present in 50% of cases [16] The only long-term

survivors are those in whom the tumour was found

inci-dentally at the time of cholecystectomy for gallstones

(carcinoma in situ).

Median survival from diagnosis is 3 months, with only

14% alive at 1 year [12] Patients with papillary and

well-differentiated adenocarcinomas have longer survival

than those with tubular and undifferentiated types [28].

The results of radical resection including partial

hepa-tectomy and radical lymphadenectomy are conflicting

[9, 16] with some series showing no survival benefit

and others claiming increased survival.

Treatment

Cholecystectomy has been recommended for all patients

with gallstones in an effort to prevent the development

of carcinoma in the gallbladder This seems drastic for a

common condition, and would lead to a large number of

unnecessary cholecystectomies.

The pre-operative diagnosis of carcinoma of the

gall-bladder should not preclude laparotomy although the

results of surgical treatment are disappointing Radical

resection including partial hepatectomy has been

attempted but with unsatisfactory results and no

con-vincing evidence of improved survival [16] The same

applies to radiotherapy and chemotherapy [1].

Endoscopically or percutaneously placed biliary

pros-theses relieve bile duct obstruction.

Other tumours

Rarely other tumours develop in the gallbladder including leiomyosarcoma, rhabdomyosarcoma, oat cell carcinoma and carcinoid tumours.

Benign tumours of the extra-hepatic bile duct

These extremely rare tumours usually remain tected until there is evidence of biliary obstruction and cholangitis They are rarely diagnosed pre-operatively Recognition is important as resection is curative.

unde-Papilloma is a polypoid tumour which projects into the

lumen of the common bile duct It is a small, soft, lar tumour, which may be sessile or pedunculated These tumours may be single or multiple; they may be cystic Occasionally they undergo malignant change Cholan- giography may show a smooth mass projecting into the bile duct Mucus secretion from the tumour can cause obstructive cholangitis.

vascu-Adenomyoma can be found anywhere in the biliary

tract It is firm and well circumscribed and varies in size

up to 15 cm in diameter It is cured by resection [11].

Fibroma is small and firm and causes early bile duct

obstruction.

Granular cell tumour is of mesenchymal origin It

affects young women, usually black, causing cholestasis [5] It must be distinguished from cholangiocarcinoma or localized sclerosing cholangitis Tumours are uniformly resectable and curable.

Carcinoma of the bile duct (cholangiocarcinoma)

Carcinoma may arise at any point in the biliary tree from the small intra-hepatic bile ducts to the common bile duct (fig 37.1).

The incidence of intra-hepatic cholangiocarcinoma is increasing Studies from England and Wales [59] and the USA [48] show a 10-fold increase between the early 1970s and the mid-1990s The explanation is unclear Although improved diagnostic techniques for cholangiocarcinoma and primary sclerosing cholangitis may have played a part, they do not alone explain the marked increase in incidence and mortality Mortality from extra-hepatic cholangiocarcinoma fell over the same period.

The treatment depends on the site Resection is the rule for extra-hepatic tumours For hilar cholangiocarci- noma surgical resection should always be considered but requires particular expertise because of the inaccessi- bility of hilar tumours, the proximity of the hepatic artery and portal vein and the need for hepatic resection

in some patients Even if not curative, surgical treatment may prolong survival with a good quality of life.

Suspicion of cholangiocarcinoma, for example after

ultrasound scan, should lead to referral to a specialist

unit This is to co-ordinate the work-up to evaluate

resectability of the tumour Modern CT techniques and

MRI with MR cholangiography allow a high degree of

non-invasive evaluation The necessity and timing of

invasive investigations depends on clinical

circum-stances ERCP and non-operative drainage of bile

per-cutaneously or after ERCP frequently introduce sepsis

which may compromise later treatment [29, 42] These

aspects emphasize the importance of a multidisciplinary

approach.

In those who are inoperable, biliary drainage by

inter-ventional radiologist or endoscopist relieves pruritus

and usually jaundice to allow satisfactory palliation.

Associations

Bile duct cancer is associated with ulcerative colitis

with or without sclerosing cholangitis (Chapter 15) The

majority of patients with primary sclerosing cholangitis

who develop cholangiocarcinoma have ulcerative

colitis Patients with primary sclerosing cholangitis and

ulcerative colitis who also have colorectal neoplasia

(dysplasia/carcinoma) are at greater risk of

cholangio-carcinoma than those without colonic neoplasia [4].

In a group of 70 patients with primary sclerosing

cholangitis followed prospectively for a mean of 30

months, 15 patients died of liver failure Five of 12 patients (40%) having an autopsy had cholangiocarci- noma — 7% of the total group [54].

Biliary malignancy is not necessarily a late tion of primary sclerosing cholangitis 30% of patients in one series had a diagnosis of cholangiocarcinoma made within 1 year of the first evidence of underlying liver disease based on abnormal liver function tests [37] Clinical features associated with malignancy were epigastric pain, weight loss and raised CA 19-9 and carcinoembryonic antigen (CEA) [37]

complica-All members of the congenital fibropolycystic family may be complicated by adenocarcinoma (Chapter 33) These include congenital hepatic fibrosis, cystic dilata- tion (Caroli’s syndrome), choledochal cyst, polycystic liver and von Meyenburg complexes Cholangiocarci- noma may be associated with biliary cirrhosis due to biliary atresia.

The liver fluke infestations of the Orient may be plicated by intra-hepatic (cholangiocellular) cholangio- carcinoma In the Far East (China, Hong Kong, Korea,

com-Japan), where Clonorchis sinensis is prevalent,

cholangio-carcinoma accounts for 20% of primary liver tumours These arise in the heavily parasitized bile ducts near the hilum.

Opisthorchis viverrini infestation is important in

Thai-land, Laos and western Malaysia [35] These parasites induce DNA changes and mutations through the pro- duction of carcinogens and free radicals, and the stimu- lation of cellular proliferation of intra-hepatic bile duct epithelium [46].

The risk of extra-hepatic bile duct carcinoma is cantly lower 10 years or more after cholecystectomy, sug- gesting a link with gallstones [17].

signifi-Pathology

The confluence of the cystic duct with the main hepatic duct or the right and left main hepatic ducts at the porta hepatis are common sites of origin (fig 37.1) Tumours of the hepatic ducts extend into the liver They cause com- plete obstruction of the extra-hepatic bile ducts with intra-hepatic biliary dilatation and enlargement of the liver The gallbladder is collapsed and flaccid If the tumour is restricted to one hepatic duct, biliary obstruc- tion is incomplete and jaundice absent The lobe of the liver drained by this duct atrophies and the other hypertrophies.

In the common bile duct the tumour presents as a firm nodule or plaque which causes an annular stricture which may ulcerate It spreads along the bile duct and through its wall.

Local and distant metastases, even at autopsy, are found in only about half of the patients They involve peritoneum, abdominal lymph nodes, diaphragm, liver

Tumours of the Gallbladder and Bile Ducts 649

Upper third 58%

Middle third 17%

Lower third 18%

Diffuse 7%

Fig 37.1 Site of cholangiocarcinoma The majority occur in

the upper third of the bile duct [60]

or gallbladder Blood vessel invasion is rare and

extra-abdominal spread is unusual.

Histologically the tumour is usually a mucin-secreting

adenocarcinoma with cuboidal or columnar epithelium

(fig 37.2) Spread along neural sheaths may be noted.

Tumours around the hilum are sclerosing with an

abun-dant fibrous stroma More distal ones are nodular or

papillary.

Molecular changes

Point mutations in codon 12 of the K-ras oncogene

are found in cholangiocarcinoma [65] p53 protein is

expressed particularly in high-grade mid and distal duct

cholangiocarcinomas [15] Aneuploidy (divergence from

the normal chromosome content) is found in hilar

cholangiocarcinoma [55] and is associated with neural

invasion and shorter survival.

Cholangiocarcinoma cells contain somatostatin receptor

RNA and cell lines have specific receptors Cell growth is

inhibited by somatostatin analogues.

Clinical features

This tumour tends to occur in the older age group,

patients being about 60 years old Slightly more males

than females are affected.

Jaundice is the usual presenting feature, followed by

pruritus — a point of distinction from primary biliary

cir-rhosis where itching usually comes first Jaundice may

be delayed if only one main hepatic duct is involved The trend of the serum bilirubin level is always upward, but periods of clearing of jaundice are found in up to 50% [31].

Pain, usually epigastric and mild, is present in about one-third of patients Diarrhoea may be related to steat- orrhoea Weakness and weight loss are marked.

The condition may be associated with chronic tive colitis, often following long-standing cholestasis due to sclerosing cholangitis.

ulcera-Examination Jaundice is deep Cholangitis is unusual

unless the bile ducts have been interfered with cally, endoscopically or percutaneously.

surgi-The liver is large and smooth, extending 5–12 cm below the costal margin The spleen is not felt Ascites is unusual.

Investigations

Serum biochemical findings are those of cholestatic

jaun-dice The serum bilirubin, alkaline phosphatase and glutamyl transpeptidase levels may be very high Fluctuations may reflect incomplete obstruction or primary involvement of one hepatic duct.

g-The serum mitochondrial antibody test is negative and a-fetoprotein is not increased.

The faeces are pale and fatty and occult blood is often present Glycosuria is absent.

Anaemia may be greater than that seen with ampullary

carcinoma; the explanation is unknown — it is not due to blood loss The leucocyte count is high normal with increased polymorphs.

Liver biopsy shows features of large bile duct

obstruc-tion In primary sclerosing cholangitis biliary dysplasia raises the possibility of coexistent cholangiocarcinoma [20].

Cytology taken at the time of ERCP or percutaneous

drainage is worthwhile, but requires cytological tise for interpretation Brush cytology is better than analysis of aspirated bile, with a sensitivity of 60% [56] Other approaches include fine-needle aspiration cytol- ogy from the suspected tumour, done under ultrasound

exper-or fluexper-oroscopy Aspiration cytology guided by scopic ultrasound is also valuable but this expertise is rare [22].

endo-In primary sclerosing cholangitis, brush cytology of dominant strictures at ERCP has a sensitivity of 60% for

cholangiocarcinoma [52] p53 and K-ras mutation lysis does not increase sensitivity However, K-ras

ana-mutations may be found ahead of the diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis [33].

The serum concentration of the tumour marker CA 19-9 is often increased in patients with biliary tract

Fig 37.2 Bile duct carcinoma: with irregular fibrous stroma.

(H & E, ¥ 40.)

malignancy Levels are also increased by cholangitis

and cholestasis The sensitivity for detecting

cholangio-carcinoma in primary sclerosing cholangitis is 50–60%

[3, 47] Combining CA 19-9 with CEA measurement

does not increase sensitivity Although CA 19-9 only has

a moderate sensitivity, it has a role in surveillance of

selected patients with primary sclerosing cholangitis if

only because early detection of bile duct malignancy by

any means is difficult.

Scanning

Ultrasound shows dilated intra-hepatic ducts with a

normal extra-hepatic biliary tree A tumour mass may be

shown in up to 80% of cases Ultrasound (real-time

together with Doppler) accurately detects neoplastic

involvement of the portal vein, both occlusion and wall

infiltration, but is less good in showing hepatic arterial

involvement [43] Intra-duct ultrasound is still

experi-mental but can provide important information on

tumour extension in and around the bile duct [58].

Enhanced CT shows bile duct dilatation, and detects

tumours in 40–70% of patients Helical CT detects

cholangiocarcinoma, as small as 15 mm diameter, in 90%

of patients, and provides information on parenchymal,

intra-hepatic bile duct and portal involvement [19] It

underestimates extra-hepatic bile duct involvement,

hepatic arterial invasion and lymph node spread.

Overall, magnetic resonance cholangiography has an

accuracy for bile duct stones and strictures of over 90%.

In cholangiocarcinoma (fig 37.3) it correctly delineates

duct obstruction and the extent of hilar tumour

sion in 80% of patients It underestimates tumour

exten-sion in 20% [66] MRI with MRCP is an important

technique for planning the treatment of malignant hilar

strictures but does not replace invasive cholangiography

which also allows brushings to be taken for cytology and

bile drainage if indicated.

CT and MRI therefore may show bile duct obstruction

and a mass but differentiation between inflammatory

and malignant biliary strictures generally depends upon

invasive techniques to obtain cytology and biopsy

There is a diagnostic problem particularly in primary

sclerosing cholangitis PET scanning using [18F]

fluoro-2-deoxy-D-glucose has been reported to detect

cholangio-carcinomas in patients with and without primary

sclerosing cholangitis with a sensitivity of 90% [30, 32]

If substantiated this would represent an advance in the

management particularly of patients with primary

scle-rosing cholangitis, although false-positive scans have

been seen in normal individuals [32].

Cholangiography

With the newer non-invasive imaging modalities now available, the role of direct cholangiography has changed Some specialist units rely on Doppler ultrasound and MRCP and avoid instrumentation of the biliary tree before surgery [7] Hepatobiliary units have their individual approach and tailor this to the patient.

Endoscopic or percutaneous cholangiography, or both, still have a role (fig 37.3) However, as emphasized above, they are not done immediately after ultrasound has shown a hilar bile duct obstruction Jaundice is often felt to be dangerous, needing immediate treat- ment, but this is only so for the septic patient or when there is renal failure It is prudent to investigate the patient non-invasively to judge the nature and extent of the hilar lesion, and then consider direct cholangiogra- phy, cytology and drainage when the management plan

is clear MRCP may be used to select the duct system for endoscopic stent drainage [27] or percutaneous puncture.

In hilar cholangiocarcinoma, ERCP shows the normal common bile duct and gallbladder with obstruction at the hilum (fig 37.3c) Contrast usually passes through the stricture(s) into dilated bile ducts above The stric- ture is passed with a guide-wire, cytology is done, and a stent placed.

Percutaneous cholangiography shows the dilated intra-hepatic ducts down to the stricture (fig 37.3d) A drain is inserted When right and left hepatic ducts are individually obstructed, puncture of both systems may

be necessary to outline the obstruction accurately Some specialist surgeons prefer the percutaneous rather than endoscopic approach to the system because it provides detailed information on tumour extension within the liver and intra-hepatic bile ducts This is of more value than the appearances of the extra-hepatic biliary tree below the stricture.

Angiography

Digital subtraction angiography (DSA) shows the hepatic artery and portal vein and their intra-hepatic branches Its use depends upon the information derived from ultrasound, CT and MRI.

Diagnosis

In the patient with deepening cholestatic jaundice the clinical diagnosis is likely to be carcinoma of the peri- ampullary region Other possibilities are drug jaundice, primary sclerosing cholangitis (Chapter 15) and primary biliary cirrhosis (Chapter 14) Cholangiocarcinoma is an

Tumours of the Gallbladder and Bile Ducts 651

Fig 37.3 A 75-year-old woman presenting with cholestatic jaundice Ultrasound showed dilated intra-hepatic ducts, a hilar mass

and a normal common bile duct (a) MRCP shows dilated intra-hepatic ducts with at least three segments obstructed in the right lobeand the left hepatic system obstructed at the hilum If non-surgical drainage is to be done, these appearances favour drainage of theleft- rather than the right-sided system (D, duodenum) (b) MRI scan shows a mass in the liver (arrow) above the hilum (c) Non-

operative drainage was chosen since the patient was considered inoperable ERCP shows a normal common duct with a hilar

structure A stent could not be placed (d) Following on the MRCP appearances, the left-sided duct system was chosen for

percutaneous cholangiography and a stent inserted

unusual cause but it should be detected if an orderly

work-up is used History and examination are usually

unhelpful.

The first step in the cholestatic patient is ultrasound

scanning Intra-hepatic bile ducts will be dilated in

cholangiocarcinoma The common duct is normal,

equivocal or may be dilated down to an extra-hepatic tumour If there is a suspicion of hilar cholangiocarci- noma and other clinical features do not indicate inoper- ability, the choice is MRCP or, if this is not available, referral to a specialist hepato-biliary unit.

If ultrasound does not show dilated bile ducts in the

cholestatic patient, other causes (Chapter 13) need to

be considered including drug jaundice (history) and

primary biliary cirrhosis (anti-mitochondrial antibody).

Liver histology will help If primary sclerosing

cholangi-tis is possible, cholangiography is diagnostic

With scanning and cholangiography it should be

pos-sible to diagnose the bile duct stricture due to

cholangio-carcinoma At the hilum, the differential diagnosis is a

benign stricture [25] or metastatic gland, in the mid-duct

carcinoma of the gallbladder, and in the peri-ampullary

region carcinoma of the pancreas Differentiation will

depend upon history and other imaging techniques.

Prognosis

Prognosis depends on the site of the tumour Those

dis-tally placed are more likely to be resectable than those

at the hilum The histologically differentiated do better

than the undifferentiated Polypoid cancers have the

best prognosis.

If unresected, the 1-year survival for cholangio

carci-noma is 50%, with 20% surviving at 2 years and 10% at

3 years [18] This reflects that some tumours are slow

growing and metastasize late Jaundice can be relieved

surgically or by endoscopic or percutaneous stenting.

The tumour kills by its site making it inoperable, rather

than by its malignancy Average survival after resection

is longer, making proper assessment in patients fit for

surgery essential.

Staging [7]

If the clinical state of the patient does not rule out

surgery the resectability and extent of tumour is

assessed Metastases, usually late, should be sought.

Low and mid common bile duct lesions are usually

resectable although vascular imaging is needed to

exclude invasion.

Hilar cholangiocarcinoma is more problematic (table

37.1) If cholangiography shows involvement of the

sec-ondary hepatic ducts in both hepatic lobes (fig 37.4, type

IV) or imaging shows encasement of the main portal vein or hepatic artery, the lesion is irresectable A pallia- tive procedure is needed.

If the tumour is limited to the hepatic duct tion, affecting one lobe of the liver only, or only obstructs the portal vein or hepatic artery on the same side, the lesion may be resectable Pre-operative imaging is aimed at establishing whether after surgical removal

bifurca-a vibifurca-able unit of liver rembifurca-ains [7] This must contbifurca-ain

a biliary radicle large enough to anastomose to bowel, and a normal portal vein and hepatic arterial branch

At surgery, further assessment is done with operative ultrasound and a search for lymph node involvement.

intra-In a department with a high resection rate, operative cholangiography predicted clinical manage- ment in 62% of patients, and angiography determined management in 80% [38].

Tumours of the Gallbladder and Bile Ducts 653

Table 37.1 Criteria of irresectability for hilar

cholangiocarcinomaBilateral bile duct involvement or multifocal disease on cholangiography

Main trunk of portal vein encased/occludedBilateral involvement of hepatic arterial or portal vein branches or both

Unilateral hepatic artery involvement and extensive contralateral bile duct involvement

Fig 37.4 Classification of hilar cholangiocarcinoma according to the involvement of bile ducts Resectability of type I to III depends

on angiographic findings Type IV (bilateral involvement of secondary hepatic ducts) indicates incurable disease In inoperablepatients median survival after stent insertion depends upon the extent of tumour [53]

Some advocate caudate lobectomy, based on the

observation that two to three bile ducts from this lobe

drain directly into the main bile ducts adjacent to the

confluence of the hepatic ducts and thus are likely to be

involved by tumour.

The proportion of cholangiocarcinomas being

resected has increased from 5–20% of patients in the

1970s to 30% or more in specialist centres in the 1990s.

This relates to earlier diagnosis and referral to a tertiary

centre, more accurate and complete pre-operative

assessment, and a more aggressive surgical approach.

The problem is to achieve a resection with

tumour-negative margins Median survival after aggressive

resection of hilar cholangiocarcinoma is 18–40 months

with good palliation for most of this time [7, 38] Local

resection of Bismuth type I and II tumours (fig 37.4)

carries a peri-operative mortality of 5% or less Liver

resection is needed for type III lesions, and carries a

greater morbidity and mortality.

Liver transplantation is not appropriate for

cholangio-carcinoma because of early recurrence in the majority

[64].

Surgical palliative procedures include anastomosis of

jejunum to the segment III duct in the left lobe which is

usually accessible despite the hilar tumour (fig 37.5).

Jaundice is relieved for at least 3 months in 75% of

patients [26] If segment III bypass is not possible

(atrophy, metastases), a right-sided intra-hepatic

anasto-mosis to the segment V duct can be done.

Non-surgical palliation

In those patients unfit for surgery or with irresectable tumours, jaundice and itching may be relieved by placing an endoprosthesis across the stricture either by the endoscopic or percutaneous route.

By the endoscopic route, stents can be inserted cessfully in about 90% of patients if a combined endo- scopic/percutaneous procedure is included after a failed endoscopic attempt The major early complication is cholangitis (7%) Thirty-day mortality is between 10 and 28% depending upon the extent of the tumour at the hilum and the mean survival is 20 weeks [53] Stenting of only one lobe is necessary [14].

suc-Percutaneous trans-hepatic endoprosthesis insertion

is also successful but carries with it a higher risk of plications such as bleeding and bile leakage (Chapter 32) Metal mesh endoprostheses, which expand to 10 mm diameter in the stricture after insertion of a 5 or 7 French catheter, are more expensive than plastic types, but have longer patency for peri-ampullary strictures [36] They may be used for hilar strictures Studies suggest a similar advantage over plastic endoprostheses [63] but their insertion requires an experienced operator.

com-There are no trials comparing surgical versus surgical palliation There are benefits and disadvantages

non-of both approaches [44] Generally, non-operative niques are appropriate for high-risk patients expected to have a shorter survival Because of recurrent stent block- age requiring replacement [24], surgical bypass should

tech-be considered as an alternative palliative approach Internal radiotherapy using an iridium-192 wire or radium needles may be combined with biliary drainage [21] The value of this technique is unproven Cytotoxic drugs are ineffective External radiotherapy has ap- peared to show some benefit in retrospective studies but

in a randomized trial showed no benefit [50] Intra-duct photodynamic therapy combined with stenting has given encouraging results in Bismuth type III and IV cholangiocarcinoma [2] There is a local tumour response

of 30–75% and hilar bile ducts occlusion can be reversed The treatment is costly and controlled studies are needed

to establish survival benefit Symptomatic treatment is that of chronic cholestasis (Chapter 13).

Cholangiocellular carcinoma

This intra-hepatic bile duct derived tumour is classified

as a primary hepatic carcinoma It becomes symptomatic

as it enlarges producing abdominal pain rather than jaundice [8] It grows rapidly with early metastasis and a particularly poor prognosis There is an association with Thorotrast (thorium dioxide), an intravenous contrast medium used many years ago Scanning shows an intra- hepatic mass Distinction from hepato-cellular carci-

Fig 37.5 Check cholangiogram after surgical bypass for hilar

cholangiocarcinoma The anastomosis is between the jejunum

and the third segment duct of the left lobe (arrow)

noma may be difficult Hepatic venous and portal vein

involvement is rare Surgery is the only chance for

effective treatment Resection is possible in 30–60% of

cases [8] One-year survival after resection is 50–60%.

Transplantation for irresectable tumour gives a median

survival of 5 months [49].

Metastases at the hilum

Cholestatic jaundice developing following the diagnosis

of carcinoma elsewhere (in particular the colon) may

be due to diffuse metastases within the liver or duct

obstruction by nodes at the hilum Differentiation

between the two is by ultrasound If dilated bile ducts

are shown and the patient is symptomatic with itching,

biliary obstruction can be relieved by insertion of an

endoprosthesis by the endoscopic or percutaneous

approach [61] Palliation is achieved depending upon

the extent of tumour but the 30-day mortality is greater

and the survival significantly shorter compared with

endoprosthesis insertion for primary bile duct

malig-nancy [53].

References

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2 Berr F, Wiedmann M, Tannapfel A et al Photodynamic

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3 Björnsson E, Kilander A, Olsson R CA 19-9 and CEA are

unreliable markers for cholangiocarcinoma in patients with

primary sclerosing cholangitis Liver 1999; 19: 501.

4 Broomé U, Löfberg R, Veress B et al Primary sclerosing

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In 1955, Welch performed the first transplantation of the

liver in dogs [118] In 1963, Starzl and his group carried

out the first successful hepatic transplant in man [101].

The number of transplants is escalating and, in 1997,

4099 patients were transplanted in the USA Elective

liver transplantation in low-risk patients has a 90%

1-year survival Improved results can be related to more

careful patient selection, to better surgical techniques

and post-operative care, and to greater willingness to

re-transplant after rejection Better immunosuppression

has contributed.

Selection of patients

The patient selected for transplant should suffer from

irreversible, progressive disease for which there is no

acceptable, alternative therapy The patient and the

family must understand the magnitude of the

under-taking and be prepared to face the difficult early

post-operative period and life-long immunosuppression.

Improved results have led to a greater acceptance of

the procedure Demand has exceeded supply of donor

organs (fig 38.1) The time spent awaiting transplant

and deaths occurring before it can be performed have increased The waiting time for low-risk patients is approximately 6–12 months Although in general this may be longer for those of blood group B and AB, group

O recipients may have the longest waiting time because group O is the universal donor type Depending on the system of organ distribution, such livers can be given to recipients having any ABO group Donor livers suitable for children are particularly rare and this has led to the split-liver technique (see fig 38.5).

The equitable distribution of the precious donor livers

is difficult Results (and costs) are much better if the patient is low risk (ambulatory) compared with high risk (intensive care) Decisions are usually made by a multi-disciplinary panel including the patient and patient’s family In the USA, the United Network for Organ Sharing (UNOS) guidelines are followed (tables 38.1, 38.2) [63] A modified Child–Pugh score is used as the basis by which to evaluate the severity of liver disease The priorities expressed by the general public are not the same as those of clinicians There has been a perceived lack of fairness in organ allocation [76] The UNOS website (www.unos.org) allows the public and clinicians access to transplant activities and outcomes Livers should be allocated for medical need and not on the basis of financial or other considerations Unaccept- able criteria include the patient’s contribution to society, inability to comply with treatment (e.g antisocial behav- iour), the patient’s contribution to the disorder (e.g drug

or alcohol abuse) and the past use of medical resources [27] Recipients are broadly defined as having an intoler- able quality of life because of liver disease or having an anticipated length of life of less than 1 year because of liver failure There are few guidelines predicting sur- vival Patients more than 65 years old have a substan- tially worse 5-year survival, but age itself is not a contraindication.

Candidates: outcome (table 38.3)

In Europe, the pattern of primary indication for liver transplantation is changing The main indication is cir- rhosis, including primary biliary cirrhosis More patients with acute and sub-acute hepatic failure are being

657

Chapter 38 Hepatic Transplantation

Deaths

1994 1996 1998

Fig 38.1 Over the last 8 years availability of donors has not

kept up with the demand for transplants Waiting time and

deaths have increased

Table 38.1 Child–Pugh scoring system to assess severity of liver disease

Points

by diuretics diuretic treatment

hypoglycaemia (glucose level <50 mg/dl)

Primary non-function of graft transplanted within 7 days

Hepatic artery thrombosis occurring within 7 days of transplantation

Acute decompensated Wilson’s disease

refractory ascites/hepato-renal syndrome (hydrothorax)

stage 3–4 encephalopathy unresponsive to therapy

Contraindications to status 2A listing:

extra-hepatic sepsis unresponsive to antimicrobial therapy

requirement for high dose or two or more pressor agents to maintain an adequate blood pressure

severe, irreversible multi-organ failure

Status 2B

Patients with chronic liver disease and a Child–Pugh score ≥10, or ≥7 and one or more of the following clinical considerations:

unresponsive variceal haemorrhage

hepato-renal syndrome

spontaneous bacterial peritonitis

refractory ascites/hepato-renal syndrome (hydrothorax)

Liver transplant candidates with hepato-cellular carcinoma can be registered as status 2B if they meet the following criteria:

thorough assessment has excluded metastatic disease

recipient has one nodule £5 cm or three or fewer nodules all £3 cm

patient is not a resection candidate

Status 3

Patients with chronic liver disease and a Child–Pugh score ≥7

included and fewer with cancer because of the poor

sur-vival due to recurrence of tumour (table 38.4).

Cirrhosis

All patients with end-stage cirrhosis should be

consid-ered for liver transplantation Selection of the right time

is difficult The patient must not be moribund, so that the

transplant will fail, or be capable of leading a relatively

normal life for a long period so that transplant is

un-necessary Indications include a prothrombin time more

than 5 s prolonged, a serum albumin concentration of less

than 30 g/l, and intractable ascites Bleeding oesophageal

varices, after failure of medical treatment, is a good

indi-cation The cost of transplant is little different from that of

long-term medical and surgical management of

compli-cations such as bleeding, coma and ascites.

The patients are poor operative risks because of

impaired blood coagulation and portal hypertension, so

that blood loss is great The technical difficulties are

greater when cirrhosis is present, particularly when the

liver is small and difficult to remove Survival is much

the same for all forms of cirrhosis.

Autoimmune chronic hepatitis

Post-transplant 5-year survival is 91% and graft survival

83% [85] Despite triple immunosuppression, 33%

develop recurrent chronic hepatitis of autoimmune type [30] This is usually asymptomatic but may be severe, leading to graft failure [86] Control is usually re- established by adjusting corticosteroid dose.

Chronic viral hepatitis

Hepatic transplantation performed for acute

fulmi-nant viral hepatitis (A, B, D and E) is not followed by graft re-infection as the viral levels are very low In the chronic situation, however, graft re-infection is very common.

Hepatitis B

Post-transplant recurrence is usual and is related to viral replication in extra-hepatic sites, particularly monocytes HBV-DNA is measured frequently A severe

fibrosing cholestatic hepatitis may develop with ballooning

of hepatocytes and ground-glass change This may be related to high cytoplasmic expression of viral antigens

in the presence of immunosuppression [7, 31] HBV may sometimes be cytopathic.

Hepatitis B immune globulin (HBIG), given before and

after transplant, improves survival However, it does not eliminate the virus and breakthrough replication can occur It must be given indefinitely and is costly Levels

of protective antibody may be achieved by a new HBIG preparation (CMRI Hb) obtained from screened vaccinated donors [4].

HBV vaccination, following discontinuation of HBIG,

may be associated with the development of protective serum titres of anti-HBs [93].

Lamivudine given before and after transplant may

control re-infection It has allowed transplant in HBV DNA and HBeAg-positive patients The high develop- ment of lamivudine failure [71] with lamivudine-resis- tant mutants is associated with re-infection [55, 65, 73] The combination of lamivudine and HBIG as prophy- laxis against reinfection is effective, so long as lamuvi- dine resistance has not occurred pre-transplant [92] Hepato-cellular cancer can develop in the trans- planted liver.

Hepatic Transplantation 659

Table 38.4 Percentage survival of 9966 patients according to

diagnosis of cirrhosis, acute liver failure and cancer (Data fromEuropean Liver Transplant Registry, 1993)

Cholestatic liver disease

Primary biliary cirrhosis

Biliary atresia

Primary sclerosing cholangitis

Secondary sclerosing cholangitis

Graft-versus-host disease

Chronic hepatic rejection

Cholestatic sarcoidosis (Chapter 28)

Chronic drug reactions (rare)

Primary metabolic disease (see table 38.5)

Acute liver failure (Chapter 8)

Malignant disease (Chapter 31)

Hepatitis delta

Transplantation is almost always followed by infection

of the graft HDV RNA and HDAg can be detected in the

new liver and HDV RNA in the serum [124] Hepatitis

only develops if there is concomitant or superinfection

with HBV.

Hepatitis B infection is inhibited by delta infection

and hepatitis B recurrence may be reduced by delta

infection In general, survival is good after transplant for

delta-infected patients.

Hepatitis C virus

Hepatitis C is the commonest indication for liver

transplantation in most centres All patients who are

positive for HCV by PCR pre-transplant will remain

positive, and 97% will develop recurrent hepatitis C

post-transplant (fig 38.2) Genetic sequencing of

vari-able regions of the viral genome pre- and post-transplant

will determine whether the infection is recurrent or

acquired Infection of the graft can come from infected

mononuclear cells which contain negative strand viral

RNA — the replicative intermediate of the viral genome.

Early results suggested that the overall 5-year survival of

patients with HCV was not worse than that with other

liver diseases [40] However, graft loss is increased and a

11–12% mortality is seen in the first year [24] Whether

long-term survival will decline due to recurrent disease

awaits further study [13].

The post-transplant course is very variable; 50% of

HCV-positive recipients, despite viraemia, will not have

graft hepatitis within 2 years of the operation [13].

Lobular hepatitis, frequently asymptomatic, may

develop 1–4 months post-transplant It is unrelated to

serum ALT The hepatitis usually progresses to chronic

hepatitis, which is often severe, with progressive fibrosis

[8] and eventually graft loss [41] Progressive fibrosing

cholestatic hepatitis may be seen [95] Re-grafting is

usually necessary.

Patients with pre-treatment HCV viral titres ing 1 ¥ 106have a 5-year survival of 57% as opposed to 84% for those with lower titres [24].

exceed-Prediction of a severe course is difficult Studies of the relationship to genotype and quasi-species are conflict- ing [8, 42] Earlier recurrence of HCV relates to the number of rejection episodes [98], with consequent immunosuppression and hence, increasing HCV viraemia The risk of severe fibrosis/cirrhosis may be greater with more aggressive immunosuppression [20] There is no difference between cyclosporin- and tacrolimus-treated patients.

Interferon is ineffective in those with particularly high serum viral titres and so does not affect survival or graft loss [97] It may increase the risk of graft rejection.

A pilot study has shown that interferon–ribavirin therapy can result in 50% clearance of HCV at the end of therapy Of initial responders, 50% will relapse [12, 14] Further controlled trials and longer follow-up are needed.

Neonatal hepatitis

This disease of unknown aetiology is associated with jaundice, giant cell hepatitis and rarely liver failure necessitating liver transplant which is curative [23].

Alcoholic liver disease

In the West, these patients are likely to provide the largest number of candidates for transplant The selection and the results obtained are discussed in Chapter 22.

Cholestatic liver disease

End-stage biliary disease, usually involving the small intra-hepatic bile ducts, is an excellent indication for hepatic transplantation (fig 38.3) Hepato-cellular function is usually preserved until late and the timing of

Increasedimmunosuppression

Fig 38.2 Mechanisms for recurrent HCV hepatitis after liver

transplantation

Biliary atresiaPrimary biliary cirrhosisGraft-vs.-host diseaseChronic rejectionCholestatic sarcoidosisChronic drug cholestasisSclerosing cholangitis

Transplant

Lossofbileducts

Fig 38.3 Diseases with disappearing bile ducts treated by

liver transplantation

the transplant is easy In every case the liver shows an

advanced biliary cirrhosis, often combined with loss of

bile ducts (‘disappearing bile duct syndrome’).

Primary biliary cirrhosis (Chapter 14)

One-year patient survival is 80% [96] Recurrence is

evident on hepatic histology, but there are no reports of

subsequent graft failure.

Extra-hepatic biliary atresia (Chapter 26)

This indication comprises 35–67% of paediatric liver

transplants Calculated 1-year survival is 75% Results

are excellent and long-term survivors have good

phy-sical and mental development, although re-transplant

and post-transplant surgery is often necessary.

A previous Kasai procedure increases the operative

difficulty and the morbidity.

Alagille’s syndrome

Transplant is required only in very severe sufferers [22].

Associated cardio-pulmonary disease may be fatal and

careful pre-operative assessment is necessary.

Primary sclerosing cholangitis (Chapter 15)

Sepsis and previous biliary surgery provide technical

problems Nevertheless, the results for transplantation

are good, 1-year survival being 70% and 5-year survival

57% Cholangiocarcinoma is a complication that greatly

reduces long-term survival Colon cancer is the most

frequent cause of death [72].

Langerhans’ cell histiocytosis accounts for 15–39% of

sclerosing cholangitis It has been successfully treated by

liver transplant [123].

Other end-stage cholestatic diseases

Hepatic transplantation has been performed for

graft-versus-host cirrhosis in a bone marrow recipient.

Other rare indications include cholestatic sarcoidosis

(Chapter 28) and chronic drug reactions.

Primary metabolic disease

Liver homografts retain their original metabolic

speci-ficity Consequently, liver transplantation is used for

patients with inborn errors that result from defects in

hepatic metabolism Patients suffering from these

condi-tions are good candidates Selection depends on the

prognosis and the likelihood of the later complication of

primary liver tumours.

Liver transplantation for metabolic disorders is

divided into those performed for end-stage liver disease or

pre-malignant change and those performed for major

extra-hepatic features (table 38.5) Overall survival is

85.9% over 5.5 years’ follow-up.

End-stage liver disease

a1-Antitrypsin deficiency

This is the most common metabolic disease leading to liver transplantation Macronodular cirrhosis will develop in about 15% before the age of 20 years Hepato- cellular carcinoma is a complication The plasma a1- antitrypsin deficiency is corrected and the lung disease stabilizes after the transplant Advanced pulmonary disease is a contraindication unless both lungs and liver are transplanted.

Genetic haemochromatosis (Chapter 23)

This is an uncommon indication for transplantation Survival is lower than for other indications, because of infection and cardiac problems Clear-cut recurrence of hepatic iron has not been reported but follow-ups are short [16].

Wilson’s disease (Chapter 24)

Liver transplants have to be considered in patients senting with fulminant hepatitis, in young cirrhotic patients with severe hepatic decompensation who have failed to improve after 3 months’ adequate d-penicil- lamine treatment, and in effectively treated patients who have developed severe hepatic decompensation follow- ing discontinuance of penicillamine.

pre-The overall survival is 72% increasing to 90% where the indication is fulminant Wilson’s disease [94].

Hepatic Transplantation 661

Table 38.5 Liver transplantation for metabolic disorders

End-stage disease or pre-malignant change

a1-Antitrypsin deficiencyWilson’s diseaseTyrosinaemiaGalactosaemiaGlycogen storage diseasesProtoporphyria

Neonatal haemochromatosisb-thalassaemia

Cystic fibrosisByler’s disease

Major extra-hepatic features

Primary oxaluria type 1Homozygous hypercholesterolaemiaCrigler–Najjar syndrome

Primary coagulation disorders (factor VIII, IX, protein C)Urea cycle defects

Mitochondrial respiratory chain defectsPrimary familial amyloidosis

Survivors transplanted for severe neurological

com-plications showed significant improvement [37].

Glycogen storage diseases

Liver transplantation has been successfully performed

for types I and IV, with survival and continued growth

into adult life.

Galactosaemia

A few patients diagnosed late develop advanced

cirrho-sis in childhood and early adult life and are candidates

for transplantation [81].

Protoporphyria

This can lead to end-stage cirrhosis and so be an

indication for liver transplantation [52]

Post-operatively, the high level of protoporphyrin in

erythro-cytes and faeces persists and the disease is not cured.

Tyrosinaemia

Hepatic transplantation is curative and should be

con-sidered early before the development of hepato-cellular

carcinoma [68].

b-Thalassaemia

Combined heart and liver transplantation has been

reported for end-stage, iron-induced organ failure in an

adult with homozygous b-thalassaemia [78].

Cystic fibrosis

Hepatic transplantation is indicated for predominant

liver involvement Combined liver–lung transplant is

often necessary The 3-year survival of young patients

with end-stage respiratory failure complicated by

cirrho-sis is 70% [28].

Byler’s disease

Byler’s disease (Progressive Familial, Intra-hepatic

Cholestasis type 1) results in death from cirrhosis or

heart failure The low serum apolipoprotein A1

concen-tration is corrected by transplant performed for cirrhosis

[19].

Correction of extra-hepatic features

Oxaluria

Primary oxaluria type I, due to deficiency of hepatic

peroxisomal alanine-glyoxylate aminotransferase, is

corrected by simultaneous hepatic and renal tation [117] Cardiac dysfunction reverses The hepatic transplantation should possibly be done before renal damage has developed.

transplan-Homozygous hypercholesterolaemia

Liver transplant produces an 80% decrease in serum lipids Cardiac transplant or coronary bypass are also usually necessary [88].

Crigler–Najjar syndrome

Liver transplant is indicated to prevent neurological sequelae when the serum bilirubin level is very high and cannot be controlled by phototherapy.

Primary coagulation disorders

The usual indication is HCV cirrhosis Transplant cures the haemophilia but the effects of HIV infection and recurrent viral hepatitis remain post-transplant complications [46].

Urea cycle enzyme deficiencies

Transplantation has been performed for ornithine carbamylase deficiency as urea cycle enzymes are pre- dominantly located in the liver [108] The decision concerning the need for transplantation is difficult as some urea cycle disorders allow a normal lifestyle.

trans-Mitochondrial respiratory chain defects

These may cause liver disease in neonates associated with hypoglycaemia and postprandial hyperlactic- acidaemia They have been treated by liver transplant.

Primary familial amyloidosis

Transplant, often by the domino technique, is performed for intractable polyneuropathy Neurological impro- vement is variable.

Acute liver failure (Chapter 8) Indications include fulminant viral hepatitis, Wilson’s disease, acute fatty liver of pregnancy, drug overdose (for instance, paracetamol), and drug-related hepatitis [11].

Malignant disease (Chapter 31) Hepatic transplantation has been disappointing in patients with liver tumours despite pre-operative attempts at identifying extra-hepatic spread Patients

with cancer have a low operative mortality, but the worst

long-term survival Carcinomatosis is the usual cause of

death Tumour recurs in 60%, perhaps because of the

immunosuppressants necessary to prevent rejection.

The peri-operative survival is 76%, but the 1-year

sur-vival only 50% and the 2-year sursur-vival 31% For all

tumours transplanted, the overall actual 5-year survival

is 20.4%.

Hepato-cellular carcinoma (Chapter 31)

The tumour must be 5 cm or less If multifocal, only three

tumours less than 3 cm each should be considered.

Staging laparoscopy is important at the time of

trans-plant Vascular invasion, even microscopic, increases the

recurrence rate and mortality.

The 2-year survival is 50 versus 83% for

non-malignant conditions.

Transplantation may be preferable to resection for

small tumours discovered incidentally in a patient with

compensated cirrhosis.

Fibro-lamellar carcinoma

The tumour is localized to the liver and cirrhosis is

absent This may be the best tumour candidate for

trans-plantation.

Epithelioid haemangio-endothelioma

This presents as multiple focal lesions in both lobes of an

otherwise normal liver The course is unpredictable and

recurrence is likely in 50% Metastatic spread does

not contraindicate surgery and this does not correlate

with survival It can be successfully treated by liver

transplantation.

Hepatoblastoma

Transplantation results in a 50% survival at 24–70

months Microscopic vascular invasion and anaplastic

epithelium with extra-hepatic spread are bad signs.

Neuro-endocrine tumours

When resection is not possible, worthwhile palliation

can result from hepatic transplantation [62].

Abdominal cluster operations for right upper

quadrant malignancy

Most of the organs derived from the embryonic foregut

are removed including liver, duodenum, pancreas,

stomach and intestine With powerful

immunosuppres-sion, donor lympho-reticular cells circulate without

causing clinical graft-versus-host disease and become

those of the recipient without causing rejection [104] The procedure is clearly very radical and patients usually die from recurrent tumour.

Cholangiocarcinoma

This is an unsatisfactory indication as tumour recurrence

is usual and 3-year survival is poor, being zero in some series In some countries, patients with cholangiocarci- noma are not accepted as transplant candidates.

Miscellaneous

Budd–Chiari syndrome (Chapter 11) Hepatic transplantation is used in those who are too ill to perform decompressive surgery and where previous portal-systemic shunts have failed [89] The 5-year sur- vival is 67–69% Recurrence of thrombosis is likely, espe- cially in those who have an underlying coagulopathy.

Non-alcoholic fatty liver disease (NAFLD)

The end-stage is macronodular fatty cirrhosis This is treated by transplantation, but 50% develop liver biopsy evidence of NAFLD post-transplant [79].

Absolute and relative contraindications

(table 38.6)

Absolute

These include uncorrectable cardio-pulmonary disease, ongoing infection, metastatic malignancy and severe brain damage.

Advanced cardiopulmonary disease

Relative (higher risk)

Age more than 60 or less than 2 yearsPrior-porta-caval shunt

Prior complex hepato-biliary surgeryPortal vein thrombosis

Re-transplantMulti-organ transplantsObesity

HIVSerum creatinine more than 2 mg/dl (180 mmol/l)Cytomegalovirus mismatch

Advanced liver disease

Transplant should not be done if the patient cannot

comprehend the magnitude of the undertaking and the

exceptional physical and psychological commitment

required [64].

Relative (higher risk)

Patients are at higher risk if they have advanced

liver disease (UNOS status 2A) and are being treated

in an intensive care unit and particularly if they are

ventilation-dependent.

Children do particularly well but technical difficulties

increase below the age of 2 years.

Risk increases with a body weight of more than 100 kg.

Multi-organ transplant adds to the risk.

A pre-transplant serum creatinine level exceeding

2.0 mg/dl (180 mmol/l) is the most accurate predictor of

post-transplant death [29].

CMV mismatch (recipient negative, donor positive)

adds to the risk.

Portal vein thrombosis makes the transplant more

difficult and survival is reduced However, the operation

is usually possible [105] An anastomosis is made

between the donor portal vein and the recipient

con-fluence of superior mesenteric vein and splenic vein, or a

venous graft from the donor is used.

Previous surgical porta-caval shunts make the

opera-tion more difficult and a distal spleno-renal shunt creates

least problems TIPS for variceal bleeding is the most

satisfactory preliminary to transplantation [2] Careful

positioning of the stent is important, avoiding an

exces-sive length down the portal vein.

Previous complex surgery in the upper abdomen also

makes the transplant technically very difficult.

Re-transplant

In Europe, primary transplant is associated with

a 71% survival at 1 year This is reduced to 47% for

re-transplantation.

General preparation of the patient

The usual clinical, biochemical and serological

investiga-tion of any patient with liver disease is detailed.

Blood group, HLA and DR antigens are recorded.

Antibodies to cytomegalovirus and hepatitis C are

mea-sured and markers of hepatitis B infection noted.

In patients with malignant disease, metastases must

be sought by all possible techniques.

Cardio-pulmonary assessment should be thorough

including the exclusion of hepato-pulmonary syndrome.

Imaging Splanchnic vasculature and particularly the

hepatic artery and portal vein must be visualized as a

guide to surgery Doppler ultrasound is routine The

hepatic arterial tree is also shown in contrast-enhanced helical CT [77]

MRI may be used as an alternative, or together with CT to exclude vascular abnormalities and silent malignancy.

The bile ducts are visualized by MRI cholangiography [44] or, if necessary, by ERCP.

The pre-transplant medical ‘work-up’ takes about 10 days It includes psychiatric counselling and confirma- tion of the diagnosis The patient may wait many months for a suitable donor liver and, during this period, inten- sive psychosocial support is necessary.

Donor selection and operation

Donation may be informed with consent from the family,

the clinician ensuring that the family have been

con-sulted, or presumed consent including the patient having

specifically indicated their wish to donate Those tries practising presumed consent tend to have higher transplant rates than those using informed consent However, Spain, with the highest donation transplanta- tion rate in Europe has the custom of informed consent, but a very well-resourced programme of trained co- ordinators Better education, support and advice is needed for all clinical staff who have contact with potential donors [76].

coun-Donor shortage has encouraged the use of livers merly regarded as unsatisfactory These include livers from donors with abnormal liver tests, elderly donors, those with prolonged ICU stay receiving inotropes, or with steatosis which was formerly an exclusion criterion Use of these marginal livers does not seem to have increased graft loss.

for-Donors are considered between 2 months and 60–65 years of age, victims of brain injury that has resulted in brain death Cardio-vascular and respiratory functions are sustained by mechanical ventilation The recovery of livers and other vital organs from heart-beating cadavers minimizes the ischaemia that occurs at normal body tem- peratures and is a major contribution to graft success Transplant across A, B and O blood groups may be fol- lowed by severe rejection It should be avoided unless necessitated by an emergency situation [48].

HLA matching is more difficult and indeed there is some evidence that selected HLA class II mismatches may be advantageous, particularly in preventing the vanishing bile duct syndrome [74].

Hepatitis B and C viral markers, CMV antibodies and HIV testing should be done.

The donor operation is as follows The hepatic tures are dissected and the liver is pre-cooled through the portal vein with Ringer’s lactate and 1000 ml of Uni- versity of Wisconsin (UW) solution perfused through the aorta and portal vein A cannula in the distal inferior

struc-vena cava provides a vent for venous outflow After

removal, the cold liver is further flushed with an

addi-tional 1000 ml UW solution through the hepatic artery

and portal vein and stored in this solution in a plastic bag

on ice in a portable cooler This routine has extended the

preservation time to at least 18 h so that the recipient

operation may be semi-elective and not performed at

unsocial hours Most centres now have designated

multi-organ retrieval teams.

If possible, and particularly for elective procedures,

the size of the donor liver should be matched to that of

the recipient This is based on a body weight within 10 kg

of the recipient Occasionally a small-sized liver is

trans-planted into a larger patient The donor liver increases in

size at the rate of about 70 ml/day until it achieves the

volume expected for the recipient’s size, age and sex

[113].

The recipient operation (fig 38.4)

The average operative time is 8 h Blood loss is variable,

volumes being minimal or massive Cell savers have

proven useful in transplants anticipated to have a high

blood loss The blood is aspirated from the abdominal

cavity, washed repeatedly, re-suspended and infused.

The hilar structures and vena cava above and below

the liver are dissected The various vessels are

cross-clamped and divided to allow removal of the liver.

During the implantation of the new liver, it is

neces-sary to occlude the splanchnic and vena caval tions During this anhepatic phase, veno-venous bypass may be used to prevent pooling in the lower part of the body and splanchnic congestion The cannulae are placed in the inferior vena cava (via the femoral vein) and the portal vein, and run to the subclavian vein The veno-venous bypass allows greater haemo- dynamic stability during the anhepatic phase of the operation.

circula-Once all vascular anastomoses are completed, the preservation fluid is flushed out of the graft before opening the blood supply to the liver Portal vein throm- bosis must be excluded Hepatic arterial anomalies are frequent, and vessel grafts from the donor should be available for arterial reconstructions.

The usual order of anastomases is: (a) supra-hepatic vena cava; (b) intra-hepatic vena cava; (c) portal vein; (d) hepatic artery; and (e) biliary system The bile duct

is usually reconstructed by direct anastomosis with external bile drainage through a T-tube in selected cases.

If the recipient bile duct is diseased or absent, side Roux-en-Y choledocho-jejunostomy is chosen Haemostasis is essential before closing the abdomen; perihepatic drains are placed.

end-to-Segmental (split) liver transplantation

Because of the difficulty in obtaining small donor livers for young children, segments of adult cadaveric livers have been used (fig 38.5, table 38.7) Two viable grafts can be obtained from a single donor liver [38, 83] Results are not quite as satisfactory as with full liver grafts (75 versus 85% 1-year survival) [17] There are more complications including increased intra-operative blood loss and biliary problems [9, 10].

Cadaveric split liver grafts are also being used in the

adult [21] The split may be done ex vivo on the bench Alternatively, the split may be done in situ with improved

results for graft survival (85%) and patient survival (90%) Two grafts of optimal quality are obtained.

Live-related transplantation This has been introduced

because of the shortage of small cadaveric grafts The liver is obtained from a live-related donor [59] This tech- nique was used originally largely in children, often with biliary atresia where small donor livers are not available.

Hepatic Transplantation 665

Fig 38.4 Completed orthotopic liver transplantation Biliary

tract reconstruction is by duct-to-duct anastomosis

Table 38.7 Strategies to overcome liver-donor shortage

Better clinician and public educationPresumed consent

Split liversLive-related donorsPartial auxiliary graftsXeno-transplantationHepatocyte transplantation

The over-all lack of cadaveric liver grafts also contributed

to the development of this approach in some countries.

There are important ethical considerations concerning

the donor, who is usually a relative, and must give free

and informed consent The transplant has the advantage

of an elective operation Ischaemia time is shortened and

there is less re-perfusion injury Living-related donation

has been extended to the adult It has been used in

primary biliary cirrhosis [56] and in acute liver failure

when a cadaveric donor was not available at short notice.

There is a recognised risk to the live donor of left

hepatectomy to provide a paediatric graft Operative

stay averages 11 days and the blood loss is only about

200–300 ml Rarely the donor may have operative and

post-operative complications such as injury to the bile

duct There have been at least two reported deaths [47].

The required size of a donation is much greater for an

adult than for a child The critical limit of graft size is

unknown, but is probably around 50% of the predicted

liver volume, although it may be as low as 25% This has

led to the use of right lobe grafts [114] In large adults

with poor hepatic reserve, only the right lobe can

provide the necessary hepatic mass Problems are

increased with postoperative cholestasis and biliary

complications [86] A combined kidney–right hepatic

lobe transplant from a living donor has been performed

[66] The patient suffered transient hepatic impairment.

Auxiliary liver transplantation

Healthy liver tissue is introduced leaving the native liver

in situ [69] It may be indicated in acute liver failure

where there is a chance that the patient’s own liver will

regenerate [111, 112] It may also be used in the treatment

of some metabolic defects [87].

A reduced size graft is usually used The left lobe

of the donor liver is excised and the right lobe mosed to the portal vein, inferior vena cava and aorta of the recipient The donor liver hypertrophies and the recipient’s own liver atrophies.

anasto-Complications, particularly portal vein thrombosis and primary graft non-function, are increased.

Auxiliary liver transplantation offers the possibility of

a life-time free of immunosuppressive therapy This is discontinued when the host liver has recovered In time the auxiliary is likely to atrophy and should probably be removed.

Xeno-transplantation

Several non-human livers have been transplanted into humans There are eight accounts of such transplants from pig, baboon or chimpanzee No recipient has lived longer than 72 h [61] The main limitation is immu- nological, including hyper-acute and delayed xeno-graft rejection and T-cell-dependent xeno-graft rejection Various control strategies are under investigation [15] but the problems will be difficult to overcome.

Human infections, particularly viruses (especially porcine endogenous retroviruses) may be introduced with the xeno-transplant There are ethical difficulties in accepting xeno-transplantation [102].

Domino liver transplantation

Structurally normal livers can be removed to control a metabolic defect such as familial amyloid polyneuropa- thy [36] Such a liver may be offered for transplant to a recipient who has given full consent The consequences

of the metabolic defect will be delayed many years.

HV(sutured)

IVCRPV

PV

LHVRHV

MHV

LBDLPVLHACBD

8

56

7

2

3

4

Fig 38.5 Diagram of the two grafts

prepared from one donor liver In thisexample the main vascular and biliarystructures are attached to the right lobe.CBD, common bile duct; CT, coeliactrunk; HV, hepatic vein; IVC, inferiorvena cava; LBD, left bile duct; LHA, leftbranch of hepatic artery; LHV, left hepaticvein; LPV, left branch of portal vein;MHV, middle hepatic vein; PV, portalvein; RHA, right branch of hepatic artery;RHV, right hepatic vein; RL, roundligament; RPV, right branch of portalvein Numbers indicate hepatic segments[38]

Hepatocyte transplantation

Transplantation of human hepatocytes is being

devel-oped to treat metabolic liver disease where a supply of

normally functioning liver cells can correct a genetic

deficiency [49] However, the recipient may require

long-term immunosuppression Transplanted hepatocytes

may be used to replace a missing or inactive enzyme, as

in the Crigler–Najjar syndrome, or inactivate a

disease-inducing gene or over-express a normal gene [25, 49].

Hepatocyte transplant may also be used in acute liver

failure to sustain liver function until the native liver has

regenerated.

Liver transplantation in paediatrics

The mean age is about 3 years, but successful transplant

has been performed at less than 1 year old [5] Scarcity of

paediatric donors may necessitate adult reduced-liver or

split-liver donations.

Post-transplant, growth is good and the quality of life

excellent [119].

The small size of the vessels and bile ducts poses

technical problems Pre-transplant anatomy should be

identified by CT or, preferably, MRI Hepatic artery

thrombosis occurs in at least 17% [106] Re-transplants

are frequent Biliary complications are also common.

One-year survival is 75.5% for children who are less

than 3 years old [82] Renal function may deteriorate

post-transplant and this is not solely due to cyclosporin

A Infections are frequent, particularly varicella,

Epstein–Barr, mycobacteria, Candida and CMV.

Immunosuppression

There have been major advances in both scientific

understanding and the therapy of rejection Multiple

therapy is usually given and the choice varies between

centres and is nowadays tailored to both individual

patient and to the underlying disease Most

immuno-suppressive regimens include a calcineurin inhibitor —

that is cyclosporin or tacrolimus These are given with

corticosteroids.

After the transplant the patient receives oral

cyclosporin or tacrolimus New formulations have

improved oral absorption and can be given immediately

after transplantation Patients receive cyclosporin

(5–10 mg/kg/day) in divided doses together with

intra-venous methylprednisolone, which is tapered to

0.3 mg/kg/day For tacrolimus the equivalent dose is

0.1 mg/kg/day.

Some centres do not use a calcineurin inhibitor

ini-tially but use azathioprine and methylprednisolone,

introducing cyclosporin or tacrolimus only when renal

function is adequate.

Cyclosporin is continued for long-term maintenance orally with 5–10 mg/kg/day In most, but not all, patients corticosteroids may be withdrawn during the first 3 months.

Cyclosporin side-effects include nephrotoxicity but the glomerular filtration usually stabilizes after a few months Nephrotoxicity is enhanced by drugs such as the aminoglycosides Electrolyte disturbances include hyperkalaemia, uricacidaemia and a fall in serum mag- nesium Other complications include hypertension, weight gain, hirsuties, gingival hypertrophy and dia- betes mellitus Lymphoproliferative diseases can be seen long term Cholestasis can develop Neurotoxicity

is shown by mood alterations, seizures, tremor and headaches.

Cyclosporin and tacrolimus can interact with other drugs leading to changing blood levels (table 38.8) Cyclosporin is costly and has a narrow therapeutic index and its use has to be monitored carefully Trough blood levels are taken, at first frequently, and then at regular intervals Optimal levels at different times after transplant have not been clearly defined.

Tacrolimus (FK 506) is more powerful than cyclosporin

in inhibiting IL2 synthesis and controlling rejection It has been used to salvage patients with repeated liver rejection [103] It is comparable to cyclosporin in terms of patient and graft survival [110, 120] There are, however, fewer episodes of acute and refractory rejection and less need for corticosteroid immunosuppression There are more adverse effects necessitating discontinuation These include nephrotoxicity, diabetes, diarrhoea, nausea and vomiting Neurological complications (tremors and headache) are more common with tacrolimus than cyclosporin

Azathioprine side-effects include myelosuppression,

cholestasis, peliosis hepatis, peri-sinusoidal fibrosis and veno-occlusive disease.

Hepatic Transplantation 667

Table 38.8 Interaction between cyclosporin (and tacrolimus)

and other drugs

Increase cyclosporin levels

Erythromycin (clarithromycin)Ketoconazole

CorticosteroidsMetoclopromideVerapamilDiltiazemTacrolimus

Decrease cyclosporin levels

OctreotidePhenobarbitonePhenytoinRifampicinSeptrin (Bactrim)Omeprazole

Both mycophenolate mofetil and serolimus are

non-nephrotoxic Serolimus inhibits B- and T-cell activity

by inhibition of IL2 pathways [116] These agents can

be used in combination with calcineurin inhibitors

(cyclosporin, tacrolimus) or alone.

Previously antilymphocyte globulin and T-cell antibodies

were given to prevent acute rejection They have been

replaced by specific monoclonal antibodies directed against

the IL2 receptor [33] These receptors are expressed only

by activated lymphocytes and the monoclonal

anti-bodies are given early to reduce acute rejection

Basilix-imab and diclizumab have been licensed, but are costly.

The difficulties in balancing the risks of too much

immunosuppression, which increases infections, with

too little immunosuppression, which increases graft

rejection, continue.

Tolerance

Donor cells have been identified in the blood of

recipi-ents of liver transplantation This chimerism could

influ-ence the host immune system with development of

tolerance to donor tissues A donor liver may be

sponta-neously accepted more often than other organs [90] This

opens up the possibility of stopping

immunosuppres-sive therapy However, this is rarely possible After a

suc-cessful 5-year survival of a primary graft, only one-third

of patients may be able to stop immunotherapy in the

subsequent 3 years The other two-thirds develop graft

abnormalities [34] Chimerism was not associated with

tolerance Factors suggesting successful withdrawal of

immunosuppression were transplantation for a

non-immunological condition, poor MHC mismatch and a

low incidence of early acute rejection.

Post-operative course

This is not easy, particularly in the adult Further surgery

such as control of bleeding, biliary reconstruction or

draining abscesses may be necessary.

Re-transplantation is required in 5–10% of patients.

The main indications are primary graft failure, hepatic

arterial thrombosis and chronic rejection Renal dialysis

may be required Results are not so satisfactory as for the

first transplant.

Factors determining an adverse result include poor

pre-transplant nutrition, Child’s grade C status, a raised

serum creatinine level and severe coagulation

abnormal-ities Poor results are also related to the amount of blood

products required during surgery, the need for renal

dialysis post-transplant and severe rejection The

opera-tion is easier in those without cirrhosis and portal

hyper-tension, and the peri-operative mortality is considerably

less.

The causes of death are surgical: technical

complica-tions (either immediate or late), biliary leaks and hepatic rejection, with or without infections often related to large doses of immunosuppressants.

The patient usually spends about 2 months in hospital

or attending outpatients and is fully rehabilitated in 6 months.

Quality of life is usually excellent in the majority of

patients with return to normal at home and work Drug ingestion and monitoring are a burden Social function- ing improves in most [54] However, only 43% of 9- month survivors are working [3] The patient’s age, duration of disability before transplant and type of job significantly affect the post-transplant employment status.

Those with recurrent disease, for instance HCV, have a worse quality of life than those without recurrent disease [100].

More than 87% of paediatric survivors are fully rehabilitated with normal growth, both physical and psychosexual.

Post-transplantation complications

(table 38.9) The three major problems are:

1 primary graft non-function (days 1-2);

2 rejection (from 5–10 days); and

3 infections (days 3–14 and on).

Table 38.9 Complications of liver transplantation

Weeks Complications

1 Primary graft non-function

Bile leaksRenalPulmonaryCNS1–4 Cellular rejection

CholestasisHepatic artery thrombosis5–12 CMV hepatitis

Cellular rejectionBiliary complicationsHepatic artery thrombosisHepatitis C

12–26 Cellular rejection

Biliary complicationsHepatitis B

EBV hepatitisDrug-related hepatitis

>26 Ductopenic rejection (rare)

EBV hepatitisPortal vein thrombosisDisease recurrence (HBV, HCV, tumours)

The presenting features of all three are very similar,

namely a large, firm, tender liver, increasing jaundice,

fever and leucocytosis Specialist investigations must be

available [53] These include CT [35], MRI and Doppler

imaging, HIDA scanning, angiography and

percuta-neous and endoscopic cholangiography.

Protocol liver biopsies are taken of the donor liver

pre-transplant and 5 days, 3 weeks and 1 year after

transplantation No particular feature in the donor liver

biopsy predicts function after transplantation However,

zonal or severe focal necrosis and neutrophil infiltration

predicts a poor early course.

Primary graft non-function

This affects less than 5% of patients between the first 24

and 48 h (fig 38.6) It is related to inadequate

preserva-tion of the donor liver, particularly a long (more than 30

h) cold preservation time and especially warm ischaemia

time, to hypo-acute rejection or to shock in the recipient.

It is marked by worsening state, hyperdynamic

instabil-ity, renal dysfunction, lactic acidosis with increases in

prothrombin time, bilirubin, transaminases and

potas-sium Blood glucose falls.

Re-transplantation is the only treatment and

should not be delayed in the hope of spontaneous

improvement.

Technical complications

Surgical complications will develop in about half of

patients They are most frequent in children with small

vessels and bile ducts.

Doppler ultrasonography is used for detection of

hepatic arterial, hepatic venous, portal venous or

inferior vena caval stenosis or thrombosis [80].

Routine ultrasound, CT or MRI is used to evaluate

hepatic parenchymal abnormalities, peri-hepatic tions and biliary dilatation.

collec-Cholangiography through the T-tube is used to define biliary abnormalities HIDA scanning or cholangiogra- phy may be used to show biliary leaks.

Guided biopsy allows aspiration of fluid collections.

Subcapsular hepatic necrosis This is related to

disproportionate size between donor and recipient It can be visualized by CT scanning and usually resolves spontaneously [1].

Bleeding This is more likely if the removal of a

dis-eased liver has left a raw area on the diaphragm or if there have been adhesions from previous surgery or infec-tion Treatment is by transfusion and re-operation

if necessary.

Vascular complications

Hepatic artery thrombosis is most frequent in children It

may be acute, marked by clinical deterioration, fever and bacteraemia, a rise in enzymes and coagulopathy and hepatic necrosis (fig 38.7) Alternatively it may be silent, presenting days to weeks later with biliary complica- tions [109] including leaks and strictures, and recurrent bacteraemia and abscess.

Doppler ultrasound is diagnostic, although triple phase helical CT may be necessary to show intra- hepatic branch occlusion The findings may be con- firmed by angiography Re-transplantation is the usual treatment.

Hepatic arterial stenosis This usually develops at the

anastomotic site If diagnosed early in the post-operative period it may be corrected surgically Later, balloon angioplasty may be successful.

Portal vein thrombosis is uncommon in adults It

pre-sents as graft dysfunction and massive ascites Urgent

Hepatic Transplantation 669

Fig 38.6 Graft ischaemia 2 days after liver transplantation.

Hepatocytes are swollen with loss of cytoplasm (H & E, ¥380.)

Fig 38.7 Hepatic infarction, 3 days post-transplant, due to

hepatic artery thrombosis An area of necrotic, infarctedhepatocytes with haemorrhage adjoins normal liver tissue (H & E, ¥150.)

revascularization is essential If not corrected,

re-transplant is necessary.

Portal vein thrombosis is often silent, presenting as

variceal bleeding weeks to months after the transplant.

Hepatic vein occlusion This is common in patients

who have had liver transplantation for the Budd–Chiari

syndrome Occasionally there is stricturing of the

supra-hepatic–caval anastomosis and this can be

treated by balloon dilatation.

Biliary tract complications

Bile secretion recovers spontaneously over a 10–12-day

period and is strongly dependent upon bile salt

secre-tion The incidence of complication is 6–34% of all

trans-plants usually during the first 3 months (table 38.10)

[67, 109].

Bile leaks may be early (first 30 days) related to the bile

duct anastomosis or late (about 4 months) after T-tube

removal Abdominal pain and peritoneal signs may be

masked by immunosuppression.

Early leaks are diagnosed by ERCP or percutaneous

cholangiography HIDA scanning may be useful They

are usually treated by the endoscopic insertion of a stent

or nasobiliary drain.

Extra-hepatic anastomotic strictures These present after

about 5 months as intermittent fever and fluctuating

serum biochemical abnormalities There is a wide

differ-ential diagnosis including rejection and sepsis They are

diagnosed by MRI cholangiography [44], ERCP or

per-cutaneous cholangiopancreatography and treated by

balloon dilatation (see fig 32.19) and/or insertion of a

plastic stent [109] Hepatic arterial patency must be

established.

Non-anastomotic or ‘ischaemic-type’ biliary strictures

develop in 2–19% [43] They are associated with

multi-factorial damage to the hepatic arterial plexus around

bile ducts Factors include prolonged cold ischaemia

time, hepatic arterial thrombosis, ABO blood group

incompatibility, rejection, foam cell arteriopathy and a

positive lymphocytotoxic cross-match Peri-biliary

arte-riolar endothelial damage contributes to segmental

microvascular thrombosis and hence to multiple

seg-mental biliary ischaemic strictures.

Non-anastomotic strictures usually develop after several months They develop in the donor common hepatic duct, with variable extension into the main intra- hepatic ducts On cholangiography the wall of the duct may appear irregular and hazy, presumably reflecting areas of necrosis and oedema Attempts are made to treat them by balloon dilatation and stenting Hepatico- jejunostomy is sometimes possible Re-transplant may

be necessary.

Biliary stones, sludge and casts These can develop any

time following transplant Obstruction, particularly biliary stricture, may be important Foreign bodies such

as T-tubes and stents may serve as a nidus for stone formation Cyclosporin is lithogenic

Treatment is by endoscopic sphincterotomy and stone extraction with naso-biliary irrigation if necessary.

Renal failure

Oliguria is virtually constant post-transplant, but in some renal failure is more serious The causes include pre-existing kidney disease, hypotension and shock, sepsis, nephrotoxic antibiotics and cyclosporin or tacrolimus Renal failure often accompanies severe graft rejection or overwhelming infection.

Pulmonary complications

In infants, death during liver transplantation may be

related to platelet aggregates in small lung vessels Intravascular catheters, platelet infusions and cell debris from the liver may contribute.

In the ICU, pulmonary infiltrates are most frequently due to pulmonary oedema and pneumonia Other causes are atelectasis and respiratory distress syndrome [99] In the first 30 days, pneumonia is usually due to

methicillin-resistant Staphylococcus aureus, Pseudomonas

and aspergillosis After 4 weeks pneumonia due to CMV

and Pneumocystis is seen Later (more than 1 year), when

the patient has developed recurrent HCV or HBV, phoproliferative disorder or chronic rejection are seen.

lym-In one report, 87% of patients with pneumonia required ventilation and 40% were bacteraemic Pyrexia, leucocytosis, poor oxygenation and cultures of the bronchial secretions indicate pneumonia and demand antibiotic therapy The overall mortality for those having pulmonary infiltrates in the ICU is 28% [99].

Pleural effusion is virtually constant and in about 18% aspiration is necessary.

A post-transplant hyperdynamic syndrome tends to normalize with time.

The hepato-pulmonary syndrome (Chapter 6) is usually corrected by liver transplant but only after

a stormy post-transplant course with prolonged aemia, mechanical ventilation and intensive care [60].

hypox-Table 38.10 Biliary complications of liver transplantation

Non-specific cholestasis

This is frequently seen in the first few days, with the

serum bilirubin peaking at 14–21 days Liver biopsy

suggests extra-hepatic biliary obstruction but

cholan-giography is normal Factors involved include mild

preservation injury, sepsis, haemorrhage and renal

failure If infection is controlled, liver and kidney

func-tion usually recover but a prolonged stay in the ICU is

usually necessary.

Rejection

Immunologically, the liver is a privileged organ with

regard to transplantation, having a higher resistance to

immunological attack than other organs The liver cell

probably carries fewer surface antigens Nevertheless,

episodes of rejection, of varying severity, are virtually

constant.

Cellular rejection is initiated through the presentation

of donor HLA antigens by antigen-presenting cells to

host helper T-cells in the graft These helper T-cells

secrete IL2 which activates other T-cells The

accumula-tion of activated T-cells in the graft leads to

T-cell-mediated cytotoxicity and a generalized inflammatory

response.

Hyper-acute rejection is rare and is due to

pre-sensitization to donor antigens Acute (cellular) rejection

is fully reversible, but chronic (ductopenic) is not The

two may merge into one another The diagnosis of

rejec-tion from opportunistic infecrejec-tions is difficult and protocol

liver biopsies are essential Increased

immunosuppres-sion to combat rejection favours infection.

Acute cellular rejection

64% of patients will have at least one episode, usually

5–20 days post-transplant and within the first 6 weeks

[121] Acute rejection does not have an adverse effect on

patient or graft survival [51, 75] There is little need to

give higher immunosuppression during the first few

days The patient feels ill, there is mild pyrexia and

tachycardia The liver is enlarged and tender Serum

bilirubin, transaminases and prothrombin time increase.

The liver enzyme changes lack specificity and a liver

biopsy is essential.

Rejection is shown by the classical triad of portal

inflammation, bile duct damage (fig 38.8) and

sub-endothelial inflammation of portal and terminal hepatic

veins (endothelialitis) (fig 38.9) Eosinophils may be

conspicuous [50], and hepato-cellular necrosis may be

seen.

Rejection may be graded into mild, moderate and

severe (table 38.11) [32] Follow-up biopsies may show

eosinophils, resembling a drug reaction, and infarct-like

areas of necrosis, perhaps secondary to portal venous obstruction by lymphocytes Hepatic arteriography shows separation and narrowing of hepatic arteries (fig 38.10) Histological severity correlates prognostically with steroid failure, early death or re-transplant [121] In 85%, treatment is successful by increasing immunosup- pression Boluses of high dose methylprednisolone are given, for example 1 g intravenously daily for 3 days Those who are steroid-resistant receive IL2 monoclonal antibody for 10–14 days Tacrolimus rescue may also be tried Those failing to respond to these measures proceed

to ductopenic rejection Re-transplant may be needed if the rejection continues.

Chronic ductopenic rejection

Bile ducts are progressively damaged and ultimately

Hepatic Transplantation 671

Fig 38.8 Acute rejection: a damaged bile duct infiltrated with

lymphocytes is seen in a densely cellular portal tract (H & E,

¥100.)

Fig 38.9 Acute cellular rejection 8 days post-transplant Liver

biopsy shows portal zone infiltration with mononuclear cellsand endothelialitis of cells lining the portal vein (H & E, ¥ 100.)

disappear [122] The mechanism seems to be

immuno-logical with aberrant expression of HLA class II antigens

on bile ducts Donor–recipient HLA class I mismatch

with class I antigen expression on bile ducts is

contributory.

The incidence of chronic rejection has decreased from

20 to 15% in the 1980s to 5% currently [57] This is due to better control of acute and early chronic rejection and to the unique regenerative capabilities of the liver.

Ductopenic rejection is defined as loss of interlobular and septal bile ducts in 50% of portal tracts Duct loss is calculated from the ratio of the number of hepatic arter- ies to bile ducts within a portal tract (normal greater than 0.7) Preferably 20 portal tracts should be studied [58] Foam cell obliterative arteriopathy increases the bile duct damage Ductopenic rejection may be graded histo- logically into mild, moderate and severe (table 38.11) [32].

Bile duct epithelium is penetrated by mononuclear cells resulting in focal necrosis and rupture of the epithe- lium Eventually bile ducts disappear and portal inflam- mation subsides (fig 38.11) Larger arteries (not seen in

a needle biopsy) show subintimal foam cells, intimal sclerosis and hyperplasia Centrizonal necrosis and cholestasis develop and eventually biliary cirrhosis Ductopenic rejection usually follows early cellular rejection (at about 8 days) with bile duct degeneration (at about 10 days) and ductopenia (at about 60 days) The onset is usually within the first 3 months but can be sooner Cholestasis is progressive.

Hepatic arterial occlusions may be a feature of chronic rejection (fig 38.12), leading to bile duct stricturing shown by cholangiography CMV cholangitis can also lead to the sclerosing cholangitis picture.

Features indicating that irreversible graft damage

Table 38.11 NIDDK-LTD nomenclature and grading of liver allograft rejection [32]

A1 (mild) Rejection infiltration in some, but not most, cholestasis, peri-venular sclerosis or

of the triads, confined within the portal hepato-cellular ballooning or necrosis and

A2 (moderate) Rejection infiltrate involving most or all of B2 (intermediate/moderate) Bile duct loss, with one of the following four

the triads, with or without spill-over into findings: centrilobular cholestasis,

lobule No evidence of centrilobular peri-venular sclerosis, hepato-cellular

A3 (severe) Infiltrate in some or all of the triads, with or B3 (late or severe) Bile duct loss, with at least two of the

without spill-over into the lobule, with or following four findings: centrilobularwithout inflammatory cell linkage of the cholestasis, peri-venular sclerosis,

triads, associated with moderate–severe hepato-cellular ballooning, or centrilobular

and drop-out

* The diagnosis of acute rejection is based on the presence of at least two of the following three findings: (a) predominantly

mononuclear but mixed portal inflammation; (b) bile duct inflammation/damage; and (c) subendothelial localization of

mononuclear cells in the portal and central veins Thereafter, the severity of rejection is graded on the above findings

† Bile duct loss in >50% of triads must be present for the diagnosis

Fig 38.10 Hepatic arteriogram in acute cellular rejection

shows separation of intra-hepatic arterial tree with marked

narrowing