493
Occasional Survey
THE SYNDROME OF DISAPPEARING
INTRAHEPATIC BILE DUCTS
SHEILA SHERLOCK
Department of Surgery, Royal Free Hospital School of Medicine,
Pond Street, London NW3 2QG
Diseases with disappearing intrahepatic
Summary
bile ducts may be developmental,
immunological, infective, vascular, or chemical in origin.
The immunological group includes primary biliary
cirrhosis, graft-versus-host disease, and sarcoidosis. HLA
class 2 antigens are displayed on the bileducts and
recognition of biliary antigens by cytotoxic T-cells leads to
destruction of interlobular ducts. Primary sclerosing
cholangitis is associated with immunological features, but
the hepatic histology is not that of immunological duct
disease. The association with immunodeficiency
syndromes, and the finding that secondary sclerosing
cholangitis may occur in patients with the acquired
immunodeficiency syndrome who are infected with
cytomegalovirus, suggest that primary sclerosing
cholangitis might be infective in origin. In bacterial
cholangitis there is contiguity between the biliary system
and the intestinal tract and usually, but not necessarily,
partial biliary obstruction. Interference with the hepatic
arterial supply to the bileducts leads to vascular cholangitis.
Chemical cholangitis follows injection of scolicidal agents
into the biliary tree. Diseases with disappearing bileducts
have a long natural history and hepatocellular failure occurs
late. In the late stages hepatic transplantation gives good
results.
INTRODUCTION
THE intrahepatic bileducts are open to several forms of
attack. This paper attempts to classify the mechanism of
destruction as being developmental, immunological,
infective, vascular, or chemical in origin (see accompanying
figure). In the early stages the impact is on the biliary system
and hepatocyte damage is minor; liver failure occurs late.
Consequently the prognosis for diseases with disappearing
intrahepatic bileducts is better than for those diseases that
affect primarily the hepatocyte. Ultimately, however, biliary
cirrhosis and hepatocellular failure develop. Because the
course of the disease is slow and hepatocyte function is
preserved until late in the disease patients with diseases in
which intrahepatic bile ducts disappear are excellent
candidates for hepatic transplantation.
THE BILIARY (DEVELOPMENTAL) ATRESIAS
These diseases generally start in intrauterine life and
are often classified as developmental, although in most
instances the abnormality is due to an extraneous, often
infectious, cause acting during the intrauterine period
or shortly after birth. Infectious agents include
cytomegalovirus, reovirus 3, and rubella. Alpha-l-
antitrypsin deficiency and an excess of a bile acid, such as
trihydroxycoprostanic acid, may be related in some cases.
The diseases result not from failure of bileducts to form
but from destruction during embryonic development.1
Histological examination may indicate the stage at which the
damage started.1 At the early stage of formation of the ductal
Classification of causes of disappearing intrahepatic bileducts.
plate, abnormal cylindrical ducts show atrophy or necrosis
of lining cells. Later the changes are of regression and
involution in normally shaped ducts. These diseases, often
grouped together as "infantile obstructive cholangio-
pathy",2 show allgrades of destruction from complete
absence (atresia) of bileducts to drastic reduction (paucity) of
numbers. The baby with complete atresia is usually dead by
age 5 years whereas paucity is compatible with survival into
adult life.
In the Alagille form of paucity of bileducts,3 the syndrome
includes the characteristic triangular facies, vertebral arch
defects, cardiovascular abnormalities, and posterior
embryotoxon in the eye. Histologically the liver shows few,
if any, interlobular bileducts and a reduced number of portal
zones 4The disease is inherited as a dominant characteristic,
and the prognosis is surprisingly good-the chronic
cholestasis is associated with little fibrosis, so neither
cirrhosis nor secondary portal hypertension develops. In
one series, only 21 of 80 patients died, liver failure being
responsible for only 4 deaths.5
IMMUNOLOGICAL CAUSES OF DISAPPEARING BILEDUCTS
Aberrant of HLA class 2 histocompatibility
expression
antigens onbileducts may increase their susceptibility to
damage because T-cells recognise stimulated class 2
antigens foreign
as and so could mediate the bileduct injury.
Primary Biliary Cirrhosis
Increased class 2 HLA expression on bileduct cells has
been reported in most patients with primary biliary
cirrhosis6 a disease with slow disappearance of intrahepatic
bileducts, so this disease might represent a failure of
immunoregulation, with a loss of tolerance to tissues bearing
a rich display of histocompatibility antigens. The pancreatic
and lacrimal ducts also display HLA class 2 antigens and
may contribute to making primary biliary cirrhosis
analogous to graft-versus-host disease, in which similar
ducts are affected.7 Indeed primary biliary cirrhosis may be
regarded as a spontaneous form of chronic liver rejection.
What triggers off the immunopathological cascade is
unknown-it may be a virus, or some other neoantigen, or
simply defective immunoregulation alone. The disease
progresses from granulomatous damage and disappearance
of septal and interlobular bileducts to biliary cirrhosis and
hepatocellular failure,8a process taking 10 to 15 years, and
often much longer.
Graft-versus-Host Disease -
Aberrant expression of HLA class 2 antigen on bileducts
is seen in the transplanted human liver undergoing rejection
and in patients with graft-versus-host disease following
allogeneic bone-marrow transplantation.9-10 Rejection is
 494
marked by progressive non-suppurative cholangitis
culminating in disappearance of interlobular bileducts; 11 the
bileduct epithelium is penetrated by mononuclear cells,
resulting in focal necrosis and rupture of the epithelium.
Similar lesions are found in graft-versus-host disease
following allogenic bone-marrow transplantation.12 In one
such patient, severe cholestatic jaundice lasted 10 years, and
serial liver biopsies confirmed progressive biliary-type
,
fibrosis and cirrhosis.13 She ultimately died in liver failure
that progressed rapidly during the last year of life. This
course strongly resembles that of primary biliary cirrhosis.
Vanishing bileducts after human liver transplantation
seem to be related to donor/recipient HLA class 1 mismatch
with class 1 antigen expression on bileduct epithelium and
also to an immunological reaction at the level of HLA class 2
antigens.14
Chronic Sarcoidosis .
Rarely, patients with chronic sarcoidosis show a clinical
picture virtually identical with primary biliary cirrhosis.15,16
Bileducts in the portal zones show destructive changes with
surrounding multiple granulomas. Such patients, unlike
those with primary biliary cirrhosis, have a negative senun
mitochondrial antibody test but a positive Kveim-Siltzbach
skin test. The mechanism of the bileduct destruction in
chronic sarcoidosis is unknown but, because of the close
histological similarity to primary biliary cirrhosis, it could be
immunological.
Primary Sclerosing Cholangitis
In primary sclerosing cholangitis, the interlobular, septal,
and segmental bileducts are replaced by fibrous cords.17-19
Larger ducts show tubular and saccular cholangiectases,
with or without infection, and these give the characteristic
cholangiographic picture of beads and strictures. Because of
its associations (see below) primary sclerosing cholangitis
has been classified as an immunological bileduct disease.
However, hepatic histology shows periductular fibrosis with
non-specific inflammation and lymphocytic and plasma cell
infiltration. Granulomas and "piecemeal" necrosis are
inconspicuous or absent. Although these findings contrast
strongly with the picture on light microscopy of the
immunological duct injury seen in primary biliary cirrhosis
or graft-versus-host disease, electron microscopy shows
periductular and intraepithelial lymphoid infiltration.2O
Similar changes are seen in primary biliary cirrhosis and
graft-versus-host disease. This would suggest lymphocyte-
mediated cytotoxicity against bileduct epithelium in all these
diseases.
About two-thirds of patients with sclerosing cholangitis
also have ulcerative colitis. Portal bacteraemia from the
diseased colon has been said to be a cause of the cholangitis,
but the disease is unaffected by colectomy and may even
precede the ulcerative colitis.21
. The histocompatibility antigen HLA-B8 is associated
with ulcerative colitis and with many diseases in which
autoantibodies are found. There is an increased prevalence
of HLA-B8 in patients with primary sclerosing cholangitis
with or without ulcerative colitis.22 Circulating antibodies to
some antigen in obstructed portal tracts are found, especially
in those with the HLA-B8 phenotype." Nevertheless, it is
difficult to fit primary sclerosing cholangitis into the
immunological pattern seen in such diseases as primary
biliary cirrhosis or autoimmune "lupoid" chronic active
hepatitis, which are associated with an increasing prevalence
of HLA-B8 among patients. In primary sclerosing
cholangitis, circulating antibodies to tissue components
such as nuclei, actin, or mitochondria are absent or present
in low titre.
Primary sclerosing cholangitis has also been associated
with several immunodeficiency syndromes, including
familial combined immunodeficiency, 24,25 hyperimmuno-
globulin M immunodeficiency,26 angioimmunoblastic
lymphadenopathy,27 and X-linked immunodeficiency.21
The immunodeficiency may reduce host defences, allowing
intestinal bacteria to overgrow and so cause ascending
cholangitis. The association may be analogous to that seen
with ulcerative colitis-ie, the sclerosing cholangitis could
well be infectious rather than immunological.
Serum immune-complex activity is higher in patients
with ulcerative colitis and primary sclerosing cholangitis
than in those with ulcerative colitis alone z9 Moreover, Fc
receptor-mediated systemic clearance of immune-complex-
like material is impaired in patients with ulcerative colitis
and chronic liver disease. 30 Finally, concentrations of biliary
immune complexes are increased in patients with primary
sclerosing cholangitis.31 It is uncertain whether all these
changes are simply secondary to biliary damage or whether
they indicate primary immune-complex injury.
Bileduct damage in primary sclerosing cholangitis may
represent a reaction to a biliary antigen. Indeed a leucocyte
migration inhibition test has shown that lymphocytes of
patients are sensitised to a biliary antigen.32 However, the
specificity of the reaction is doubtful since patients with
primary biliary cirrhosis and chronic active hepatitis may
show similar changes.
When insulted, intrahepatic bileducts disappear. The
problem is to decide when disappearance is primary and
when it is a consequence of injury. However, the common
end pathway seen in primary biliary cirrhosis, graft-versus-
host disease, and some cases of sarcoidosis are similar and
suggest immunological injury. Sclerosing cholangitis is
much more difficult to classify.
INFECTIVE CHOLANGITIS
Bacterial Infections
Bacterial cholangitis is rare in the absence of mechanical
biliary obstruction, which results in overgrowth of enteric
organisms in the upper small intestine and, presumably,
ascending infection.33 The walls of the damaged ducts are
infiltrated with polymorphs, the epithelium is destroyed,
and ultimately the bileduct is replaced by a fibrous cord, the
appearances resembling those of primary sclerosing
cholangitis. The causes include choledocholithiasis, biliary
strictures, and stenosis of biliary-enteric anastomoses.
There is a point at which the bileduct destruction and biliary
cirrhosis persist even when the cause of the biliary
obstruction (eg, gallstones) is removed.
If the common bile or hepatic duct is surgically
anastomosed to a stagnant loop of duodenum, continued
access of gut organisms to the biliary system can result in
bacterial cholangitis without biliary obstruction. A similar
sequence may follow sphincteroplasty.
The sclerosing cholangitis associated with infection by the
Chinese liver fluke (Clonorchis sinensis) is related to
secondary infection, usually with Escherichia coli, following
biliary obstruction by the fluke.
Viral and Other Non-bacterial Infections
In the neonate, cytomegalovirus and reovirus have a
tropism for bileduct epithelium, and obliterative cholangitis

results. Immunosuppressed patients, particularly those
with human immunodeficiency virus infection, may be
prone to cholangitis. In patients with the acquired
immunodeficiency sydrome (AIDS) cytomegalovirus
infection has caused progressive mucosal irregularities of the
intrahepatic and extrahepatic bileducts, with ultimate duct
destruction.34 Cryptosporidia may cause a mild cholangitis,
but biliary strictures are unlikely.35 However, in one patient
with transfusion-related AIDS a picture resembling
sclerosing cholangitis developed and cryptosporidia,
Candida albicans, and Klebsiella pneumoniae were found in
the gallbladder tissue and bile.36
HISTIOCYTOSIS X
A cholangiographic picture identical with that of primary
sclerosing cholangitis may complicate histiocytosis X.37
The biliary lesions progress from a hyperplastic to a
granulomatous, xanthomatous, and, finally, a fibrotic
stage.38 Clinically, the picture resembles primary sclerosing
cholangitis.
VASCULAR CAUSES OF DISAPPEARING BILEDUCTS
The bileducts are richly supplied by the hepatic artery.
Interference leads to ischaemic necrosis and the ultimate
disappearance of the bileducts, both extrahepatic and
intrahepatic.
High-resolution, polyester-resin casts show that the
hepatic arterial supply of the bileducts between the
confluence of the right and left hepatic duct and the first
part of the duodenum is essentially axial, and largely
towards the porta.39 Injury to this supply-for instance,
during cholecystectomy-leads to ischaemia of the duct
wall, damage to the ductal mucosa, and entry of bile into the
duct, tocause fibrosis and stricture.’ A similar sequence can
complicate hepatic transplantation, especially if the segment
of recipient duct is too short and thus deprived of its arterial
supply. Biliary ischaemia secondary to intimal thickening of
hepatic arterioles is a rare feature of chronic allograft
rejection in man."
5-fluorodeoxyuridine (5-FUDR) can be infused into the
hepatic artery through an implantable pump to treat hepatic
metastases from colorectal adenocarcinoma. This therapy
may be followed by biliary strictures and a picture
resembling primary sclerosing cholangitis.41,42 Ducts in zone
1 (portal) are affected as these depend mainly on hepatic
arterial supply. The narrowing of the main bileducts can be
so severe that treatment by the insertion of an endoscopic
biliary stent may be necessary.43 Bileduct necrosis has also
followed hepatic arterial embolisation for malignant liver
tumours.44
Cytomegalovirus causes colonic vasculitis with
consequent haemorrhage.45 It is possible that the sclerosing
cholangitis complicating cytomegalovirus infections may
have a vascular basis.
CHEMICAL (CAUSTIC) CHOLANGITIS
Hydatid cysts often communicate with the biliary tree
and sclerosing cholangitis has followed the injection of a
scolicidal solution (2% formaldehyde, 20% sodium
chloride or alcohol).46,47 Within months, the strictures result
in jaundice, biliary cirrhosis, and portal hypertension. Only
a part of the biliary tree is usually affected. Similar lesions
have been produced in animals by injecting formaldehyde or
20% sodium chloride into the biliary tree.8
495
DISCUSSION
The processes by which the intrahepatic bileducts can be
destroyed are of five main types--developmental,
immunological, infective, vascular, and chemical.
The developmental group start in utero. Some may have a
truly developmental origin, but in the majority an extrinsic
(non-developmental) cause, such as alpha-1-antitrypsin
deficiency or a virus, operates.
The immunological group, exemplified by primary
biliary cirrhosis and hepatic graft-versus-host disease, is ,.
marked by loss of tolerance to HLA class 2
histocompatibility antigens on the bileduct and cytotoxic
attack by lymphocytes. Treatment, theoretically, is by
immunosuppression. In the case of graft-versus-host
disease, intravenous hydrocortisone and cyclosporin A are
the most satisfactory drugs. The various drugs that have
been used to treat primary biliary cirrhosis range from
corticosteroids,48 to azatliioprine,49 D-penicillamine,50
chlorambucil,51 and colchicine. 52 Reported trials have
usually been too short, too small, and poorly controlled.
Statistically significant long-term benefits are difficult to
establish in disease with such a long and varied natural
a
history. Rarely, sarcoidosis produces a similar immuno-
logical bileduct injury and here cortoicosteroids may be
useful.
The end picture of sclerosing cholangitis as demonstrated
by cholangiography may be due to a variety of causes.
Primary sclerosing cholangitis is associated with
immunological features. Immunodeficiency may simply be
the mechanism that allows microorganisms to attack the
bileduct epithelium. Similar bileduct abnormalities are
being reported in other immunodeficient states such as
AIDS.32,33 Other immunological associations, such as HLA
B8, may rather be with the ulcerative colitis than with the
biliary tract disease. More attention should be paid to the
role of infection in the aetiology of primary sclerosing
cholangitis.
Bacterial cholangitis has two major associations-access
of intestinal microflora to the biliary passages and biliary
obstruction. Obstruction without infection probably does
not lead to disappearance of bileducts.
Interference with the hepatic arteriolar supply to the
bileducts leads to necrosis of bileduct epithelium. Sclerosing
cholangitis can follow intrahepatic arterial chemotherapy or
traumatic biliary stricture and, possibly, some of the biliary
features of liver-transplant rejection may be vascular in
origin. More detailed studies of the hepatic arterial tree are
needed in all forms of sclerosing cholangitis.
Whatever the mechanism, once the bileducts have
vanished they do not return. In the case of primary biliary
cirrhosis, primary and secondary sclerosing cholangitis, and
partial biliary atresia a slow biliary cirrhosis develops over 10
to 15 years, the speed depending on the extent of bileduct
loss. The process is much quicker in the graft-versus-host
reaction. In all these groups the end-stages can usually be
predicted and hence the time when liver transplantation
becomes the only worthwhile therapeutic option.53
Prognosis after transplantation will depend on the suitability
of the patient in other respects, including psychosocial
stability, age, and concomitant diseases, but generally
children with biliary atresia can look forward to a 1-year
post-transplant survival of 85%, followed by a virtually
normal life style,51 while the 1-year survival after transplant
for primary biliary cirrhosis in patients is 83%, and that for
primary sclerosing cholangitis is 75%.54 Retransplant for
chronic rejection results in a 46% survival at 1 year. 54
496
Results for these primary biliary diseases are much better
than for other forms of cirrhosis, where the overall 1-year
survival is 60%, falling to 50% for those aged over 50 years.
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Public Health
ENTERITIS NECROTICANS AMONG KHMER
CHILDREN AT AN EVACUATION SITE IN
THAILAND
STUART JOHNSON1 PETER ECHEVERRIA1
DAVID N. TAYLOR1 SAKTI R. PAUL2
RUDI CONINX3 JUN SAKURAI4
BOONCHUAY EAMPOKALAP5 PRASARN JIMAKORN6
ROBIN A. COOKE7 GREGOR W. LAWRENCE8
PETER D. WALKER9
Armed Forces Research Institute of Medical Sciences, Bangkok,
Thailand;1 Catholic Relief Services, Surin, Thailand;2 United
Nations Border Relief Operation, Bangkok;3 Tokushima Bunri
University, Tokushima, Japan;4 Bamrasnaradura Hospital,
Bangkok;5 Department of Pathology, Chulalongkorn University,
Bangkok;6 Anatomical Pathology, Royal Brisbane Hospital,
Australia;7 Queensland Institute of Medical Research, Brisbane;8
and Wellcome Laboratories, Beckenham, Kent9
Summary A severe illness characterised by bloody
diarrhoea and intestinal dysfunction was
recognised at an evacuation site on the Thai-Kampuchean
border. From June, 1985, to July, 1986, the illness occurred
in 62 Khmer children aged 10 months to 10 years (mean 4
years); it was characterised by bloody diarrhoea (94%), fever
(90%), and abdominal pain (78%). The overall mortality
rate was 58%. Among 16 children who died and underwent
necropsy, small-intestinal necrosis of varying severity was
found; in 5 of these children small-intestinal lesions with
areas of full-thickness necrosis were seen that histologically
resembled those in cases of enteritis necroticans (pigbel) in
36. Cockerill RR, Hurley DX, Malagelada JR, et al. Polymicrobial cholangitis and
Kaposi’s sarcoma in blood-product transfusion-related acquired immune
deficiency syndrome. Am J Med 1986; 80: 1237-41.
37. Thompson HH, Pitt HA, Lewin KJ, Longmire WP, Jr. Sclerosing cholangitis and
histiocytosis. Gut 1984; 25: 526-30.
38. Engelbreth-Holm J, Teitum G, Christensen E. Eosinophil granuloma of bone-
Schuller-Christian’s disease. Acta Med Scand 1944; 118: 292-312.
39. Northover JMA, Terblanche J. A new look at the arterial supply of the bile duct in man
and its surgical implications. Br J Surg 1979; 66: 379-84.
40. Terblanche J, Allison HE, Northover JMA. An ischemic basis for biliary strictures
Surgery 1983; 94: 52-57.
41. Kemeny MM, Battifora H, Blayney DW, et al. Sclerosing cholangitis after continuous
hepatitic artery infusion of FUDR. Ann Surg 1985; 202: 176-81.
42. Shea WJ, Demas BE, Goldberg HI, Hohn DC, Ferrell LD, Kerlan RK. Sclerosing
cholangitis associated with hepatic arterial FUDR chemotherapy: radiographic-
histologic correlation. AJR 1986; 146: 717-76.
43. Siegel JH, Ramsey WH. Endoscopic biliary stent placement for bile duct stricture after
hepatic artery infusion of 5-FUDR. J Clin Gastroenterol 1986; 8: 673-76.
44. Makuuchi M, Sukigara M, Mori T, et al. Bile duct necrosis: complication of
transcatheter hepatic arterial embolization. Radiology 1985; 156: 331-34.
45. Goodman MD, Porter DD. Cytomegalovirus vasculitis with fatal colonic hemorrhage.
Arch Pathol 1973; 96: 281-84.
46. Mirouze D, Bories P, Pommier-Layrargues G, et al. Cholangite sclerosante sécondaire
a une formolisation accidentelle des voies biliares chez 5 malades porteurs d’un
kystehydatique du fois. (re production experimentale). Abstracted from
Gastroenterol Clin Biol 1983; 7: 200-01.
47. Belghiti J, Huguier M, Fekete F. Caustic Sclerosing cholangitis. A complication of the
surgical treatment of hydatid disease of the liver. Arch Surg 1986; 121: 1162-65.
48. Mitchison HC, Watson AJ, Bassendine MF et al. A pilot double-blind controlled trial
of prednisolone treatment in primary biliary cirrhosis (PBC). J Hepatol 1986; 1: 527
(Abst).
49. Heathcote J, Ross A, Sherlock S. A prospective controlled trial of azathioprine in
primary biliary cirrhosis. Gastroenterology 1976; 70: 656-60.
50. Epstein O, Jain S, Lee RG, et al. D-penicillamine treatment improves survival in
primary biliary cirrhosis. Lancet 1981; 1: 1257-59.
51. Hoofnagle JH, Davis GL, Schafer DF, et al. Randomized trial of chlorambucil for
primary biliary cirrhosis. Gastroenterology 1986; 91: 1327-34.
52. Kaplan MM, Alling DW, Zimmerman HJ, et al. A prospective trial of colchicine for
primary biliary cirrhosis. N Engl J Med 1986; 315: 1448-54.
53. Sherlock S. Hepatic transplantation. Southern Med 1987; 80: 357-61.
54. Gordon RD, Shaw BW, Iwatsuki S. Indications for liver transplantation in the
cyclosporine era. Surg Clin N Am 1986; 66: 541-56.