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Opisthorchiasis
and Clonorchiasis
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The human liver flukes, Clonorchis sinensis (C),
Opisthorchis viverrini (A) and O.
felineus (B), remain important public health
problems in many endemic areas. C. sinensis is
wide spread in China, north Vietnam and Korea while
O. viverrini is endemic in Southeast Asia including
Thailand, Lao PDR, Cambodia and central Vietnam. Human
gets infection by eating raw or under cooked
Cyprinoid freshwater fish habouring infective
metacercariae. Recent reports suggested that about 35
million humans are infected by C. sinensis
globally; with up to 15 million human infections in
China alone
and another 6 million by
O. viverrini
in Thailand. More
than 600 million people, mainly in Aisa, are at risk of
the two liver fluke infection. The infections are
associated with several hepatobiliary diseases including
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hepatomegally, cholangitis, fibrosis of the periportal system,
cholecystitis, gallstone, and are major aetiological agents of
bile duct cancer, cholangiocarcinoma. The liver fluke endemic
areas of Khon Kaen, north-east Thailand has been reported the
highest incidence of this liver cancer in the world.
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Life
cycle |
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Life cycle of Opisthorchis viverrini. The adult
worms inhabit in the intra- and extrahepatic biliary
system. Embryonated eggs containing miracidium laid from
gravid worms are passed through the bile and eventually
feces. After reaching freshwater, these eggs are
ingested by Bithynia snails and hatched. The
miracidia then transform to sporocysts and asexual
reproduction occur giving rediae and cercariae.
Free-living cercariae, after exit the snail attach,
penetrate and transform to metacercariae encysted mainly
in the muscle of about 18 susceptible species of fish in
the family Cyprinidae. Metacercariae are infective to
final definitive hosts including humans, dogs and cats
when they ingest raw or inadequately cooked fish. After
ingestion, the metacercaria is digested by gastric and
intestinal juices, respectively. Excysted juvenile
flukes at the duodenum then migrate up through the
ampulla of Vater and the common bile duct into the
intrahepatic bile ducts where they mature and fertilize.
Some worms are from in the common bile duct, cystic duct
and gallbladder. |
(from
http://www.dpd.cdc.gov/dpdx/HTML /opisthorchiasis.htm
and PLoS Medicine, July, 2007)
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Epidemiology |
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Geographical and age-related patterns of human infection overlap
with dietary habit. Raw or partially fermented fish dishes are a
well-established dietary tradition
of Laos people and the
ethnic Laos in north-east Thailand. Fresh fish dishes may
contain large numbers of metacercariae and are eaten
occasionally. C. sinensis, although largely eliminated
from Japan and drastically reduced in Korea, remains prevalent
and may be increasingly common in parts of Taiwan, Hong Kong,
Vietnam, Macao and China. Human infection occurs in 24 Chinese
provinces, with one major focus in the south (especially
Guangdong and Guangsxi provinces) and another in the north-east
(Henjian). Some Chinese people enjoy eating raw fish dipped in
hot rice porridge, and children reportedly catch and eat raw
fish during play. Control efforts in north-east Thailand have
led to a drop in the prevalence of O. viverrini infection
among the population of 20 million from approximately 35% in
1981, to 24 to 30% in 1992, 18.6% in 1994 and 15 % in 2000
38. The infection remains common in Laos with an
extensive distribution in the southern region and prevalences
ranging from 32 to 60%.
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Clinical
features |
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Most chronically liver fluke infected individuals have
few specific signs or symptoms, except an increased
frequency of palpable liver, as shown in community-based
studies. Haematological
and biochemical
features are unremarkable, even in heavy
infections. Ultrasonography, however, reveals a high
frequency of gallbladder enlargement, sludge, gallstones
and poor function in asymptomatic individuals.
Symptomatic cases of Opisthorchis and
Clonorchis infection
generally experience pain in the right upper quadrant,
diarrhoea, loss of appetite, indigestion and
fullness. Severe
cases may present with weakness, lassitude,
weight loss, ascites and oedema. Complications may
include cholangitis,
obstructive jaundice, intra-abdominal mass,
cholecystitis and |
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gallbladder or intrahepatic stones. Such stones are
particularly frequent in clonorchiasis.
The most important clinical
manifestation of liver fluke infection is an enhanced
susceptibility to cholangiocarcinoma. Case-control
studies in Thailand suggest a fivefold increased risk
during O. viverrini infection of any intensity,
while heavily infected people may face a 15-fold risk.
Moreover, up to 27-fold has been reported by using anti-
liver fluke antibody.
The
radiologic evidence of clonorchiasis determined by a
combination of contrast-enhanced helical compute
tomography and cholangiographic imaging by magetic
resonance cholangiography and ultrasonography,
consisting of diffuse dilatation of the |
intrahepatic bile ducts up to the peripheral margin was
associated with an increased risk of CCA (odd ratio =
8.6).
A history of raw fish consumption, positive serological
test for clonorchiasis and area of residence were also
linked to increased risk
of CCA.
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Pathology
and pathogenesis |
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Grossly, liver enlargement and dilated subcapsular bile
ducts with thick fibrotic walls can be seen in heavily
infected cases. Microscopically, bile duct pathology is
characterized by desquamation of epithelial cells and
chronic inflammation with infiltration of lymphocytes,
monocytes, eosinophils and plasma cells. Granulomatous
inflammation arround the eggs is occasionally observed
along the bile ducts. Epithelial hyperplasia may occur
at early stage of infection.
In severe cases, adenomatous hyperplasia, and
goblet cell metaplasia may be seen. Periductal fibrosis
is the most prominent histologic feature of chronic
infection. This corresponds to periportal echoes
detected by ultrasonography. The pathology of
fluke-associated cholecystitis consists of fibrosis, infiltration
of mast cells and eosinophils and |
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mucosal hyperplasia of the gallbladder wall. Perforation
of the gallbladder wall is uncommon in liver fluke
infection. Parasites and eggs have been observed in the
nidus of gallbladder and intrahepatic stones. |
Pathogenesis of liver fluke-mediated tissue damage may
be directly via mechanical or chemical irritation and/or
immune-mediated. Mechanical injury from the activities
of feeding, movement and migration of flukes contributes
to biliary ulceration through its suckers. Chemical
irritation results as the liver fluke secretes or
excretes metabolic products from the tegument and
excretory openings into the bile. Some of these products
are highly mitogenic to fibroblast or biliary cell lines
when co-cultured in vitro with the flukes. This
suggests that excreted or secreted fluke products may
cause hyperplasia of biliary epithelial cells typical of
opisthorchiasis. Moreover, the fluke excretory-secretory
products are also highly immunogenic and stimulate
marked inflammatory infiltration in the intrahepatic and
extrahepatic bile ducts in animals experimentally
infected with Opisthorchis. Nitric oxide and
other reactive oxygen intermediates produced by
inflammatory cells during infection might exert direct
cytotoxic and mutagenic effects and increased cell
proliferation.
Increased formation of 8-nitroguanine
(8-NO2-G)
and
8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)
has been observed in experimentally infected animals, a
response that is enhanced with repeated infection
and considered to be mutagenic. Increased endogenous
production of N-nitroso compounds and enhanced
hepatic activation of carcinogens in these areas of fibrosis
may create highly mutagenic conditions for the
chronically proliferating bile duct epithelium. All
together these form an ideal environment for cancer
development.
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Diagnosis |
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Detection of egg in faeces is the conventional
diagnostic method for liver fluke infection. The most
frequently used methods to detect eggs in the faeces are
the Kato thick smear, Stoll’s dilution and the
quantitative formalin ethyl acetate concentration
technique. Several immunodiagnostic tests have been
described for Opisthorchis and Clonorchis
infections.
While most antigens of these flukes are non-specific and
antibodes persist long after treatment, good results
have been gained from new serological tests using
individual antigens and those detecting isotype-specific
antibodies. Faecal antigen detection by
enzyme-linked immunosorbent assays (ELISA) using
monoclonal antibodies against secretory antigens and DNA
probes also |
shows promise. However, more recent attention has been
focussed on the detection of egg DNA in faecal specimen
by polymerase chain reaction (PCR) which is effective in
the diagnosis of liver fluke infection in experimental
animals as well as in humans.
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Treatment |
Treatment with praziquantel at 40 mg/kg body weight in a single
dose is effective against opisthorchiasis and clonorchiasis.
This regimen has been used most commonly in large-scale
treatment programmes.
The most effective regimen particularly for clonorchiasis
is 25 mg/kg three times over a day (total dose 75 mg/kg) was
recommended. Side effects, such as dizziness, vomiting and
abdominal pain, occur frequently but are transient and rarely
severe.
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Prevention
and control |
Prevention of human liver fluke infection can be facilitated by
treatment (to reduce the excretion of eggs), sanitation (to
prevent eggs from reaching water sources) and health education
(to discourage the eating of raw fish). Control of snail vectors
by molluscicides is not considered feasible because of their
widespread distribution and resistance to
adverse conditions. To be
most effective, health education should be designed and
delivered in a culturally sensitive manner with the aim of
stimulating behaviour change as well as simply providing
information. Targetting young age groups, for example, school
children, may be an attractive choice for long term control.
Large-scale efforts in endemic areas by public health ministries
have probably had a major impact on the intensity of all three
infections.
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Bibliography |
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1.
Sripa et al. Liver fluke induces cholangiocarcinoma. PLoS
Medicine 2007;
4:
1148-1155.
2.
Sithithaworn P, Sripa B, Kaewkes S, Haswell MR. Foodborne
trematodes. In Manson’s Tropical Diseases 22 th Ed. (in
press)
3.
http://www.dpd.cdc.gov/dpdx/HTML /opisthorchiasis.htm |
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