Update on hepatobiliary flukes: fascioliasis, opisthorchiasis and clonorchiasis

<strong>Update</strong> on hepatobiliary flukes: fascioliasis, opisthorchiasis
and clonorchiasis
Luis A. Marcos a,b , Angelica Terashima a and Eduardo Gotuzzo a
a Institute of Tropical Medicine Alexander von
Humboldt, Universidad Peruana Cayetano Heredia,
Lima, Peru and b Internal Medicine Department,
University of Texas Health Science, Houston, Texas,
USA
Correspondence to Eduardo Gotuzzo, MD, Instituto de
Medicina Tropical Alexander von Humboldt,
Universidad Peruana Cayetano Heredia. Av. Honorio
Delgado 430, San Martin de Porres, Lima, Peru and
Departamento de Enfermedades Infecciosas,
Tropicales y Dermatológicas, Hospital Nacional
Cayetano Heredia, Lima, Peru
Tel: +51 1 482 3910; fax: +51 1 482 3404;
e-mail: egh@upch.edu.pe
Current Opinion in Infectious Diseases 2008,
21:523–530
Introduction
Liver fluke infections (phylum Platyhelminthes; class
Trematoda; family Fasciolidae and Opisthorchiidae)
caused by Fasciola hepatica, Fasciola gigantica, Opisthorchis
viverrini, Opisthorchis felineus and Clonorchis sinensis are
major public health problems in east Asia, east
Europe, Africa and Latin America. Currently, more than
780 million people are at risk of infection with these five
trematodes [1]. The present review focuses on recent
findings about the clinical features, diagnosis and management
of these parasitic infections in developing and
developed countries (Table 1).
Fascioliasis
Fascioliasis is an infectious parasitic disease caused by
F. hepatica or F. gigantica (Trematoda; Fasciolidae; large
flukes, 20–40 mm in length) (Fig. 1). It is estimated
that 17 million people are infected in the world and
91.1 million are at risk of infection [1]. Both species
Purpose of review
Hepatobiliary flukes – Fasciola, Opisthorchis, Clonorchis – are a major public health
problem in east Asia, east Europe, Africa and Latin America. The present review focuses
on current knowledge of clinical, diagnostic and treatment aspects caused by
hepatobiliary flukes that can be applied to current protocols in endemic areas.
Recent findings
Specific risk factors and geographic areas for these flukes have been heavily reported
recently, with millions of people infected worldwide. Human cases in nonendemic areas,
related to immigration and the international food trade (i.e. raw vegetables and fish),
have also been reported. Diagnostic imaging changes include track-like lesions that are
a characteristic feature of acute fascioliasis on computed tomography scanning of the
liver. Newly available diagnostic serological tests may detect early infection and,
therefore, help reduce severe clinical complications such as recurrent cholangitis,
cholecystitis, hepatic tumours, cysts, calcification, cholelithiasis, pancreatitis, most
importantly, cholangiocarcinoma related to Opisthorchis viverrini and possibly
Clonorchis sinensis, and liver fibrosis associated with Fasciola hepatica infections.
Highly effective antiparasitic treatment is available for all flukes.
Summary
There is a better understanding of risk factors, clinical manifestations and complications,
novel diagnosis tests and effective treatment, which together should help reduce the
morbidity and mortality of these infections.
Keywords
biliary tract, flukes, liver
Curr Opin Infect Dis 21:523–530
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7375
overlap in many areas of Africa and Asia [18], whereas
F. hepatica is a major concern in the Americas (i.e. Peru
and Bolivia), Europe and Oceania [18,19 ,20 ]. The
geographical pattern of these flukes is not uniform.
The rural areas of the Andean Region of Peru and Bolivia
are the most constantly affected regions in the world with
prevalence rates between 6 and 68% [2 ,20 ,21]. The
proximity of these rural areas to big industrialized cities
creates a potential source of infection to nonendemic
areas [22]. Women are affected more than men, with higher
prevalence rates, more severe infections and with more
reported liver or biliary complications [2 ,3 ,4,19 ], and
children are affected more than adults [2 ,19 ,20 ]. The
main source of infection is the consumption of raw vegetables
contaminated with metacercariae such as watercress,
alfalfa juice, contaminated water from irrigation
man-made channels or salads [2 ,4,23,24].
Clinical manifestations: acute and chronic phases
The clinical picture usually reflects the worm burden,
phase and the duration of infection. Fascioliasis has two
0951-7375 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/QCO.0b013e32830f9818
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

524 Gastrointestinal infections
Table 1 Geographical distribution, clinical syndromes, diagnosis and treatment of fascioliasis, opisthorchiasis and clonorchiasis
Liver fluke
Fasciola
hepatica;
Fasciola
gigantica
Opisthorchis
viverrini
Opisthorchis
felinus
Clonorchis
sinensis
Geographical
distribution Clinical syndromes Diagnosis Treatment References
Americas (mainly
Peru and Bolivia),
Europe, Asia, western
Pacific, North Africa
Thailand, Laos,
Cambodia,
Vietnam
Russian Federation,
Siberia, Ukraine,
Kazakhstan
North-east China,
southern Korea, Japan,
Taiwan, northern
Vietnam and the far
eastern part of Russia
Acute: hypereosinophilia,
hepatomegaly with hypodense
track-like lesions by CT,
prolonged fever; chronic:
biliary obstruction, cholangitis,
cirrhosis
Acute: asymptomatic; chronic:
right upper quadrant abdominal
pain, flatulence, fatigue, and hot
sensation over the abdomen,
mild hepatomegaly, jaundice
cholangitis, cholangiocarcinoma
Acute: high-grade fever, malaise
arthralgia, lymphadenopathy, and
skin rash; high eosinophilia and
increased liver enzymes; chronic:
suppurative cholangitis and liver
abscess
Acute: Usually asymptomatic,
but some may have fever, rash,
malaise and right upper quadrant
abdominal discomfort; chronic:
gallbladder and intrahepatic
duct stone, recurrent pyogenic
cholangitis, cholecystitis, liver
abscess and possible
cholangiocarcinoma
distinct clinical phases related to parasite migration, acute
and chronic, and both manifest a variety of symptoms and
signs. Chronic infection is generally detected in epidemiological
studies, whereas acute infection might be
detected in the emergency room. The first acute or
invasive phase lasts from 3–5 months and is caused by
the migration of immature larvae from the duodenum to
the liver, finally reaching the bile ducts (Fig. 2). Symptoms
include prolonged fever, hepatomegaly causing
abdominal pain, mild eosinophilia (early infection) or
hypereosinophilia (mid or late acute infection) and
multiple hypodense lesions seen on computed tomography
(CT) scan similar to metastases [3 ]. Of note, one of
the most frequent presentations in this acute phase is
hypereosinophilia. However, it can also be seen as acute
cholecystitis with eosinophilia. Other CT findings are
subcapsular hematomas, hepatic cysts, residual hepatic
calcifications and severe anaemia [3 ,25]. Interestingly,
hyperbilirubinaemia is absent in the acute phase [3 ].
Other manifestations are anorexia, weight loss, nausea,
vomiting, cough, diarrhoea, urticaria, lymphadenopathies
and arthralgias [3 ,24,26]. Occasionally, the juvenile
larvae reach other anatomic locations such as the subcutaneous
tissue, pancreas, eye, brain and stomach wall,
among others [27].
The chronic phase begins after approximately 6 months,
when the parasite matures in the bile ducts. It may last
several years (>10 years) and is asymptomatic in half of
the cases [26]. When symptoms appear, these reflect
commonly biliary obstruction with upper abdominal pain
Fas2-ELISA, RST,
Kato–Katz
ELISA, Kato–Katz,
ether–formalin
concentration technique
Kato–Katz, ether–
formalin concentration
technique
Kato–Katz, ether–formalin
concentration technique
Triclabendazole
(10 mg/kg) single
dose with meals,
may repeat a second
dose if continue O&P
positive for eggs
Praziquantel
(40–50 mg/kg)
single dose
Praziquantel (25 mg/kg)
three times a day for
one day (total dose
75 mg/kg)
[2 ,3 ,4,5 ,6]
[7 ,8 ,9,10 ]
[28 ], intermittent jaundice [26], intrahepatic cystic
abscesses with prolonged fever [29], eosinophilic cholecystitis
[30] and extrahepatic cholestasis with elevation of
liver enzymes, mainly alanine aminotransferase, aspartate
aminotransferase, total bilirubin and gamma-glutamyl
transpeptidase (GGT) [31]. In endemic areas, an elevated
GGT or alkaline phosphatase would be a strong indicator
of fascioliasis. Occasionally, the diagnosis is not made
until unnecessary surgery has been performed [30], or
after laparoscopic cholecystectomy [32], or during endoscopic
retrograde cholangiopancreatography [33]. Other
clinical complications are bacterobilia and gallstones as
recently demonstrated by in-vivo models [34,35]. Gastrointestinal
symptoms may persist even after treatment in
about 2–4% of patients [36]. Eosinophilia may be absent
in half of the chronic patients, so a normal eosinophil
count does not rule out the infection. For instance, only
47% of patients (n ¼ 277) seen in the emergency room
with chronic infection presented with eosinophilia [37].
Similarly, only half of the infected patients have eosinophilia
[26]. In a Turkish study, two out of 18 patients
(11%) with fascioliasis had eosinophilia [38]. In
conclusion, the eosinophil count cannot be used for
screening purposes in endemic areas, because more than
50% of patients will be excluded, at least in the chronic
phase.
Consequences of chronicity of infection in fascioliasis
Recent studies have shown a strong association between
fascioliasis and liver fibrosis. It seems that hepatic fibrosis
may evolve in some susceptible hosts, depending on the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
[11]
[12–17]
CT, computed tomography; ELISA, enzyme-linked immunosorbent assay; O&P, ova and parasite examination; RST, rapid sedimentation technique.

Figure 1 Life cycle of human fascioliasis
time and burden of infection. For instance, almost 50% of
cattle infected chronically by fascioliasis had cirrhosis
[5 ]. In addition, hepatic cirrhosis has been reported in
infected children [27,39] and adults [40,41], especially
those with high-density infections. New data on the
pathogenesis of hepatic involvement associated with
F. hepatica infection have implicated cathepsin L1 and
its collagenolytic function associated with tissue invasion
[42 ] with proteolytic activity, leading to collagen type I
expression and ultimately hepatic fibrosis (Marcos,
unpublished observation).
On the contrary, chronic infection may also cause a
persistent immune-suppression status [43 ], suggesting
that the infected host may be susceptible during chronic
infection to other Th2-associated pathogens. Further
immunologically based studies will be needed to clarify
associations of this infection with a broad spectrum of
medical conditions as well as with other parasites.
<strong>Update</strong> on hepatobiliary flukes Marcos et al. 525
Reproduced with permission from Division of Parasitic Diseases, Centers for Disease Control and Prevention (www.dpd.cdc.gov/DPDx/HTML/
Fascioliasis.htm).
Criteria for diagnosis in both phases
The diagnosis of the acute phase is confirmed by serology
or response to therapy or both [3 ]. Fas2-enzyme-linked
immunosorbent assay (ELISA) is more specific than
Western blot and Arc II [44,45 ]. The largest human
diagnostic study has been carried out in Peru, where the
Fas2-ELISA (cathepsin L1-based antibody) was validated
including a total of 634 infected children from
endemic areas. The sensitivity was 92.4% and specificity
83.6%, with a negative predictive value of 97.2% [45 ].
In diagnostic imaging, the most common finding by
ultrasonography or CT scan is usually misdiagnosed as
malignancy. For example, ultrasonography findings
include focal areas of increased echogenicity, multiple
nodular or irregular lesions of variable echogenicity or a
single complex mass in the liver [46] resemble malignancy.
The most common CT or MRI findings or both
include multiple hepatic metastasis-like lesions, which
change in position, attenuation, and shape in time,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

526 Gastrointestinal infections
Figure 2 Juvenile Fasciola hepatica migrating in the peritoneal
cavity, causing destruction and haemorrhages (haematoxylin
and eosin; T250)
The peritoneal biopsy was performed because of suspicion of metastases
or a primary carcinoma. Case seen in the Institute of Tropical
Medicine Alexander von Humboldt, Lima, Peru.
track-like hypodense lesions with subcapsular location,
low-density serpiginous tortuous tunnel-like branching
lesions ranging from 2–10 mm or subcapsular hematomata
(Fig. 3) [3 ]. In MRI, the hypodense
lesions observed in the CT scans are hypointense in
T1-weighted images and hyperintense in T2 images
[47–49]. Another clue to suspecting acute fascioliasis is
Figure 3 Late stage of acute fasciola infection (5 months of
symptoms)
Lesions are more central than subcapsular. Computed tomography scan
after venous contrast showing a variety of changes including nodular,
perivascular, some serpiginous (arrows), track-like and subcapsular–
peripheral lesions. Most lesions are central, scattered throughout the
liver parenchyma. Adapted from [3 ].
the presence of hypergammaglobulinaemia [27]. Finally,
a diagnostic criterion is significant clinical improvement
and decreasing levels of eosinophils in the 3–5 days after
a trial of triclabendazole [3 ].
Coproparasitological tests are applied to confirm the
chronic infection, detecting the eggs in the stool. A
procedure that is easy to perform, highly sensitive and
cheap would be the ideal test technique in endemic areas.
Our group has carried out several epidemiological–
clinical studies using the rapid sedimentation technique
(RST) described by Dr Hugo Lumbreras in Peru in 1962
[50], with favourable results in hundreds of patients with
fascioliasis [3 ,4,19 ,21–24,26,27,37,45 ]. The RST
may be applied in rural areas and major health centres.
The Kato–Katz technique is performed to measure the
intensity of infection. Multiple stool samples are required
because of the intermittent deposition of parasite ova.
Ultrasonography imaging findings in the chronic phase
are nonspecific and include hepatomegaly, splenomegaly,
periportal fibrosis, thickened gall bladder wall,
dilated common bile duct, parasites in gall bladder and
common bile duct, cholelithiasis, cystic lesions in the
liver and ascites [31]. The detection rate of chronic
F. hepatica infection by ultrasonography is disappointingly
low and not specific. In a study of 76 patients with
chronic fascioliasis evaluated by abdominal ultrasonography,
parasites were visualized in only 11 patients (14%)
[3 ,8 ]. In CT scans, residual liver calcification may be
seen in the chronic phase (Fig. 4) [3 ].
Figure 4 Computed tomography scan showing residual lesions
12 months after treatment for fascioliasis
There are ovoid, calcified, popcorn-like lesions, with multiple calcified
nodular foci scattered throughout the liver parenchyma. Adapted from
[3 ].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Effective treatment
Triclabendazole is the treatment of choice for both
phases of fasciola infection [6]. The cure rate exceeds
90% for acute stages after a single dose of 10 mg/kg [3 ],
and similar results have been obtained in the treatment of
chronic infections [51,52 ]. The most frequent adverse
event is biliary colic caused by the passage of dead or
dying parasites passing through the bile ducts. There is
an urgent need to have drugs available in rural endemic
areas.
Clonorchiasis and opisthorchiasis
Clonorchiasis is an infection caused by C. sinensis,
whereas opisthorchiasis is caused by O. viverrini and
O. felineus. C. sinensis and O. viverrini, the small Asian
liver flukes (8–15 mm in length), are very similar in adult
morphology and genetics but differ in geographic distribution
[53 ]. There are 601 and 79.8 million people at risk
Figure 5 Life cycle of Chlonorchis sinensis
<strong>Update</strong> on hepatobiliary flukes Marcos et al. 527
of infection with Clonorchis and Opisthorchis, respectively
[1]. C. sinensisis is endemic in north-east China, southern
Korea, Japan, Taiwan, northern Vietnam and the far
eastern part of Russia [12], and O. viverrini is endemic
in Laos, Thailand, Vietnam and Cambodia. In Thailand,
approximately 6 million people are infected with
O. viverrini [7 ]. In China, clonorchis infections have
more than tripled over the last decade, with 15 million
people infected in 2004 [13]. Similar to fascioliasis, the
geographical pattern of these small flukes is not uniform.
For instance, in Thailand, the greatest prevalence of
opisthorchiasis is in the north (19.3%) and northeast
(15.7%) compared with the central (3.8%) and southern
regions (0%). O. felineus is endemic in the Soviet Union,
Kazakhstan and Ukraine. In general, the infection is
acquired by eating raw or uncooked cyprinoid fish products
in rural areas or dishes such as koi-pla [8 ] (Fig. 5).
In contrast with the larger fluke, F. hepatica, these small
flukes migrate to the liver through the duodenum via the
Reproduced with permission from the Division of Parasitic Diseases, Centers for Disease Control and Prevention (www.dpd.cdc.gov/DPDx/HTML/
Clonorchiasis.htm).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

528 Gastrointestinal infections
ampulla of Vater into the bile ducts, where they mature to
adult worms in less than a month. The adult flukes reside
in medium-sized and small intrahepatic bile ducts and,
occasionally, in the extrahepatic bile ducts, gallbladder
and pancreatic duct, where they can live for many years in
the liver, even for decades.
Clinical manifestations
Because these flukes do not penetrate the liver parenchyma,
their disease manifestations are caused by the
obstruction of the biliary tract, where they can cause
prominent inflammation. Flukes can occasionally gain
access to the pancreatic tract, where they can cause
obstruction and pancreatitis in addition.
Clonorchis sinensis
The acute infection is usually asymptomatic, but some
patients may present fever, rash, malaise and right upper
quadrant abdominal discomfort. Chronic infection
reflects the worm burden, including recurrent pyogenic
liver cholangitis, cholecystitis, obstructive jaundice,
hepatomegaly, cholecystitis, multiple hepatic tumours
[14] and cholelithiasis [15,16]. The association of clonorchiasis
and cholangiocarcinoma has also been reported
[17].
Opisthorchis viverrini
In acute infection, only 5–10% of heavily infected
patients have nonspecific symptoms such as right upper
quadrant abdominal pain, flatulence, fatigue and a hot
sensation over the abdomen. In the chronic phase, mild
hepatomegaly occurs, mainly in more heavily infected
patients (egg counts >10 000 eggs per gram). Jaundice
and splenomegaly are not observed. Intrahepatic duct
stones and recurrent suppurative cholangitis are common
manifestations of opisthorchiasis. Whenever jaundice and
ascending cholangitis are detected, fluke-related cholangiocarcinoma
should be suspected.
Opisthorchis felineus
In acute infection, acute symptoms occur 2–4 weeks after
eating raw fish. These include high-grade fever, nausea,
vomiting, abdominal pain, malaise, arthralgia, lymphadenopathy
and skin rash [11]. Peripheral eosinophilia is a
common finding, especially during the initial 2–6 weeks
of the infection, together with raised liver enzymes. In
chronic infection, eosinophilia is usually milder. Patients
may present with suppurative cholangitis and liver
abscess because of biliary obstruction.
Consequences of chronicity of infection in clonorchiasis
and opisthorchiasis
In general, these flukes cause inflammation around the
biliary tree, severe hyperplasia of epithelial cells, metaplasia
of mucin-producing cells in the mucosa and progressive
periductal fibrosis. There are clear associations
between O. viverrini infection and cholangiocarcinoma in
the context of the intensity of infection, parasite-specific
antibody response and abnormalities of the biliary tract.
The higher the intensity and anti-O. viverrini antibody
titres, the higher the risk for cholangiocarcinoma [54].
The International Agency for Research on Cancer
recognizes this parasite as a ‘category I carcinogen’.
The lesions that predispose to malignant changes in
O. viverrini are dilatation of subcapsular medium and
large-sized bile ducts with prominent fibrotic wall,
periductal inflammatory cell infiltration, goblet cell metaplasia,
epithelial and adenomatous hyperplasia and periductal
fibrosis. The pathogenesis of O. viverrini-mediated
hepatobiliary changes may be due to mechanical irritation
or its metabolic products [9]. Several N-nitroso
compounds and their precursors occur at low levels in
fermented food, such as preserved mud fish paste (pla ra),
a condiment that is a ubiquitous component of the
cuisine of north-eastern Thailand and Laos [10 ]. The
study of O. viverrini genes should expedite molecular
studies of cholangiocarcinogenesis and accelerate
research focused on developing new interventions, drugs
and vaccines, which might help in controlling O. viverrini
and related flukes [55]. Similarly, recent studies show a
strong association between C. sinensis and the development
of cholangiocarcinoma [17]. For instance, a recent
epidemiological study in Korea correlates the prevalence
of C. sinensis and the incidence rate of cholangiocarcinoma.
C. sinensis prevalence was 2.1% in Chuncheon,
7.8% in Chungju and 31.3% in Haman, whereas cholangiocarcinoma
incidence rate was 0.3, 1.8 and 5.5 per
100 000 persons, respectively [56]. Hepatocellular carcinoma
also has been associated with clonorchiasis, along
with hepatitis B virus and alcohol consumption as cofactors
[57]. It seems plausible that cholangiocarcinogenesis
associated with clonorchiasis is the cumulative end result
of a multifactorial carcinogenic mechanism, although the
mechanisms involved are not completely understood.
Improving diagnosis with new serological tests
Serological tests may be helpful but cannot distinguish
between recent or past infection. Currently, the Ov-CP-1based
ELISA shows a sensitivity of 95% and specificity of
96% in serum coinfected with hookworm, minute intestinal
fluke, S. stercoralis, Taenia spp., Giardia lamblia and
Escherichia coli infection [58]. The sensitivity and specificity
are similar to other studies using an ELISA based
on recombinant trematode cysteine protease such as
C. sinensis (sensitivity, 81.3–96%; specificity, 92.6–
96.2%) [59,60]. Human clonorchiasis or opisthorchiasis
is primarily diagnosed by the detection of eggs in faeces.
The Kato–Katz method is accepted as the best for faecal
examination, although sometimes the eggs may not be
detected because of biliary obstruction or intermittent
egg excretion similar to fasciolasis. In light infections,
with less than 10 adult worms in the biliary tract, a PCR
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

detecting the DNA of the adult parasite in stools may be
helpful [61]. Intrahepatic duct dilatation is the most
common finding on ultrasound imaging (76% of patients),
and increasing periductal echogenicity and gallbladder
sludge are seen only in patients with heavy infection [62].
Recently, Ruangsittichai et al. [63] reported high sensitivity
and specificity using a recombinant eggshell protein
with potential for the serodiagnosis of human opisthorchiasis.
However, detection of O. viverrini DNA is expensive
and requires skilful professional personnel.
Treatment
Praziquantel, a derivative of pyrazinoisoquinoline, is the
drug of choice for O. viverrini, O. felineus and C. sinensis
treatment. For O. viverrini, a single dose (40–50 mg/kg) of
praziquantel treatment is indicated, with a cure rate
between 91–97%. For clonorchiasis, the recommended
dose of praziquantel is 25 mg/kg three times at 5-h
intervals in 1 day (total dose 75 mg/kg), with a cure rate
of 83–85% [7 ,12].
Conclusion
A large number of people continue to have infections
with hepatobiliary flukes. Most of them are asymptomatic
but have potential risk for developing severe complications.
The most promising advances appear to be the
evolution of new serological diagnostic techniques with
high sensitivity and specificity, which might detect more
cases in endemic areas. The RST and Kato–Katz should
be applied for faecal examination in all endemic areas.
Although triclabendazole and praziquantel are highly
effective, the emergence of resistance is a well recognised
problem in animal infections and could impact future
human treatment. Alternative treatment strategies,
including single or combination therapies with artemisinin
derivatives, trioxolanes and other compounds such as
tribendimidine, are being explored [64,65 ,66,67]. With
all these new research findings, future ambitious intervention
programmes in endemic countries should evaluate
the impact on morbidity and mortality on a greater
scale.
Acknowledgement
The findings and conclusions in this review are those of the authors and
do not necessarily represent the views of the Centers for Disease
Control and Prevention.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 566–567).
1 Keiser J, Utzinger J. Emerging foodborne trematodiasis. Emerg Infect Dis
2005; 11:1507–1514.
<strong>Update</strong> on hepatobiliary flukes Marcos et al. 529
2 Marcos LA, Terashima A. <strong>Update</strong> on human fascioliasis in Peru: diagnosis,
treatment and clinical classification proposal. Neotrop Helminthol 2007;
1:85–103.
This study provides a good overview of the current state of knowledge in
F. hepatica in Peru in the last decade on the basis of 1800 human cases.
3 Marcos LA, Tagle M, Terashima A, et al. Natural history, clinico-radiologic
correlates and response to triclabendazole in acute massive fascioliasis. Am J
Trop Med Hyg 2008; 78:222–227.
There are few reviews of acute fascioliasis correlating clinical picture, diagnosis,
CT findings and treatment response.
4 Marcos LA, Maco V, Samalvides F, et al. Risk factors for Fasciola hepatica
infection in children: a case-control study. Trans R Soc Trop Med Hyg 2006;
100:158–166.
5 Marcos LA, Yi P, Machicado A, et al. Hepatic fibrosis and Fasciola hepatica
infection in cattle. J Helminthol 2007; 81:381–386.
This study associated the chronic infection, worm burden and the development of
liver fibrosis in cattle infected by fascioliasis.
6 Keiser J, Engels D, Buscher G, Utzinger J. Triclabendazole for the treatment of
fascioliasis and paragonimiasis. Expert Opin Investig Drugs 2005; 14:1513–
1526.
7 Kaewpitoon N, Kaewpitoon SJ, Pengsaa P. Opisthorchiasis in Thailand:
review and current status. World J Gastroenterol 2008; 14:2297–2302.
Good review in the current state of knowledge on opistorchiasis in Thailand since
1950.
8 Sayasone S, Odermatt P, Phoumindr N, et al. Epidemiology of Opisthorchis
viverrini in a rural district of southern Lao PDR. Trans R Soc Trop Med Hyg
2007; 101:40–47.
This study provides information regarding the epidemiology of Opisthorchis in an
endemic area.
9 Sriamporn S, Pisani P, Pipitgool V, et al. Prevalence of Opisthorchis viverrini
infection and incidence of cholangiocarcinoma in Khon Kaen, Northeast
Thailand. Trop Med Int Health 2004; 9:588–594.
10 Sripa B, Kaewkes S, Sithithaworn P, et al. Liver fluke induces cholangiocarcinoma.
PLoS Med 2007; 4:201.
Good review and nice description of liver flukes and cholangiocarcinoma in Asia. It
described the pathogenesis from infection to cancer.
11 Tselepatiotis E, Mantadakis S, Papoulis E, et al. A case of Opisthorchis
felineus infestation in a pilot from Greece. Infection 2003; 6:430–432.
12 Rim HJ. Clonorchiasis: an update. J Helminthol 2005; 79:269–281.
13 Lun ZR, Gasser RB, Lai DH, et al. Clonorchiasis: a key foodborne zoonosis in
China. Lancet Infect Dis 2005; 5:31–41.
14 Liao WC, Wang HP, Chiu HM, et al. Multiple hepatic nodules: rare manifestation
of clonorchiasis. J Gastroenterol Hepatol 2006; 21:1497–1500.
15 Park DH, Son HY. Clonorchis sinensis, images in clinical medicine. N Engl J
Med 2008; 358:16.
16 Stunell H, Buckley O, Geoghegan T, Torreggiani WC. Recurrent pyogenic
cholangitis due to chronic infestation with Clonorchis sinensis. Eur Radiol
2006; 16:2612–2614.
17 Choi D, Lim JH, Lee KT, et al. Cholangiocarcinoma and Clonorchis sinensis
infection: a case-control study in Korea. J Hepatol 2006; 44:1066–1073.
18 Mas-Coma S, Bargues MD, Valero MA. Fascioliasis and other plant-borne
trematode zoonoses. Int J Parasitol 2005; 35:1255–1278.
19 Marcos LA, Terashima A, Leguia G, et al. Fasciola hepatica infection in Peru:
an emergent disease. Rev Gastroenterol Peru 2007; 27:389–396.
This study reported approximately 1700 patients infected by F. hepatica from
1963 to 2007 in Peru, describing the epidemiology, clinical picture, diagnosis and
treatment.
20 Parkinson M, O’Neill SM, Dalton JP. Endemic human fasciolosis in the Bolivian
Altiplano. Epidemiol Infect 2007; 135:669–674.
A meta-analysis of epidemiological surveys from 38 communities in the Bolivian
Altiplano shows incidences of up to 67% of infected population, and prevalence is
age related with the highest infection rate in children aged 8–11 years.
21 Marcos L, Maco V, Florencio L, et al. High prevalence rates of human
fascioliasis in Peru: an emerging disease. Rev Per Enf Infec Trop 2005;
3:8–13.
22 Marcos LA, Romani L, Florencio L, et al. Hyperendemic and mesoendemic
areas of Fasciola hepatica infection close to Lima city: an emergent disease?
Rev Gastroenterol Peru 2007; 27:21–26.
23 Marcos LA, Maco V, Terashima A, et al. Hyperendemicity of human fascioliasis
in the Mantaro valley: risk factors of Fasciola hepatica infection. Rev Gastroenterol
Peru 2004; 24:158–164.
24 Marcos LA, Maco V, Terashima A, et al. Fascioliasis in relatives of patients with
Fasciola hepatica infection in Peru. Rev Inst Med Trop Sao Paulo 2005;
47:219–222.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

530 Gastrointestinal infections
25 Maeda T, Yamada H, Akao N, et al. Unusual radiological findings of Fasciola
hepatica infection with huge cystic and multilocular lesions. Intern Med 2008;
47:449–452.
26 Marcos LA, Maco V, Terashima A, et al. Clinical characteristics of Fasciola
hepatica chronic infection in children. Rev Gastroenterol Peru 2002;
22:228–233.
27 Marcos LA, Maco V, Castillo M, et al. Report of cases of fascioliasis in the
Specialized Children Health Institute in Peru (1988–2003). Rev Gastroenterol
Peru 2005; 25:198–205.
28 Rana SS, Bhasin DK, Nanda M, Singh K. Parasitic infestations of the biliary
tract. Curr Gastroenterol Rep 2007; 9:156–164.
Good review of biliary parasite infection and radiologic imaging.
29 Aroonroch R, Worawichawong S, Nitiyanant P, et al. Hepatic fascioliasis due
to Fasciola hepatica: a two-case report. J Med Assoc Thai 2006; 89:1770–
1774.
30 Umac H, Erkek AB, Ayaslioglu E, et al. Pruritus and intermittent jaundice as
clinical clues for Fasciola hepatica infestation. Liver Int 2006; 26:752–753.
31 El-Shazly AM, Soliman M, Gabr A, et al. Clinico-epidemiological study of
human fascioliasis in an endemic focus in Dakahlia Governorate. J Egypt Soc
Parasitol 2001; 31:725–736.
32 Bulbuloglu E, Yuksel M, Bakaris S, et al. Diagnosis of Fasciola hepatica cases
in an operating room. Trop Doct 2007; 37:50–52.
33 Fullerton JK, Vitale M, Vitale GC. Therapeutic endoscopic retrograde cholangiopancreatography
for the treatment of Fasciola hepatica presenting as
biliary obstruction. Surg Innov 2006; 13:179–182.
34 Valero MA, Navarro M, Garcia-Bodelon MA, et al. High risk of bacterobilia in
advanced experimental chronic fasciolosis. Acta Trop 2006; 100:17–23.
35 Valero M, Santana M, Hernandez J, Mas-Coma S. Risk of gallstone disease in
advanced chronic phase of fascioliasis: an experimental study in a rat model.
J Infect Dis 2003; 188:787–793.
36 Rondelaud D, Dreyfuss G, Vignoles P. Clinical and biological abnormalities in
patients after fascioliasis treatment. Med Mal Infect 2006; 36:466–468.
37 Blancas G, Terashima A, Maguina C, et al. Human fascioliasis and gastrointestinal
involvement: study of 277 patients in Cayetano Heredia National
Hospital. 1970–2002. Rev Gastroenterol Peru 2004; 24:143–157.
38 Turhan O, Korkmaz M, Saba R, et al. Seroepidemiology of fascioliasis in the
Antalya region and uselessness of eosinophil count as a surrogate marker and
portable ultrasonography for epidemiological surveillance. Infez Med 2006;
14:208–212.
39 Almendras-Jaramillo M, Rivera-Medina J, Seijas-Mogrovejo J, Almendras-
Jaramillo K. Hepatic fascioliasis in children: uncommon clinical manifestations.
Arq Gastroenterol 1997; 34:241–247.
40 Heredia D, Bordas JM, Mondelo F, Rodes J. Gallbladder fascioliasis in a
patient with liver cirrhosis. Med Clin (Barc) 1984; 82:768–770.
41 Sanchez-Sosa S, Rojas-Ortega S, Reed-San Roman G, Torres-Santana MA.
Massive hepatobiliary fascioliasis. Rev Gastroenterol Mex 2000; 65:179–
183.
42 Stack CM, Donnelly S, Lowther J, et al. The major secreted cathepsin L1
protease of the liver fluke, Fasciola hepatica: A leu-12 to pro-12 replacement
in the nonconserved C-terminal region of the prosegment prevents complete
enzyme autoactivation and allows definition of the molecular events in prosegment
removal. J Biol Chem 2007; 282:16532–16543.
This study provides a molecular insight into the regulation of cathepsin L1, a major
immunogenic cysteine proteinase released by F. hepatica.
43 Gironès N, Valero MA, García-Bodelón MA, et al. Immune suppression in
advanced chronic fascioliasis: an experimental study in a rat model. J Infect
Dis 2007; 195:1504–1512.
This study shows that chronic fascioliasis may increase the risk for other infections
in an animal model.
44 Espinoza JR, Timoteo O, Herrera-Velit P. Fas2-ELISA in the detection of
human infection by Fasciola hepatica. J Helminthol 2005; 79:235–240.
45 Espinoza JR, Maco V, Marcos L, et al. Evaluation of Fas2-ELISA for the
serological detection of Fasciola hepatica infection in humans. Am J Trop Med
Hyg 2007; 76:977–982.
This study validates the Fas2-ELISA for human diagnosis of fascioliasis. It was
evaluated with hundreds of infected children in three different cities in Peru.
46 Cosme A, Ojeda E, Cilla G, et al. Fasciola hepatica study of a series of 37
patients. Gastroenterol Hepatol 2001; 24:375–380.
47 Kabaalioglu A, Cubuk M, Senol U, et al. Fascioliasis: US, CT, and MRI findings
with new observations. Abdom Imaging 2000; 25:400–404.
48 Aksoy DY, Kerimoglu U, Oto A, et al. Fasciola hepatica infection: clinical and
computerized tomographic findings of ten patients. Turk J Gastroenterol
2006; 17:40–45.
49 Orlent H, Selleslag D, Vandecasteele S, et al. Clinical challenges and images
in GI. Fasciola hepatica infection and Von Hippel-Lindau disease type 1 with
pancreatic and renal involvement. Gastroenterology 2007; 132:467–468.
50 Lumbreras H, Cantella R, Burga R. A rapid sedimentation procedure to
investigate Fasciola hepatica eggs in stools, its evaluation and use in field.
Rev Med Peru 1962; 31:167–174.
51 Talaie H, Emami H, Yadegarinia D, et al. Randomized trial of a single, double
and triple dose of 10 mg/kg of a human formulation of triclabendazole in
patients. Clin Exp Pharmacol Physiol 2004; 31:777–782.
52 El-Tantawy WH, Salem HF, Mohammed Safwat NA. Effect of fascioliasis on
the pharmacokinetic parameters of triclabendazole in human subjects. Pharm
World Sci 2007; 29:190.
This study explains triclabendazole’s properties, effectiveness and safety in humans.
53 Park GM. Genetic comparison of liver flukes, Clonorchis sinensis and
Opisthorchis viverrini, based on rDNA and mtDNA gene sequences. Parasitol
Res 2007; 100:351–357.
This study suggests that Clonorchis and Opisthorchis are virtually identical
despite belonging to entirely different genera and coming from different geographical
areas.
54 Honjo S, Srivatanakul P, Sriplung H, et al. Genetic and environmental
determinants of risk for cholangiocarcinoma via Opisthorchis viverrini in a
densely infested area in Nakhon Phanom, Northeast Thailand. Int J Cancer
2005; 117:854–860.
55 Laha H, Pinlaor P, Mulvenna J, et al. Gene discovery for the carcinogenic
human liver fluke, Opisthorchis viverrini. BMC Genomics 2007; 8:189.
56 Lim MK, Ju YH, Franceschi S, et al. Clonorchis sinensis infection and
increasing risk of cholangiocarcinoma in the Republic of Korea. Am J Trop
Med Hyg 2006; 75:93–96.
57 Tan SK, Qiu XQ, Yu HP, et al. Evaluation of the risk of clonorchiasis inducing
primary hepatocellular carcinoma. Zhonghua Gan Zang Bing Za Zhi 2008;
16:114–116.
58 Watthanakulpanich D, Waikagul J, Anantaphruti MT, Dekumyoy P. Evaluation
of Bithynia funiculata snail antigens by ELISA: serodiagnosis of human
opisthorchiasis.
28:593–598.
Southeast Asian J Trop Med Public Health 1997;
59 Nagano I, Pei F, Wu Z, et al. Molecular expression of a cysteine proteinase of
Clonorchis sinensis and its application to an enzyme-linked immunosorbent
assay for immunodiagnosis of clonorchiasis. Clin Diagn Lab Immunol 2004;
11:411–416.
60 Zhao QP, Moon SU, Lee HW, et al. Evaluation of Clonorchis sinensis
recombinant 7-kilodalton antigen for serodiagnosis of clonorchiasis. Clin
Diagn Lab Immunol 2004; 11:814–817.
61 Duenngai K, Sithithaworn P, Rudrappa UK, et al. Improvement of PCR for
detection of Opisthorchis viverrini DNA in human stool samples. J Clin
Microbiol 2008; 46:366–368.
62 Choi MS, Choi D, Choi MH, et al. Correlation between sonographic findings
and infection intensity in clonorchiasis. Am J Trop Med Hyg 2005; 73:1139–
1144.
63 Ruangsittichai J, Viyanant V, Vichasri-Grams S, et al. Opisthorchis viverrini:
identification of a glycine-tyrosine rich eggshell protein and its potential as a
diagnostic tool for human opisthorchiasis. Int J Parasitol 2006; 36:1329–
1339.
64 Keiser J, Utzinger J. Food-borne trematodiasis: current chemotherapy and
advances with artemisinins and synthetic trioxolanes. Trends Parasitol 2007;
23:555–562.
65 Keiser J, Utzinger J. Artemisinins and synthetic trioxolanes in the treatment of
helminth infections. Curr Opin Infect Dis 2007; 20:605–612.
This is an excellent review of current and future prospects for therapy of trematodes.
66 Keiser J, Xiao SH, Dong Y, et al. Clonorchicidal properties of the synthetic
trioxolane OZ78. J Parasitol 2007; 93:1208–1213.
67 Keiser J, Utzinger J, Xiao SH, et al. Opisthorchis viverrini: efficacy and
tegumental alterations following administration of tribendimidine in vivo and
in vitro. Parasitol Res 2008; 102:771–776.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.