Palabras claves: Fasciola hepatica - Fascioliasis/diagnóstico - Fascioliasis/epidemiología
– Zoonosis - Revisión - Perú.
1. Internal Medicine Department, University of Texas, Houston, TX, USA.
2. Institute of Tropical Medicine Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
Neotrop. Helminthol., 1(2), 2007
85
Human Fasciola hepatica infection in Peru is an emerging infectious disease. In this review we describe the
fascioliasis situation in Peru, based on the most recent studies about epidemiology, diagnostic tools and
treatment. We propose a new clinical classification according to the stage of the disease. Recent reports
have highlighted the clinical variability ranging from an indolent to a severe life-threatening infection.
Increasing numbers of human cases have been reported worldwide, especially from the Andean Region in
South America. Most common clinical manifestations in the acute phase are: hepatomegaly, fever, weight
loss, and eosinophilia. In the chronic phase, it can be mild and unspecific, including: biliary obstruction,
bacterobilia, liver cystic calcifications, gallstones, and liver fibrosis. The Rapid Sedimentation Technique
described by Lumbreras should be applied to diagnose the chronic phase as well as for epidemiological
studies in endemic areas. The direct smear only detects 2% of cases. The novel diagnostic test Fas2 (ca-
thepsin L1) ELISA has a sensitivity of 92.4% and specificity of 83.6% in 634 Peruvian subjects in endemic
areas and it is helpful for both the acute and chronic phases. The most common radiological abnormalities
in the acute phase are: track-like hypodense hepatic lesions, liver “abscesses” and/or subcapsular hemato-
mas. Abdominal ultrasound has a low sensitivity in chronic cases and is not recommended for screening.
Triclabendazole is the treatment of choice even with a single dose (cure rate ≥ 90 %) for both phases, but
resistance is now a concern in animals. The new arsenal of available information can be applied to preven-
tion and control programs in Peru.
Abstract
Resumen
La infección humana por Fasciola hepatica en el Perú es una enfermedad infecciosa emergente. En esta
revisión describimos la situación de la fasciolosis en el Perú, en base a los estudios mas recientes sobre
epidemiología, métodos de diagnóstico y tratamiento. Proponemos una nueva clasificación clínica en base
al estado de la enfermedad. Estudios recientes han destacado la variabilidad clínica de esta infección que
puede comprender desde una infección indolente a una severa que puede comprometer la vida del pa-
ciente. Un incremento en el número de casos humanos ha sido reportado en todo el mundo, y en especial
en la Región Andina de Latinoamérica. Las manifestaciones clínicas más comunes en la fase aguda son:
hepatomegalia, fiebre, pérdida de peso y eosinofilia. En la fase crónica, esta puede ser leve e inespecífica,
pero también severa como obstrucción biliar, colangitis, quistes calcificados hepáticos, cálculos vesiculares
y fibrosis hepática. La Técnica de Sedimentación Rápida descrita por Lumbreras debe ser aplicada para el
diagnóstico de la fase crónica y para estudios epidemiológicos en zonas endémicas. El examen directo solo
detecta 2 % de los casos. El nuevo examen diagnostico ELISA Fas2 (catepsina L1) tiene una sensibilidad
del 92,4 % y especificidad del 83,6 %, y esto fue observado en 634 sujetos peruanos en áreas endémicas y es
útil tanto para la fase aguda como la crónica. Las anormalidades radiológicas más comunes en la fase aguda
son: lesiones hipodensas hepáticas en forma de “camino”, abscesos hepáticos y hematoma subcapsular. La
ecografía abdominal tiene una baja sensibilidad en casos crónicos y no es recomendada para tamizaje. El
triclabendazol es el tratamiento de elección con una dosis única (tasa de curación ≥ 90 %) para ambas fases,
pero casos de resistencia a la droga es ahora una preocupación aunque solo en animales. El nuevo arsenal
de información disponible puede ser aplicado a los programas de prevención y control en el Perú.
Key words: Fasciola hepatica - Fascioliasis/diagnosis - Fascioliasis/epidemiology - Zoonosis - Review - Peru
REVIEW/ARTÍCULO DE REVISIÓN
UPDATE ON HUMAN FASCIOLIASIS IN PERU: DIAGNOSIS, TREATMENT
AND CLINICAL CLASSIFICATION PROPOSAL
ACTUALIZACIÓN EN FASCIOLOSIS HUMANA EN EL PERÚ: DIAGNÓSTI-
CO, TRATAMIENTO Y PROPUESTA DE CLASIFICACIÓN CLÍNICA
Luis A. Marcos1,2; Angélica Terashima.2
Suggested citation: Marcos, LA & Terashima, A. 2007. Update on human fascioliasis in Peru: diagnosis, treatment and
clinical classification proposal. Neotropical Helminthology, vol. 1, no. 2, pp. 85-103.
Neotrop. Helminthol., 1(2) , 2007
© 2007 Asociación Peruana de Helmintología e Invertebrados Afines (APHIA)
Human fascioliasis in Peru
Marcos, LA & Terashima, A
86
A) Life cycle
The adult F. hepatica flukes are large, flat, brown and
leaf-shaped, measuring approximately 2.5 to 3 by 1
to 1.5 cm. The broad, anterior portion is covered
with scale-like spines. The adult fluke lives in the
common and hepatic bile ducts of the human or
animal host. The eggs are oval, yellow-brown, and
measure approximately 130 to 150 by 60 to 90 µm.
When parasite eggs in mammalian stool are
deposited in tepid water (22-26°C) miracidia appear,
develop, and hatch in 9-14 days. These miracidia
then invade many species of freshwater snails, in
which they multiply as sporocyst and redia for 4-7
weeks. They leave as free-swimming cercaria that
subsequently attach to watercress, water lettuce,
mint, parsley, or khat. Free-swimming cercaria may
remain suspended in the water and encyst over a
few hours.
When humans consume contaminated plants or
water, the larvae excyst in the duodenum, migrate
through the bowel wall and peritoneal cavity, and
penetrate the Glisson capsule, actions that initiate
the acute larval, hepatic, and invasive stages of
human infection. Larvae sometimes also travel to
ectopic body sites. This stage may last 3-5 months,
during which the larvae mature and migrate
through the liver into the large hepatic and common
bile ducts. Mature flukes consume hepatocytes and
duct epithelium and reside for years in the hepatic
and common bile ducts and occasionally in the gall
bladder; this is the chronic adult biliary stage of
infection. Adult fluke worms produce eggs about 4
months (with a range of 3-18 mo) after infection;
these eggs traverse the sphincter of Oddi and
intestine and then continue the cycle of infection.
Acute and chronic stages can overlap, particularly
in a high-level infection.
B) Intermediate hosts in Peru
Snails of the family Lymnaeidae are of great
parasitological importance, because of their
capacity to act as intermediate hosts for numerous
trematode parasites, including those of medical and
veterinary impact such as F. hepatica (Tantalean et al.,
1974). In Peru, F. viatrix (=F. viator) and L. diaphana
(Cordova et al., 1961) have been recognized to have
Figure 1. Lesions are more central than subcap-
sular. Case with CT scan after endovenous con-
trast showing nodular images (arrows), perivascu-
lar, some serpiginous (arrowhead), track-like and
subcapsular-peripheral lesions = Pathognomonic
of fascioliasis. Most lesions are central, scattered
throughout the liver parenchyma. Splenomega-
ly is present. *With permission of Marcos et al.,
2008.
The liver flukes Fasciola hepatica and F. gigantica
infection cause the zoonotic disease fascioliasis. In
Peru, F. hepatica is endemic, while F. gigantica has
never been detected. Recent advances around
the world have elucidated better the geographic
distribution (including paleoparasitology), clinical
manifestations, novel diagnostic tools and treatment
regimens in this parasitic infection. Likewise, the
increased recognition of human fascioliasis has led
to the World Health Organization (WHO) to include
fascioliasis into the list of important human parasitic
diseases (Mas-Coma, 2005). We need to emphasize
that in spite of the fact we have searched extensively
about fascioliasis in the Peruvian literature, there
were many difficulties and limitations to find more
valorous information.
This article highlights recent progress in human
fascioliasis in Peru, its impact on clinical practice,
from epidemiology to recent vaccines, and
emphasizes persistent gaps in our knowledge that
merit further study (Summarized in conclusions &
Figure1).
The aim of this review is to update the knowledge in
fascioliasis in Peru, based on the most recent studies
about epidemiology, diagnostic tools, treatment and
we propose a novel clinical classification according
to the stage of the disease.
INTRODUCTION EPIDEMIOLOGY
Neotrop. Helminthol., 1(2), 2007
87
the ability to be intermediate hosts for fascioliasis.
They are distributed throughout Peru but in special
in the highlands valleys of the Andean Region.
C) Geographic distribution of F.
hepatica
C.1. In the world: A cosmopolitan
parasite?
New evidence has showed that F. hepatica was first
documented in the Gallo-Roman period (Da
Rocha et al., 2006). Currently, an estimated of 91
million people are at risk of this infection (Keiser
& Utzinger, 2005). Globally, the total estimated
number of people infected is 2.4 million in 61
countries (In Haseeb et al., 2002). In the world,
the Andean Region of South America is the most
affected by this parasitic infection. For example,
up to 67% prevalence in the Bolivian Altiplano
(Esteban et al., 1999; Parkinson et al., 2006) and
72% in the Peruvian Altiplano (Marcos et al.,
2005a). The number of people infected in some
countries has been estimated as well. For example,
830,000 in Egypt, 742,000 in Peru, 360,000 in
Bolivia, 37,000 in Yemen, 20,000 in Ecuador
and 10,000 in Iran. Likewise, a higher number
of human cases have been reported in the last
years around the world: Argentina (Kleiman et
al., 2007), Venezuela (Incani et al., 2003), Chile
(Llanos et al., 2006), Ecuador (Trueba et al.,
2000), Mexico (Cruz Lopez et al, 2006), Turkey
(Turhan et al., 2006; Kaya et al., 2006), Thailand
(Aroonroch et al., 2006), Japan (Inoue et al., 2007),
Korea (Lee & Kim. 2006), USA (Graham et al.,
2001; Fullerton et al., 2006), Tunisia (Khelifi et
al., 2006) and Lebanon (Birjawi et al., 2002).
Most reported cases are clinical complications of
the infection; the real number of subjects with
fascioliasis is undoubtedly underestimated. For
example, in Peru, recent epidemiological studies
were initiated from the complicated cases seen in
the clinical setting in Lima hospitals, after that,
multiple studies were carried out throughout
Peru and we will present the results in the
next paragraphs which will guide clinicians in
endemic areas to recognize the infection with
the only objective to treat it before developing
complications.
C.2. Situation of F. hepatica in Peru
The current situation of human fascioliasis in
Peru is dramatic, though unknown for most
clinicians. The highest prevalence rates by
coprological tests range from 8% in Cajamarca
(Knobloch et al., 1985); 34.2% in Santa Ana,
Junín (Stork et al., 1973); 28.3% in the same
region 31 years later (Marcos et al., 2004); 15.7%
in Asillo, Puno (Mas-Coma et al., 1999a); and
35% in the same area 9 years later (Esteban et
al., 2002); and by serological tests up to 36.3%
in Junín (Marcos et al., 2004). Most cases are
school-age children 5-15 years old. A number
of cases has been reported in many Peruvian
hospitals; in Arequipa, 220 cases were reported
until 1977 (Picoaga et al., 1980); in Cuzco, 18
cases were diagnosed in patients undergoing
cholecystectomy (Vilca, 1982); in Lima, where
fascioliasis is not endemic, 16 cases were reported
in the 90´s in the Arzobispo Loayza Hospital
(Jimenez et. al., 2001) and 277 cases in a period of
32 years in Cayetano Heredia National Hospital
(Blancas et al., 2004); and in Cajamarca, 101
cases were observed from 1996 to 2001 (Alban
et al., 2002).
A recent study done by our group confirms the
high number of infected humans in our country.
Almost 1701 cases were reported from 1963 to
2005 throughout Peru with 70% of the Peruvian
territory likely infected (Marcos et al., 2007e).
This number of cases was increased to 1877 by
the observations carried out by Mayta-Tristan
& Caro (2008). The number of cases may still
be underestimated in these reports because
only complicated chronic severe infections were
included. Furthermore, new endemic areas (e.g
Huarochiri and Canta in Lima, Peru) continue
to be identified by studying family members of
index cases diagnosed in urban areas (Marcos et
al., 2007a). This might be a strategy for Public
Health to uncover endemic areas in future
studies.
In the Institute of Tropical Medicine Alexander von
Humboldt of the Universidad Peruana Cayetano
Heredia, Lima, Peru; under this strategy, we
have discovered the areas of where patients with
fascioliasis originated; some reported others only
seen in the clinical setting (Terashima, personal
communication). The division was made by
Human fascioliasis in Peru
Marcos, LA & Terashima, A
88
departments and towns and the following are the
most likely endemic areas in Peru. In Lima: Canta,
La Chaqui, Huarochirí, Sangallaya, San Pedro
de Casta, Marcahuasi, San Damián, Yauyos,
Huaral, La Florida, Acos, Aucayama, Oyón,
Caujul, Huancahuasi, Churin, Chancay (Huiza,
1973; Raymondi, 1986; Marcos et al., 2007a;
Maco et al., 2003). In Ancash: Huari, Pallasca,
Rahuapampa, Aija, Huacllan. Huachón, La
Merced, Huaraz, Recuay, Cotaparaco, Ocros,
Huayllas, Caraz (Cantella et al., 1964; Fabian,
2003; Lopez De Guimaraes et al., 1995; 1999).
In Cajamarca: Celendín, La Libertad de Pallan,
Cajamarca, Baños del Inca (Shaullo), Chota, San
Miguel, Llapa, Sitacocha, Mangle, La Encañada,
Contumazá, Chilete, San Juan (Lumbreras,
1964; Knobloch et al., 1985; Ortiz et al., 2000).
In Pasco: Pasco. In Huanuco: Huanuco,
Tingo María (Tapia & Manrique, 1975). In
Junin: Jauja, Huertas, Julcán, Yauli, Molinos,
Condorsinja, Santa Ana, Pancán, Concepción,
9 de Julio, El Tambo, Huala, Huancayo, Sicaya,
Chupaca, Quilcas, Tarma (Terashima, 1970;
Naquira et al., 1972, Ramos, 1991; Marcos et al.,
2004), Chupaca (Cornejo et al., 2003). In Cuzco:
Sicuani, Cuzco, Cusco (Abarca, 1989; Rivera,
1977), Urubamba, Paucartambo, Caycay, Pacor,
Vilcabamba, Vilcanota, Calca, San Salvador,
Canchis, Anta (Valdivia et al., 1990), San Pedro
de Cacha (Castro et al., 1964; Vilca, 1982;
Fernandez, 1997). In Abancay: Apurimac,
Cotabambas, Ñahuinlla, Pamputa, Aymares
(Tataje, 1986; Jiménez et al., 2001). In Ayacucho:
Huanta, Huamanga, Cora Cora, La Mar, San
Miguel, Vilcashuaman (Blancas et al., 2004). In
Arequipa: Arequipa (Cerpa, 1989, Perez, 1995),
La Campiña, Uchumayo, Camaná, Ocoña,
Sachaca (Perez, 1998), Caraveli (Ayaqui, 2000).
In Ica: Chincha Alta (Blancas et al., 2004; Marcos
et al., 2005b). In Moquegua: Puquina. In Tacna:
Candarave. In Amazonas: Chachapoyas (Ibañez
et al., 2004). In Puno: Azángaro, Asillo, Progreso,
Ilave, Cabanillas, Yunguyo, Desaguadero
(Esteban et al., 2002; Marcos et al., 2002, 2005a,c;
2006). In Huancavelica: Acobamba, Tayacaja,
Ñahuimpuquio, Antajaja (Chinchihuasi),
Huancavelica (Valencia et al., 2005), Churcampa,
El Carmen, Paucarbambilla (Jiménez et al.,
2001). Some of these areas have been explored
and reported several human cases, others not
yet; we strongly recommend to students and
academicians involved in the medical field to
look for human cases in these areas and report
them. A geographical system has been described
recently in order to localize endemic areas in the
Andean Region using climatic data to calculate
forecast indices and other parameters (Fuentes et
al., 2005) but not yet widely available.
In summary, these results suggest that Peru is
one of the countries with the widest regional
distribution of human fascioliasis brought on
by F. hepatica in the world. A rural population of
almost 8 million people is estimated at risk in this
country (WHO, 1995). Some regions still have
the same – or an even higher - prevalence rate
than years before. This fact is explained by the
lack of control and prevention measures in those
very regions. Human fascioliasis should no longer
be considered a secondary zoonosis especially in
Peru; but rather, an important human parasitic
disease.
D) Risk Factors for F. hepatica infection
One of the singular epidemiological features
of human fascioliasis in Peru is the route of
infection how some people are infected by F.
hepatica, since the classical watercress, is not as
common here as in other countries. In a serie of
277 patients with fascioliasis diagnosed in Lima,
only 45.6 % mentioned having eaten watercress,
the rest have acquired it from eating other plants
such as lettuce (31.6 %), alfalfa (10.5 %), or
spinach (5.3 %), drinking water from puquiales
(10.5 %) (Natural water from small streams), or
emollients (5.3 %) (emollients are warm beverage
made from various plants, chiefly alfalfa and
watercress, and supposed to be good for liver
diseases), among others (Blancas et al., 2004).
Interestingly enough, the emollients may be a
risk factor in the Mantaro Valley, Junín (Marcos
et al., 2004).
Others mention that the vehicle of contamination
varies, depending on the region such as in
France, Taraxacum dens leonis (dandelion leaves),
Valerianella olitora (lamb’s lettuce), and Mentha
viridis (spearmint); in the Islamic Republic of
Iran, other green leafy Nasturtium spp. and
Mentha spp.; and in the Bolivian Altiplano, Juncus
andicola (Juncaceae), Juncus ebracteatus (Juncaceae),
Mimulus glabratus (Scrophulariaceae), Nostoc sp.
(Cianofitas), among others (Bjorland et al., 1995;
Neotrop. Helminthol., 1(2), 2007
89
Mas-Coma et. al., 1999b). Water also has been
described as a possible risk factor (Mas-Coma
et al., 1995). According to Esteban et al. (2002),
there are two main vehicles of infection in Peru:
water from streams and watercress; however,
there are at least 40% of patients who deny
exposure to them (Blancas et al., 2004). There is a
need of disclosing additional factors involved in
fascioliasis transmission, to improve control and
prevention programs in the near future.
In the searching of risk factors in Peru, a number
of epidemiological studies have been carried out in
endemic areas (Table 1). Housing characteristics
(material, water and sewage), relation to water
supply (channels, river, streams), water supply
itself, consumption of certain plants or vegetables
such as lettuce, onion, spinach, salads, watercress
juice, drinking water from streams, breeding
of llamas or alpacas, history of having taken
antihelmintic drugs, past coprological diagnosis
of intestinal parasitosis and history of surgery,
were not significantly associated with F. hepatica
infection.
Alfalfa juice, emollients and water from the
irrigation channels which carry the metacercariae
play a key role in the transmission of fascioliasis
in endemic areas. Hypothetically, exportation
of plants or other products could lead to
transmission in non-endemic areas, as some
patients have been reported in Lima (Marcos et
al., 2007c). Treatment of contaminated plants
with high doses of potassium permanganate
decreases metacercaria viability and could be
used to prevent infection (Ashrafi et al., 2006)
but not evaluated in endemic areas yet. The
control and prevention programs under this
epidemiological evidence have a support and
enthusiastic programs will likely appear in the
following years.
E) Role of Gender in fascioliasis
There is a tendency for women to have higher
prevalences and to be more insensitively infected.
In a 60 children case-control study in Puno, the
intensity of the infection was mild to moderate
(101 and 400 eggs per gram -epg), two cases had
more than 401 epg (up to 528 epg); and only one
had less than 100 epg.
The intensity of infection is measured by
means of Kato-Katz Technique quantifying the
eggs per gram of feces (Katz et al., 1972). The
intensity was higher in girls than boys, as was
reported in a previous study in the same region
(Esteban et al. 2002) and in the Northern Bolivian
Altiplano (Esteban et al., 1999). This latter finding
deserves special attention: women show more
complication rates than do men in adulthood,
as has been reported in a total of approximately
Table 1. Risk factors associated to Fasciola hepatica infection in humans in Peru.
Risk factor
Multivariate Analysis
Drinking [u1]
Living close to irrigation channels
Multivariate Analysis
Eating salads
Multivariate Analysis
Drinking alfalfa juice
Familiarity with aquatic plants
Univariate Analysis
Water supply from channels
Consumption of aquatic plants
Breeding 5 or more cattle
Owning dogs
Defecation site in fields
Familiarity with aquatic plants
Breeding more than 5 sheep
Odds Ratio =
OR(Confident Interval
CI 95%)
5.2 (1.7-15.6)
7.2 (2.8-106.7)
3.3 (1.2 - 9.0)
4.5 (1.7—11.1)
4.3 (1.7—10.5)
2.4 (1.1-5.3)
2.5 (1.1-5.6)
2.5 (1.1-5.6)
3.2 (1.3-8.1)
2.6 (1.3-5.6)
3.9 (1.8-8.3)
0.3 (0.1-0.7)
pvalue
p<0.05 p<0.05
p<0.05
p< 0.001
p< 0.001
p=0.03 p=0.028
p=0.028
p=0.01
p=0.01
p=0.000
p=0.003
Reference
Marcos et al., 2004
Marcos et al., 2005
Marcos et al., 2006
Marcos et al., 2006
Human fascioliasis in Peru
Marcos, LA & Terashima, A
90
622 cases in Peruvian hospitals since 1970 (Fig.
2); around 55% are women, in which there is an
increase of abdominal surgeries. The percentage
is more evident as age increases (Picoaga et al.,
1980; Vilca, 1982; Jimenez et al., 2001; Alban
et al., 2002; Blancas et al., 2004). In conclusion,
more women are infected with Fasciola and have
more complications from the infection.
A) Acute phase of F. hepatica infection: a
classic triad?
The acute phase, up to 4 months in duration, is
characterized by the migration of larvae from the
duodenum through the intestinal wall, peritoneal
cavity, across Glisson’s capsule entering the liver
parenchyma and reaching the biliary ducts.
While there have been few series of acute cases
reported in the literature, the clinical picture,
laboratory data and radiological findings of acute
fascioliasis have nevertheless been clearly described
(Marcos et al., 2007c). The classic triad consists of
hypereosinophilia, right upper quadrant (RUQ)
pain (“Murphy sign”) and fever. A serie of 10
carefully described Peruvian cases of acute massive
fascioliasis found that RUQ pain was present in 80
%, fever ≥ 38ºC (70 %), malaise (60 %), anorexia (50
%), weight loss >10 kg (50 %), nausea and vomiting
(30 %) (Marcos et. al., 2007c). The RUQ pain and
positive “Murphy sign” was misdiagnosed with
“acute cholecystitis” and the CT abdominal findings
were very similar to metastases (see Imaging Section).
Interestingly, hyperbilirrubinemia was absent
(Table 3) (Marcos et al., 2008). In some patients the
eosinophil counts were slightly elevated, being a few
days later >1500 cells per mm3, this finding was also
found in large series of patients recently (Marcos
et al., 2005b; Gil-Gil et al., 2006). This laboratory
abnormalities are explained because of the parasite
larva migration through the liver. Histologically,
it produces subcapsular hemorrhages, hepatic
degeneration, eosinophils infiltration, lymphocytes
and macrophages, fibrosis, venous thrombosis,
appearance of necrotic cords with giant cells and
granulation tissue and granuloma-containing
parasite eggs (Dalton, 1999; Hamir et al., 2002) and
even eggs in the blood vessels (Marcos et al., 2006). In
humans, subcapsular hemorrhages (Loja et al., 2003;
Marcos et al., 2007c), hepatic rupture (Montesinos et
al., 1971), multiple hepatic abscesses (Marcos et al.,
2007c), hepatic necrosis (Kim et al., 1999; Marcos et
al., 2007c), liver calcifications (Marcos et al., 2007c)
and severe anemia (Vilchez et al., 1983); have been
reported. Fascioliasis must be ruled out in any
patient in an endemic area with hepatic dysfunction
or liver failure without known cause.
Ectopic migration and other clinical
manifestations:
In the acute stage (Migratory nodule under •
CLINICAL AND LABORATORY
MANIFESTATIONS IN F. HEPATICA
INFECTION: NEW EVIDENCE
(SUMMARIZED IN TABLE 2)
Figure 2. Distribution by age and gender of fascioliasis in Peru between
1963-2004.
*p=0.003; when groups (0-10/11-
20) were compared with the rest of
groups (≥21 years)
** There was no significant difference
among genders (p>0.05).
With permission of Marcos et al.,
2007c..
0
20
Women
Number of cases
Men
40
60
80
100
120
140
0-10
79
88
126
106
81
56
59
43
60
34
35
21
26
5
11-20 21-30 31-40 41-50 51-60 > 61
Neotrop. Helminthol., 1(2), 2007
91
the skin or peritoneal cavity, Arthralgias,
Lymphadenopathies, Hemolytic anemia,
Seizures, Pleural effussion).
In the chronic stage (Subcutaneous nodules and
Gastric nodule).
A slightly elevated eosinophil count does not exclude
a diagnosis of acute fascioliasis, and a repeated cell
blood count a few days later will show a dramatic
elevation. Despite the typical abdominal pain in
RUQ, this might be not specific in subjects with
multiple parasitic infections, as occurs in endemic
rural areas. However, acute fascioliasis should be
ruled out in any patient from endemic area who
presents with abdominal pain with eosinophilia. A
•
liver function test might be the next step (depending
on the clinical context) and if altered, a serological
test needs to be ordered to confirm diagnosis though a
trial with triclabendazole may be initiated if serology
is not available. A rapid clinical improvement in the
next day and decrease levels of eosinophils will be
seen in the next 3-5 days.
Sometimes, the juvenile larvae may reach other
anatomic locations such as the subcutaneous tissue,
pancreas, eye, brain, stomach wall, etc. This is called
ectopic fascioliasis and it might be not unusual to
see them in endemic areas if clinicians carefully
examine the patient’s skin (Fernan Zegarra et al.,
1961; Bejar et al., 1996; Beltran et al., 2004).
Table 2. Proposed clinical classification according to the stage of fascioliasis
from a review of 1700 cases in Peru
*Asymptomatic cases are occasionally seen in native people in endemic areas (acute stage) or detected by routine coprological studies
in endemic areas (chronic stage).
Stage of Disease
Acute
Chronic most
common presenta-
tion
a) Complicated
b) Uncomplicated
Oligo-symptomatic
- Mild diffuse abdominal pain
- Eosinophilia
- Hyperglobulinemia
- Mild abdominal pain in RUQ
or epigastrium or asymptomatic.
- Dizziness.
Clinical Picture
- Prolonged fever (weeks or months)
- Abdominal pain with hepatomegaly.
- Eosinophilia (any cell count level)
- Biliary hemorrhage
- Hepatic Rupture (seen in CT scan)
- Anemia- Lost weight - Urticaria
- Hepatic Abscesses
- Abdominal pain in RUQ
- Biliary colicky (not associated with food)
- Nausea, Vomiting
- Recurrent or intermittent jaundice
- Urticaria
Liver:
- Hepatic Abscesses
- Liver fibrosis and ultimately cirrhosis
- Necrotic granuloma (increase ALT and AST)
- Tumors
Biliary:
- Cholangitis choledocolithiasis
- Cholecystitis
- Tumors (s)
Liver:
- Cysts
- Nodules
- Tumor (s)
Biliary:
- Colicky
- Chronic cholecystitis
Human fascioliasis in Peru
Marcos, LA & Terashima, A
92
Normal values are as follows: for haemoglobin, 13 to
18 g per deciliter; for the leukocyte count, 4 x 10 9 to 11
x 109 per liter; for the eosinophil count, less than 0.5
x 10 9 per liter; for alanine aminotransferase (ALT),
6 to 53 U per liter; for aspartate aminotransferase
(AST), 13 to 33 U per liter. Alkaline phosphatase,
5 to 216 U per liter. *With Permission of Marcos
et al., 2008.
B) Chronic phase of F. hepatica infection:
silent or severe?
The chronic phase occurs months to up to 13.5
years after infection (Chatterjee et al., 1975; Dan et
al., 1981). It develops when adult parasites deposit
eggs in the biliary ducts (MacLean, 1999). It is
asymptomatic in approximately half of the cases
(Marcos et al., 2002) and is associated to dizziness
(OR=2.5; p=0.016) and a history of jaundice
(OR=3.5; p=0.011) (Marcos et al., 2006). Symptoms
usually reflect biliary obstruction with colicky pain
in the right upper quadrant (RUQ) or epigastric
area (Jimenez et al., 2001; Maco et al., 2003) or with
extrahepatic cholestasis (Dobrucali et al., 2004). In
a large clinical-epidemiological study, increased
liver enzymes were found in endemic areas (ALT
elevated in 21.5 %, AST elevated 21.9 %, total
bilirubin elevated 16.5 %, GGT elevated 80.6
%, and alkaline phosphatase 76.4 %), as well as
imaging abnormalities including hepatomegaly,
splenomegaly, periportal fibrosis, thickened gall
bladder wall, dilated common bile duct, parasites in
gall bladder and common bile duct, cholelithiasis,
biliary duct stones, cystic liver lesions, focal lesions
in the liver and ascites (El-Shazly et al., 2001).
Excluding viral liver infections, F. hepatica infection
is a significant cause of cholestasis in endemic areas
(p<0.05) (El-Shazly et al., 2005). These recent studies
•
suggest that chronic infection is severe and most of
the time the hepatic damage is silent.
Chronic fascioliasis causes multiple complications.
It may present as an acute eosinophilic cholecystitis
(Umac et al., 2006) which requires emergent surgery
(Umac et al., 2006), laparoscopic cholecystectomy
(Bulbuloglu et al., 2007), or even endoscopic
retrograde cholangiopancreatography (Fullerton
et al., 2006). The parasites appears as intrahepatic
cystic lesion(s) (Aroonroch et al., 2006), which can
be associated with abscesses. In a rat model, a
significant increased risk of bacterobilia in the
chronic infection has been demonstrated (Valero et
al., 2006) as well as gallstones (Valero et al., 2003). An
abscess in the liver may be secondary to fascioliasis
and the treatment implies both broad-spectrum
antibiotics and triclabendazole (see treatment section).
However, even after successful treatment, the RUQ
pain and weight loss may be still present in about
2-4 % of patients (Rondelaud et al., 2006) but it is
unclear this mechanism.
Eosinophilia is not always present in the chronic
phase. Only 47 % of 277 complicated cases had
eosinophilia at presentation (Blancas et al., 2004),
whereas 50 % of subjects with chronic fascioliasis
had eosinophilia in endemic areas (Marcos et
al., 2002). In Turkey, only 11 % of 18 cases with
fascioliasis had eosinophilia (Turhan et al., 2006).
However, there was a significant difference between
cases and controls in a study performed in Puno,
when it was compared the absolute eosinophil count
(mean ± SD = 680.5 ± 850.5 cases vs. 297.4 ± 392.9
controls; p=0.005) and percentage with eosinophilia
(43.5 % cases vs. 17.6 % controls; p=0.006).
Eosinophilia may be the first sign for suspicion on
fascioliasis in endemic areas, but also these subjects
may have multiple intestinal parasites that may
increase eosinophil count especially helminths; or
they may have other conditions such as asthma,
among others. Clinicians need to be aware of these
associations to have a comprehensive diagnostic
approach. In summary, if a patient from endemic
areas presents with eosinophilia and suspicion of
any biliary tract abnormality, fascioliasis must be
included into the differential diagnosis. Serial stool
samples using the Rapid Sedimentation Technique
describe by Lumbreras (Lumbreras et al., 1967) must
be the next step (see Diagnosis Section). Further
studies will clarify the likely cause of eosinophilia in
endemic areas.
Table 3. Time of infection and laboratory analy-
sis results on presentation in acute massive fas-
cioliasis
Time of disease (weeks)
LABORATORY ANALYSIS
Hemoglobin (g/dl)
Liver span (cm) x CT
Leukocyte count (x10-9/liter)
Eosinophil count (x10-9/liter)
ALT (U/liter)
AST (U/liter)
Alkaline phosphatase
(U/liter)
Range (Mean ± SD)
0.5 – 22 (7.7±6.7)
10.3-14.7 (12.3 ± 1.5)
12-16 (14.1 ± 1.4)
10.0-26.5 (17.3 ± 5.8)
3.2-16.8 (10.5 ± 4.8)
28-202 (88.3 ± 57.6)
21-74 (52.6 ± 19.3)
55-1800 (529 ± 552)
Neotrop. Helminthol., 1(2), 2007
93
B.1. Chronicity, liver fibrosis and sequalae
F. hepatica infection is able to cause bile duct
hyperplasia. Many years ago, a study showed
that F. hepatica has the ability to produce proline
in vitro (Campbell et al., 1981) and is associated
with bile duct hyperplasia in vivo (Wolf-Splenger
& Isseroof, 1983). Increasing levels of type I and
III collagen were finally demonstrated in an in
vivo study in infected rats with fasciola which had
significant bile duct hyperplasia (Mark & Isseroff,
1983). Biochemical and histological studies
corroborate later the important role of proline
in the enlargement of the bile duct in fascioliasis
(Modavi & Isseroff, 1984). These changes seen
in the collagen composition of the bile duct are
similar to those produced in cirrhosis of the liver
and other pathologic conditions including wound
healing. Furthermore, the number of parasites
seems to be critical in hepatic damage and
liver fibrosis. In Peru, out of 30 livers of cattle
50% had liver cirrhosis (Marcos et al., 2007b).
In Zambia, fibrosis and calcifications in livers
of cattle were associated to fasciola infection
as well, being worst in the vicinity of the bile
ducts (Phiri et al., 2006). In two animal studies,
thickened walls of bile ducts and severe cirrhosis
were found microscopically (Haridy et al., 1999;
Shirai et al., 2006). In goats, again the number of
parasites was associated with the severity of the
liver lesions (e.g. hepatic calcareous granuloma),
including marked cirrhosis and death. These
findings were observed mainly in goats given
more than one infective dose (Perez et al., 1999).
On the other hand, liver cirrhosis has been
reported in children (Almendras-Jaramillo et al.,
1997; Marcos et al., 2005b) and adults (Heredia
et al., 1984; Sanchez-Sosa et al., 2000) especially
with massive infections.
In Peru, we developed the an experimental rodent
model to study the pathogenesis of liver fibrosis
associated with F. hepatica, concluding that the
intensity of infection may be a determinant of
fibrosis progression, these results provide a basis
for further studies both in vitro and in vivo (Marcos,
unpublished data). The process of infection by F.
hepatica and its stimulation of fibrosis is likely to
be dynamic. The parasite secretes proteins which
may interact with the hepatocytes, extracellular
matrix, hepatic stellate cells (the regulator cells
of liver fibrosis from any injury) and other liver
components or cells. Further application of
this model in future studies may uncover new
insights into the clinical aspects and pathogenesis
of a common parasitic disease that affects
many habitants of poor countries. This can
create potential experimental and therapeutic
approaches. Liver fibrosis caused by F. hepatica
infection places this parasitic infection in a new
dimension into the chronic liver diseases and
urge multidisciplinary control and prevention
programs in endemic areas to at least stop the
progression of the disease.
A) Abdominal Ultrasound (U/S)
Ultrasound (U/S) findings in the acute phase include
focal areas of increased echogenicity, multiple
nodular or irregular lesions of variable echogenicity,
or a single complex mass in the liver (Gonzáles-
Carbajal et al., 2001; Cosme et al., 2001; 2003) very
similar to metastases or cancer. In the chronic phase,
the U/S is less specific. F. hepatica adult parasites
may be visualized in the gallbladder (Bonniaud et al.,
1984) and the diagnosis confirmed by ultrasound-
guided aspiration of the gallbladder (Kabaalioglu et
al., 1999) but it is invasive and it is not routinely used.
In a study of 76 subjects with chronic fascioliasis
evaluated by means of abdominal U/S, in only
11 patients (14 %) were parasites visualized and in
only 2 cases (2.6 %) were parasites spontaneously
moving. Thus, the detection-rate of F. hepatica
chronic infection by U/S was disappointingly low
(Ritcher et al., 1999), and not specific (Turhan et. al.,
2006). Liver U/S may be useful in the acute phase
but not for chronic cases.
B) Computed Tomography Scan (CT)
Multiple liver lesions, which change in position,
attenuation, and shape in time; are strongly suggestive
of acute fascioliasis. Interestingly, initial lesions may
be strongly confused with hepatic metastases. The
most common findings are: hepatomegaly, track-
like hypodense lesions with subcapsular location,
subcapsular hematoma and cystic calcifications
(Loja et al., 2003; Marcos et al., 2008). The hepatic
lesions correlate with time of infection. Early
infection is associated with contrast enhancement
of Glisson´s capsule due to inflammation stimulated
IMAGING STUDIES AND ITS
UTILITY IN FASCIOLIASIS
Human fascioliasis in Peru
Marcos, LA & Terashima, A
94
as the juvenile parasite penetrates the liver capsule
(Hidalgo et al., 1995). This occurs in the early stage of
the acute infection (first month of infection). In the
intermediate stage (after the first month of infection),
multiple hypodense nodular areas (abscess-like
lesions) or low-density serpiginous tortuous tunnel-
like branching lesions ranging from 2 to 10 mm
are created by parasite migration through the liver
may be visualized in the subcapsular region (Kim
et al., 1995; Han et al., 1999; MacLean & Graeme-
Cook, 2002; Gonzalo-Orden et al., 2003). In the late
stage (≥ 3 months), necrotic granuloma are seen,
which appear as a single non contrast-enhanced
hypodense irregular mass in the liver parenchyma,
more central than peripheral (Kim et al., 1999;
Noyer et al., 2002).
C) Magnetic Resonance Imagings (MRI)
Few cases showing MRI imaging have been
reported. T2-weighted turbo-spin-echo image MRI
showed a homogeneous hyperintense area located
subcapsular containing multiple hypointense areas.
T1-weighted 3D gradient-echo image displayed
homogeneous contrast-enhancement (Orlent et al.,
2007). The hypodense lesions observed in the CT
scan are of hypointense signal in T1-Weighted and
hyperintense in T2 (Kabaalioglu et al., 2000; Aksoy
et al., 2006).
Accurate identification of early fascioliasis has
historically been difficult since the diagnosis of the
acute phase is only confirmed by serology (Incil et
al., 2001) and response to therapy (Marcos et al.,
2007c), this last very important in endemic rural
poor areas where only the treatment is available but
no serology. In Peru, we have available an ELISA
for fasciola with good outcomes. The Fas2 ELISA
detects the antibodies against Fas2 which is a major
antigen of the adult parasite. Fas2 ELISA is more
specific (92 %) than Western blot (72 %) and Arc II
(37 %) (Maco et al., 2002; Espinoza et al., 2005). In
2007, a study evaluating Fas2 ELISA in 634 children
from 1-16 years old in three endemic areas in Peru,
the overall sensitivity of Fas2-ELISA was 92.4 %,
the specificity 83.6 %, and the negative predictive
value 97.2 %. These results show that Fas2-ELISA
is a highly sensitive immunodiagnostic test for the
detection of F. hepatica infection in children living in
human fascioliasis endemic areas (Espinoza et al.,
2007).
However, serological tests has limited availability in
endemic rural poor areas, whereas economic, simple
and affective coprological tests still playing the main
role in the detection of chronic cases. The Rapid
Sedimentation Technique (RST) described by Dr.
Hugo Lumbreras in Peru (Lumbreras et al., 1967)
has been used for more than 12 studies over the past
5 years (Marcos et al., 2002; 2004; 2005a; 2005b;
2005c; 2006; 2007a; 2007b; 2007c; 2007d; 2007e)
detecting the highest prevalence rates in this country,
and it has been also compared with other techniques
such as ether-formol concentration method (Maco
et al., 2002) and Kato-Katz technique (Canales and
others, unpublished data) but the RST has better
outcomes. The Kato-Katz technique may be used to
measure the intensity of infection (Katz et al., 1975)
when indicated. Thus, we strongly recommend
that the Rapid Sedimentation Technique should be
applied in any future coprological epidemiological
studies carry out in Peru.
Many years ago, parenteral dihidroemetina at doses
of 1 mg/kg for ten days was used. Then, bithionol
was applied at doses of 30 to 50 mg/kg every third
day with a total of 10 to15 doses; but it is cardiotoxic
and very expensive.
Triclabendazole (TCBZ) was introduced in the
early 1980s for the treatment of F. hepatica infections
in livestock. It is the treatment of choice for human
fascioliasis (Keiser et al., 2005) and has been
placed on the WHO List of Essential Medicines
(http://www.who.int/medicines/publications/
essentialmedicines/en/). The cure rate is more than
90 % for acute stages with a single dose at 10 mg/kg
(Marcos et al., 2008) and similar results have been
obtained for chronic infections (Apt et al., 1995;
Talaje et al., 2004; El-Tantawy et al., 2007). Despite
its efficacy, triclabendazole is only registered in
four countries: Egypt (registered in 1997), Ecuador
(2001), Venezuela (2001) and France (2002).
The importance of this treatment has been well
demonstrated in Egypt where a pilot study treated
1280 school children with TCBZ, the prevalence of
infection decreased from 5.2 % in 1996 to 1.2 %
in 2002/2003 (Abdussalam et al., 1995). However,
DIAGNOSES OF FASCIOLIASIS:
SEROLOGICAL, COPROLOGICAL
TESTS AND LIMITATIONS
TREATMENT OF ACUTE AND
CHRONIC PHASES
Neotrop. Helminthol., 1(2), 2007
95
the intensive use of triclabendazole has resulted in
the development of resistance at least in animals
(Mottier et al., 2006).
In Peru, two clinical trials haven been carried out in
endemic areas for chronic F. hepatica infection. The
first, using the veterinary triclabendazole (Fasinex®
10 %), a single dose of 10 mg/kg cure 96 %, whereas
10 mg/kg in two following days, cure 100 %; no
major adverse effects were registered (Terashima
and others, unpublished data). The second clinical
trial, using the triclabendazole for humans (Egaten
®), patients were randomly allocated in two groups
to receive a single dose of triclabendazole 10mg/
kg or 15 mg/kg divided in two doses (7.5 mg/kg
each one) orally after fatty meals; the cure of both
schemes were >95 %; and no major side effects
were reported (Marcos and others, unpublished
data). In summary, a dose of 7.5 mg/kg every 12
hours after meals, by having similar tolerability but
more efficacy than the former dose of 10 mg/kg as
a single dose, should be considered in the control
programs for endemic areas to ensure the success of
the cure where the follow up is difficult to achieve a
sustainable control.
Besides the effect of two doses in the cure rate, both
studies also focused on the side effects, being the
most important the abdominal pain as biliary colic
during the first week of treatment. This is caused
by the passage of dead or dying parasites through
the bile ducts (Ritcher et al., 1999; Millan et al.,
2000). Antispasmodics may decrease or avoid these
transitory episodes of abdominal pain and should be
used in most cases. Physicians in endemic areas are
encourage to evaluate a patient with hepatomegaly,
eosinophilia and fever for fascioliasis, and a single
dose of triclabendazole is effective and it may use as
a diagnostic criterion (Marcos et al., 2008)
In Peru, it is available the veterinary use though lately
the Ministry of Health included the triclabendazole
in the priority list of medications. Other authors
have proposed 10 mg/kg per day, repeated dose
in 48 hours with a cure rate of 100 % (Apt et al.,
1995; Tataie et al., 2004). In the clinical setting,
the tolerability of the drug has been excellent and
there had not major side effects. (Terashima, 1997;
1999; Ortiz et al., 2000). Today, the treatment of
choice for fascioliasis, acute or chronic phase is
triclabendazole.
Given the unlikelihood of any new drugs against F
hepatica being developed in the foreseeable future,
the emergence of resistance represents an important
threat (Alvarez-Sanchez et al., 2006) but resistance
in human cases have not been reported so far.
Since fascioliasis continues to cause large economic
losses worldwide in veterinary, development
of effective vaccines is an important advance.
Preliminary studies in animals have reported
significant advances (Spithill & Dalton, 1998;
McManus & Dalton, 2006). Cysteine proteinases
released by F. hepatica play a key role in parasite
feeding, migration through host tissues and in
immune evasion. A recombinant cysteine proteinase
(CPFhW) expressed as inclusion bodies in Escherichia
coli was used for enteral vaccination of rats against
fascioliasis. In that study, oral vaccination reduced
the parasite burden by 78-80 % after a challenge with
metacercariae (Kesik et al., 2005). The glutathione
transferase superfamily (GST) from liver fluke has
phase II detoxification and housekeeping roles,
and has been shown to contain protective vaccine
candidates (Chemale et al., 2006). Promising future
basic research will yield meaningful immunological
targets to prevent the infection especially in the
well-recognized endemic areas and in particular
in children but so far the vaccines are targeted to
animals but not for humans.
Human Fascioliasis is an emerging parasitic
infection disease in Peru.
Endemic areas are over the world being the
Peruvian Andean Region in South America the
most affected areas.
Recognized risk factors are overall consuming
aquatic plants such as alfalfa juice, emollients,
lettuce, atajo (a plant from the streams),
watercress, drinking water from the streams,
salads. Exporting aquatic plants may disseminate
fascioliasis to non-endemic areas.
Familial Fascioliasis is a common phenomenon.
Up to 76 % of relatives of the index case may
have the parasitic infection. Eating salads is the
most common route of dissemination of the
infection to the family.
Clinical manifestations can vary from indolent to
life-threatening. In the acute phase: abdominal
pain, hepatomegaly, fever, eosinophilia, and
1.
2.
3.
4.
5.
VACCINATION MAY BE
POSSIBLE
CONCLUSIONS
Human fascioliasis in Peru
Marcos, LA & Terashima, A
96
elevated transaminases, hypodense lesions by
CT scan. In the chronic phase, patients may
present with biliary obstruction (intermittent
jaundice most commonly), bacterobilia, liver
cystic calcifications, cholelithiasis and liver
fibrosis.
Characteristic imaging findings in fascioliasis
include track-like hypodense lesions with
subcapsular location, hepatic abscesses and/
or subcapsular hematomas in the acute phase.
Abdominal ultrasound has a low sensitivity
for detection and it is not recommended for
screening for chronic infection.
Improved serological test (Fas2 ELISA) has
been developed and when applied in endemic
areas may lead to the detection of more cases
but limited in poor areas.
Rapid Sedimentation Technique (RST)
described by Lumbreras (simple, economic and
effective) should be routinely used in endemic
areas for diagnosis and follow up.
If acute phase is suspected, next step is order a
serological test. If it is not available, start with
triclabendazole at 10mg/kg single dose; and
then reasses clinical picture next 24-48 hours
and decreased eosinophils next 3-5 days. If not,
it is unlikely the diagnoses of fascioliasis.
For suspicion on chronic cases, the RST must
be performed in serial stool samples.
Triclabendazole is the treatment of choice
(cure rate ≥90 %) for both phases. Resistance
has been detected in animals. Abdominal pain
within the first week of treatment is common.
Adjuvant antispasmodic therapy should also be
used.
Vaccine development could prove an important
advance.
To suspect in F. hepatica human infection, a
history and physical needs to be taken on all
fronts: epidemiology, clinical picture depending
on the phase, diagnosis both serology and
coprology, response to treatment and to test in
the relatives.
We would like to kindly thank Dr. Eduardo Gotuzzo,
Director of the Institute of Tropical Medicine
Alexander von Humboldt, Universidad Peruana
Cayetano Heredia, Lima, Peru; for his invaluable
help during many years and his contributions to this
review. Dr. Raúl Tello, Blgo. Marco Canales and
Mrs. Carmen Quijano, Laboratorio de Parasitología,
6.
7.
8.
9.
10.
11.
12.
13.
Instituto de Medicina Tropical Alexander von
Humboldt for their help in the laboratory. Dr.
Charles Talakottour, Internal Medicine Department,
University of Texas, Houston, Texas, USA, for his
help reviewing this manuscript. There is no grant
source to acknowledge and the authors have no
conflicts to declare.
Conflict of Interests: None
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Correspondence to author:
Angelica Terashima
Laboratorio de Parasitologia, Instituto de Medicine
Tropical Alexander von Humboldt, Av. Honorio
Delgado 430, Urb. Ingeniería. San Martín de
Porres AP 4314, Lima 100. Perú.
E-mail:
aterashima@upch.edu.pe
luis.a.marcos@uth.tmc.edu
Telefax: (51)–1382-1021.
Telephone: (51)-1382-1021
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