human liver flukes: a review - Biblioteca Virtual de la Real Academia

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Research and Reviews ill Parasitology. 57 (3-4): 145-218 (1997)
© 1997 Asociaci6n de Parasit61ogos Espafioles (A.P.E.)
Published by A.P.E.
Printed in Barcelona.
Spain
HUMAN LIVER FLUKES: A REVIEW
S. MAS-COMA &
M.D. BARGUES
Departamento de Parasitologia. Facultad de Farmacia, Universidad de Valencia,
Av. vicent Andres Estelles sin, 46100 Burjassot - Valencia, Spain
Received 21 Apri11997;
accepted 25 June 1997
REFERENCE:MAS-COMA(S.) & BARGUES(M. D.). 1997.- Human liver flukes: a review. Research and Reviews in Parasitology,
57 (3-4): 145-218.
SUMMARY:Human diseases caused by liver fluke species are reviewed. The present knowledge on the following 12 digenean species belonging to
the families Opisthorchiidae, Fasciolidae and Dicrocoeliidae is analyzed: Clonorchis sinensis, Opisthorchis feline us, O. viverrini, Fasciola hepatica, F. gigantica, Dicrocoelium dendriticum, D. hospes, Eurytrema pancreaticum, Amphimerus pseudofelineus, A. noverca, Pseudamphistomum
truncatuin, and Metorchis conjunctus. For each species the following aspects of the parasite and the disease they cause are reviewed: morphology,
location and definitive hosts. reports in humans, geographical distribution. life cycle. first intermediate hosts, second intermediate hosts if any, epidemiology. pathology. symptomatology and clinical manifestations. diagnosis, treatment, and prevention and control.
KEY WORDS: Human diseases, Clonorchis sinensis, Opisthorchis felineus, O. viverrini, Fasciola hepatica, F. gigantica, Dicrocoelium dendriticum,
D. hospes, Eurytrema pancreaticum, Amphimerus pseudofelineus, A. noverca, Pseudamphistomum truncatum, Metorchis conjunctus, review.
CONTENTS
Introduction
Clonorchis sinensis
Morphology ..
Location and definitive hosts.
Reports in humans ..
Geographical distribution
Life cycle.
First intermediate hosts
Second intermediate hosts
Epidemiology
Pathology, symptomatology
and clinical manifestations
Diagnosis
Treatment.
Prevention and control
Opisthorchis viverrini
Morphology.
Location and definitive hosts
Reports in humans
Life cycle
First intermediate hosts.
Epidemiology
and clinical manifestations.
Diagnosis.
Treatment
Prevention and control.
Opisthorchis felineus
Morphology
Reports in humans ..
Geographical distribution.
Life cycle
Epidemiology
Diagnosis
Treatment
Fasciola hepatica
Morphology ..
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Reports in humans.
Life cycle
First intermediate hosts .
Epidemiology.
and
Diagnosis.
Treatment.
Fasciola gigantica .
Morphology.
Reports in humans.
Life cycle.
Epidemiology.
and
Diagnosis.
Treatment.
Dicrocoelium dendriticum .
Morphology.
Reports in humans.
Life cycle.
First intermediate hosts .
Second intermediate hosts.
Epidemiology.
and
Diagnosis.
Treatment.
Dicrocoelium hospes
Morphology
.
Reports in humans.
Life cycle.
Epidemiology.
and
Diagnosis.
Treatment.
Eurytrema pancreaticum
.
Morphology.
Reports in humans.
Life cycle.
Epidemiology.
and
Diagnosis.
Treatment.
Amphimerus pseudofelineus
.
Amphimerus noverca .
Pseudamphistomum
truncatum .
Metorchis conjunctus .
References.
Introduction.
Clonorchis sinensis .
S. MAs-CoMA
clinical manifestations.
clinical manifestations
.
.
.
.
& M.D. BARGUES
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Human
liver flukes:
a review
Opisthorchis viverrini.
Opisthorchis [elineus ..
Fasciola hepatica .
Fasciola gigantica.
Dicrocoelium dendriticum.
Dicrocoelium hospes ..
Eurytrema pancreaticum ..
.
Amphimerus noverca ..
Pseudamphisiomum
truncatum ..
Metorchis conjunctus.
INTRODUCTION
Among digenean parasites affecting the liver of human beings, the following 12 species belonging to three
trematode families are involved:
A) Opisthorchiidae: Clonorchis sinensis (Cobbold, 1875)
Looss, 1907; Opisthorchis felineus (Ri volta, 1884)
Blanchard, 1895; Opisthorchis viverrini (Poirier, 1886)
Stiles et Hassall, 1896; Amphimerus noverca (Braun,
1902) Barker, 191 I; Amphimerus pseudofelineus
(Ward, 1901) Barker, 1911 (= Opisthorchis guayaquilensis Rodrfguez G6mez et Montalvan, 1949); Metorchis conjunctus (Cobbold, 1860) Looss, 1899; and
Pseudamphistomum truncatum (Rudolphi, 1819) Liihe,
1908;
B) Fasciolidae: Fasciola hepatica (Linnaeus, 1758); and
Fasciola gigantica Cobbold, 1855;
C) Dicrocoeliidae: Dicrocoelium dendriticum (Rudolphi,
1819) Looss, 1899 (= Fasciola lanceolata Rudolphi,
1803; = Dicrocoelium lanceatum Stiles et Hassall,
1898); Dicrocoelium hospes Looss, 1907; and Eurytretna pancreaticum (1anson, 1889) Looss, 1907.
All these species have in common the hepatic location
(bile ducts, gall bladder) of the adult stage of the parasite
at the level of the definitive host (ectopic forms are however frequent in humans, mainly in fasciolids), but in
the case of E. pancreaticum the main location of the
adults is in the pancreas and less frequently in the bile
ducts.
These are the species already confirmed affecting the
human liver, but this does not mean that they are all.
There are also other digenean species whose adult stages
are hepatic and whose potentiality to infect humans appears evident. For instance, Metorchis albidus (Braun,
1893) Looss, 1899, an hepatic parasite of carnivorous
mammals in the Holarctic and which is transmitted through rnetacercariae in fish, is considered as a potential
source of infection to man, at least in Kazakhstan (SIDOROY & BELY AKOYA, 1972) and Lithuania (L1 NIK,
1983). Another species, Pseudamphistomum aethiopicum Pierantoni, 1942, a member of a genus whose species are all hepatic parasites in mammals (Y AMAGUTI,
1971), has already been found in humans in Ethiopia,
but causing cyst-like nodules in the internal wall of the
small intestine (CACCIAPUOTI,1947).
Among the human liver fluke species, C. sinensis, O.
viverrini, O. felineus and F. hepatica are of great medi-
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cal importance owing to the large number of people infected (the estimated number of people infected can be
counted in millions in each case), allowing us to really
speak of human endemic areas (see RIM et al., 1994).
The species D. dendriticum, F. gigantica and D. hospes,
in this order, constitute an intermediate group according
to their importance in humans, human cases being relatively numerous but usually isolated (the estimated number of people infected can be counted in hundreds in
each case). Finally, E. pancreaticum, P. truncatum, A.
pseudofelineus, A. noverca and M. conjunctus have been
reported in humans only very sporadically (less than ten
published cases for each parasite), although recent studies in the former USSR have shown that P. truncatum
may be more prevalent (KHAMIDULLI et al., 1991). At
any rate, all these diseases are undoubtedly largely underestimated, for different reasons: A) they develop subclinically or only with mild symptoms when parasite number is scarce, which may be the situation in numerous
cases, so that infected persons do not attend specialists;
B) the diseases they cause can be confused with infections of different etiology; C) not all diagnosed cases are
finally published.
Several of these liver fluke diseases have a geographical distribution including endemies in several countries
in Eastern Europe and in Asia, in which important political changes in recent years have led to an increasing
opening. That is why these diseases have recently acquired new relevance, efforts being made today by concerned institutions to recognize the serious, yet neglected,
problems associated with these trematode infections.
RIM et al. (1994) appropriately allude to this question
with the terms of «ignored or emerging» and emphasize
the significant economic impact associated with these
infections: absenteeism, hospitalization, treatments and
repeated treatments, direct cost to health-care systems,
disability and agricultural economic losses.
Moreover, the actual frame can change in the near future if appropriate control measures are not undertaken,
owing to the recently signed GATT international agreement, replaced by the World Trade Organization (WTO)
in 1995. All these twelve fluke diseases are food-borne
infections and the significant increase of international
food exchange which can be expected in the future as the
consequence of facilitated export/import activities between countries can be at the base of infections and the
appearance of the mentioned diseases far away from the
S.
148
areas where they are today endemic. This may evidently
concern especially the fish-born trematode diseases,
among which the most important are C. sinensis, O. viverrini and O. felineus, all three causing diseases so far
clearly restricted in geographical distribution (it appears
to be more difficult in the case of plant- and insect born
trematodiases). The possibility of geographical range extending in the three opisthorchiid species through fish
commerce will mainly depend of the capacity of these
parasites to adapt to new snail strains or species, but this
does not mean that human infections will not be able to
occur in non-endemic zones by this way. F. hepatica and
D. dendriticum are already good examples of large distribution spread to their present wide geographical
range, originated through the exportation of living livestock some time ago. The potential banning or importation of fish and fish products from endemic countries
would cause significant economic losses to fish farmers.
All this has already been taken into account by the international organisms, which have recently started specific
activities on these questions (RIM et al., 1994).
Worth mentioning, finally, is the problem posed in recent decades by the spread of freshwater snails, which
act as first intermediate hosts of several human liver
fluke species, outside and even very far away from the
original endemic zones. Despite the fact that many of
these flukes are not very specific at second intermediate
(if any) and definitive host levels (many of these parasites use cosmopolitan domesticated mammal species as
definitive host rather than man), most of them present,
like digeneans in general, endemic areas with well delimited geographical boundaries as the consequence of
their marked specificity for their respective first intermediate snail host species. Among molluscan species involved in the transmission of human liver flukes, this phenomen of spread mainly concerns lymnaeid and thiarid
species (MADSEN& FRANDSEN,1989; POINTlER& MC
CULLOUGH,1989), and appears to be related to the extensive trade in freshwater aquatic plants and aquarium
fish (MADSEN & FRANDSEN, 1989). The geographical
spread of fascioliasis (there is no second intermediate
host in the life cycles of Fasciola spp.) and its relationships to the spread of lymnaeid species is already well
known (BORAY, 1978). In the case of opisthorchiids,
transmission foci outside of the original endemic zones
have not been found so far, but the spread of thiarid
snails must be taken into account, owing to the fact that
the other hosts involved in their life cycles (fish; cats,
dogs and even cosmopolitan peridomestic rats) are available and can be colonized by the flukes everywhere.
The world-wide necessity of enforcing drastic measures is evident. In certain countries, like Australia and the
U.s.A., a very stringent policy has been followed in order to prevent the import of undesirable animals and
plants. An important and effective measure is rigorous
inspections of shipments of aquarium fish and plants, but
even so lymneids were able to pass the controls in Australia (BORAY, 1978). In addition to the quarantine regu-
MAS-COMA
&
M.D.
BARGUES
lations in the recipient countries, it is necessary that exporters in the country of origin assume some responsibility for removing snails from shipments of plants and ornamental fish for aquaria and botanical gardens to
minimize the risk of the spread of snails (MADSEN &
FRANDSEN, 1989). In the U.S.A, special instructions
have been issued so that the quarantine authorities may
readily identify exotic land and freshwater snails
(BURCH, 1960, 1982). Such instructions would be useful
on a world-wide scale (MADSEN& FRANDSEN,1989).
CLONORCHIS
SINENSIS
Morphology
The adult stage of the Chinese or Oriental liver fluke,
C. sinensis, is a flat, delicate, transparent, aspinose fluke,
attenuated anteriorly and somewhat rounded posteriorly,
8-25/1,5-5 mm in size. The oral sucker is slightly larger
than the acetabulum, which is about a fourth of the way
from the anterior extremity. A prominent pharynx is followed by two un branched caeca reaching the posterior
body end. The excretory vesicle is long and sigmoid.
Near the posterior end there are two large branched testes in tandem, with branches surpassing caeca bilaterally. The common vas deferens enlarges in the equatorial region into a large serpentine seminal vesicle
terminating in a weakly muscular ejaculatory duct which
opens through the preacetabular, median genital pore.
Cirrus pouch and cirrus are lacking. The ovary is small,
median, pretesticular and trilobed. The seminal receptacle is large and transverse, located just behind the ovary,
outside the caeca. The vitelline follicles are small, dense,
bilateral and confined to the equatorial third of the
worm. The uterus ascends intraceacally in broad, tightly
packed loops, to the genital atrium. The eggs are broadly
ovoid, thick-shelled, light yellowish-brown, with a large,
convex operculum, which fits into a rimmed extension
of the eggshell. At the abopercular end there is frequently a small tubercular or comma-shaped protuberance. Mature eggs are embryonated when laid and measure 26-35/12-19 urn (average 29/16 pm).
The adult stage of C. sinensis inhabits the bile ducts,
gall bladder (mainly in heavy infections) and occasionally the pancreatic duct of man and fish-eating mammals. Man appears to be the most suitable definitive
host. The natural definitive hosts other than man are dog,
hog, cat, wild cat, marten, badger, mink, weasel, and rat
(Rattus norvegicus) and also camels. Among them, studies in natural transmission foci have demonstrated that
dogs, cats, pigs, and rats constitute effecti ve reservoir
hosts. In some regions where prevalence of infection
among humans is very low or lacking, as in some parts
of China, prevalence of infection is usually high among
149
Human liver flukes: a review
these mammals. Concerning
experimental
susceptibility,
guinea pigs are the most susceptible,
rabbits, rats, hamsters, dogs are relatively
susceptible,
and mice are less
susceptible.
Several bird species have also been found
infected, both naturally and experimentally
in the gall
bladder (Y AMAGUTI, 1975).
Reports in humans
C. sinensis is an important parasite of man in the far
eastern part of Asia, around the Sea of Japan, East China
Sea and South China Sea. Human cases have been reported from nine countries in Asia, with an estimated 290
million people at risk and seven million infected (RIM et
al., 1994). Humans of China, Taiwan, Korea, Japan,
Hong Kong, Vietnam, Laos, Kampuchea
(= Cambodia),
and the Far East of Russia, are more or less usually detected as infected with the parasite.
Human clonorchiasis
is truly endemic
at least in
China, Taiwan, Korea, Japan, Vietnam and the Far East
of Russia, where the first and second intermediate
hosts,
and thus real transmission
foci, are found and where the
population is accostumed
to eating raw fish. The relative
frequency of human cases reported in other countries is
related to two epidemiologically
important aspects of the
parasite biology: the marked resistance of the metacercariae in fish (they withstand certain types of preparation
of fish, such as salting, pickling, drying, and smoking)
and the very long life span of the adult stage in man.
The first aspect explains most cases found in countries
neighbouring
the true endemic region. In Hong Kong
human infection
is known to be highly endemic,
but
neither the snail nor fish intermediate
hosts are indigenous to the area. Infected fish originating
from China
and shipped in daily provide the Hong Kong population
with Yu shun Chuk, raw fish congee (BUNNAG & HARI·
ASUTA, 1984). Several years ago, reports in Hong Kong
told about a prevalence
in one fourth of the population
(GIBSON & SUN, 1971) or up to 65,5% (HOU & PANG,
1964), and even today clonorchiasis
is the most important parasitic disease (Ko, 1991), being more common in
wealthy people than in low-wage earners owing to the
high price of imported fish. In recent years, however, the
prevalence
seems to have decreased because of control
measures applied in China (CROSS, 1984; CHA ,1988).
Persons originating
from Laos (BE -ISMAlL et al.,
1982; CATANZARO & MOSER, 1982; LUONG DlNH GIAP
et al., 1983; DRINKA & SHEEHY, 1985; O'LEARY, BERTHlAUME&SAKBU
,1985; YANGCOetal., 1987;SHERet
al., 1989; PAPILLO, LESLlE & DEAN, 1989; ONA & DYTOC, 1991) and Kampuchea
(= Cambodia) (CA TANZARO
& MOSER, 1982; BEN-IsMAIL et aI., 1982) are more or
less usually found infected with C. sinensis and detected
as immigrants in other countries. Clonorchis infections in
persons of Thailand, Malaysia, Singapore and Philippines (CROSS & BASACA-SEVILLA, 1984) also seem mainly
acquired through fish imported from endemic countries,
but also acquired while visiting there. Consumption
of
frozen, dried, or pickled fish shipped from endemic areas
probably accounts for infection in persons who have never left the Hawaiian Islands (BlNFORD, 1934).
The second aspect is mainly related to human cases reported in several other countries all around the world,
even so far as for example the USA (CATA ZARO & MoSER, 1982; DRINKA & SHEEHY, 1985; YANGCO et aI.,
1987; PAPlLLO, LESLlE & DEAN, 1989; NISHIOKA &
Do NELLY, 1990; ONA & DYTOC, 1991), Canada (MC
SHERRY, 1981; COLQUHOUN & VISVANATHAN, 1987),
Hawaii (O'LEARY, BERTHIAUME & SAKBUN, 1985), Panama (CALERO, 1967), Surinam (OOTSBURG & SMITH,
1981), Brazil (LEITE et al., 1989), France (BEN-lsMAIL
et aI., 1982; LUONG DINH GIAP et al., 1983), Saudi Arabia (AL-KARAwl & QATTAN, 1992) or Australia (ATTWOOD & CHOU, 1978), etc., all being imported cases related with travelling
persons (immigrants,
refugees).
Although clonorchiasis
is frequently diagnosed in Orientals in the Western Hemisphere,
up to the present there is
no evidence that the infection has become established in
regions outside the endemic Asian area. This does not
mean an absence of risk of geographical
spread of C. sinensis. Asian thiarid snails, including species such as
Thiara granifera and Melanoides tuberculata, which are
known to act as first intermediate
snail hosts of this liver
fluke, have undergone an enormous geographical
spread
in the last decades and have successfully colonized several regions in other continents (MADSEN & FRA DSEN,
1989; POINTIER & Mc CULLOUGH, 1989). This phenomenon, added to the lower specificity of the parasite at
the levels of second intermediate
fish host and definitive
mammal (dogs, cats, pigs, rats) host, gives rise to the
possibility of geographical
spread of the parasite. There
are even localities such as Sao Paulo, in Brazil, where
persons having originally acquired the infection in the
endemic
far eastern Asian region have been detected
(LEITE et al., 1989) and an intermediate
snail host species (M. tuberculatai has already been established after
several years (V AZ et al., 1986).
The geographical
distribution of C. sinensis appears to
coincide with the distribution
of the main intermediate
snail host species Parafossarulus manchouricus and closely related hydrobiid snail species. Accordingly,
C. sinensis is present in China, Taiwan, Korea, Japan, Vietnam and the Far East of Russia. In this wide geographical
zone, the incidence of clonorchiasis
varies considerably
from one district to another, even within small regions
(RIM, 1982a).
In China, the present situation of clonorchiasis
shows
a distribution
in 24 provinces,
municipalities
and autonomous regions. Studies have shown that the prevalences range between I and 57%. In southern China the regions neighbouring
Hong Kong and in front of Taiwan,
such as Guangdong
and Guangxi Zhuangzu, and in northern China the regions situated north of Korea and bor-
S. MAS-COMA & M.D. BARGUES
150
dering Russia, such as Heilongjiang, Jilin and Liaoning,
appear to be the zones with highest infection (L1, 1991).
In Taiwan, the prevalence and distribution of human
clonorchiasis in the periods of 1954-1959,1960-1963 and
1963-1969 were reviewed by CHOW (1960), KIM &
Ku TZ (1964) and CROSS (1969), respectively. In these
years, human infections were reported from nearly every
county on the island, the prevalence rates varying considerably. According to CROSS(1984), CHEN& HSIEH(1984),
RIM(1986) & CHE (1991), today the disease continues to
be found in almost every city/county, with the human infection rate ranging between
and 57%, human prevalence usually being 20-50% in heavy endemic areas. Studies in recent years show that the disease is extending to
new endemic localities in which human prevalences of up
to 10-20% are found. Rats, cats, dogs and above all pigs
develop the role of main reservoirs on the island.
In Korea, general estimations speak of 4,5 million infected people (BUNNAG& HARI ASUTA, 1989; HARI AS TA, PUNGPAK& KEYSTO E, 1993). Endemic areas are
scattered all over the country and the most extensive and
intensive endemic regions are found mainly along the
Nakdong River and the lower reaches of the other rivers.
Several years ago, prevalences and parasite burden reached up to 82,9% and 10698 eggs/g of faeces in certain
areas of the Gimhae Gun county, the heaviest endemic
area in the delta of Nakdong River, near Busan, the most
southeastern part of Korea (RIM, 1982 ). A survey between 1973 and 1982 revealed high infection rates
among people living in the basins of the 6 main rivers,
Han, Gum, Nakdong, Mangyong, Yongsan and Seomjin.
In people living away from the rivers infection was
usually low (SONG, LEE & RIM, 1983). More recently,
according to RIM (1990), Joo & HO G (1991) and MAuRICE(1994) it seems that prevalences are slowly decreasing due to mass treatment programmes. In the Pohang
industrial area, along the Hyusnag River, endemicity
markedly decreased compared with previous data, but
remains endemic (KIM, HAN, PARK, LIM & HONG,
1990). In the vecinity of River Ahnseong, prevalence
was 11,0% and, according to age, it showed an increase
followed by a decrease (100 & Ho G, 1991).
In Japan, KOMIYA& SUZUKI(l964b) enumerated the
widely distributed endemic areas: Sendai Plain with the
basin of the Kitagami River as its center; Noshiro area
around the pond of Asanai-numa; the basin of the Tone
River; Lake Kasumigaura and its vecinity; the Kanbara
area; Kaga Plain; the basin of Lake Suwa; Nobi Plain;
the eastern area of Lake Biwa; the coastal area of Kojima Bay; the downstream area of the Yoshino River; the
basin of the Onga River; and the basin of the Chikugo
River. Areas where it was only sporadically found were
Hyogo, Toyama, Fukui, Hiroshima, Ehime, Kawaka,
Kochi, and Kumamoto Prefetures. The review by KoMIYA (1966) demonstrated that prevalences had progressively decreased through time, from a 44,4% infection in
1917 to 26,0% in 1948. Worth mentioning is that in Japan, the most infected persons show light infections with
°
less than 1000 eggs/g of faeces and without clinical manifestations (RIM, 1986). The incidence of infection has
been markedly reduced among the under-40 age group
during the past few years. The decrease is attributed to
the low snail population in these endemic areas due to
industrialization, insecticide pollution of water, land reclamation, and health education (Bu NAG & HARI ASUTA, 1984; RIM, 1982a, 1986).
In Vietnam, the most heavily infected area is found in
the northern part of the country, in the delta of the Red
River, embracing the counties in and around Haiphong
and Hanoi, with prevalences reaching up to 73% in early
studies (RIM, 1986). More recently, in Ha Nam Nin Province, prevalences were of 37,2% in men, 18,3% in women, and as high as 25,8% in the intermediate snail host
Melanoides tuberculata (KIE, BRO SHTEI & FAN,
1990). The sporadic cases of clonorchiasis in South
Vietnam with clinical records were all people from the
orth (RIM, 1986).
In Russia, human cases have been reported in the far
eastern part, namely in the Amur River Territory and
Khabarovsk Territory. Infection rates in snails, fish and
cats were 2,9%, 9,5% and 74,6%, respectively (POSOKHOV, 1982; POSOKHOV,DOVGALEV& BRYU ETKI A,
1987; KORABLEV& KOL'TSOV, 1992).
Life cycle
C. sinensis follows a triheteroxenous life cycle which
develops in fresh water. The adults deposit the eggs in
the biliary passages of the definitive mammal host. Eggs
are excreted with faeces after passing through the intestinal tract. Egg production (eggs/day/worm) varies with
the kind of definitive hosts: 2400 in cats, 1600 in guinea
pigs, and 1125-2000 in dogs, 4000 in rabbits. Although
the eggs contain fully developed miracidia, they do not
hatch upon reaching water. The miracidium hatches only
after ingestion by suitable fresh water snail species. The
miracidia hatch out in either the intestine or the rectum
of the snail, then penetrate the digestive wall and become sporocysts in the peridigestive regions within 4
hours after infection.
The sporocyst is oval-shaped and measures about
90/65 urn. It gives rise to cercariogenous rediae, which
escape from the sporocyst to locate themselves in the
connective tissue around the posterior part of the snail
oesophagus, but also in other parts of the snail, 14-17
days after feeding. Rediae are almost sausage-shaped
and increasing in size according to development (0,351,73/0,08-0,13 mm). From 5 to 50 cercariae are produced inside each redia. The mature cercaria is of pleurolophocercous type, with a spinous body wall carrying a
number of slender hairs, two pigmented eyespots, penetration glands consisting of four inner and three outer
pairs, and a tail with a membranous keel on its dorsal
and ventral surface (RIM, I982a). The cercarial body is
of 130-260/43-80 urn and the tail of 258-490/28-53 urn
in size (Y AMAGUTI,1975).
Human
liver flukes:
IS I
a review
Cercariae escape from rediae and from the snail hosts,
to become free swimming
in water. They are positively
phototactic
and geotropic. The longevity of the cercaria
in water is about 24 hours at 12-27° C and 28-29 hours at
8-9° C, time period in which the free swiming cercaria
perishes unless it encounters a fish. The cercaria penetrates beneath the scales and, losing its tail, encysts as an
ovoid metacercaria,
chiefly in the muscles and subcutaneous tissues, less often on the scales, fins, and gills of
the freshwater fish (RIM, 1982a). In 5 weeks they develop into encysted metacercariae,
presenting an outer and
an inner hyaline wall secreted by the parasite and a surrounding capsule formed by the tissues of the fish. The
metacerarial
cyst measures
121-160/85-140
urn (KOMIYA & SUZUKI, 1964 a; Y AMAGUTI, 1975). Metacercariae die after 7 hour of desiccation
at room temperature,
3 min at a temperature
of 65° C, and also after 2,5 hourr
at 39-40° e. With regard to the duration of the viability
of the metacercaria,
B I FORD (1934) indicated that the
metacercariae
would remain viable in fish sent from the
Orient to Hawaii
for human consumption.
WYKOFF
(1958) determined
the length of time the metacercariae
remain viable after being taken out of the fish host in Japan and sent to the USA under refrigeration.
An average
of 16 days elapsed between the death of the fish and the
arrival of the metacercariae
in Washington,
D.e. It was
found that from the time of arrival until 40 days after death of the fish host, there was no significant decrease in
viability, and apparently 50% were viable after 60 days
when kept at 3-6° e.
When the definitive host ingests living metacercariae
by consuming
raw fish, the parasites excyst in the duodenum. The freed larva migrates to the common bile
duct by way of Ampulla of Vater after 4 to 7 hr and then
to the distal biliary ducts, where it becomes a mature
worm. In 2 weeks, after their arrival in the biliary ducts,
the parasites grow to adult stage and initiate their sexual
activity, but it takes another 12 days for the egg to appear in the stools. The prepatent period varies according
to the definitive hosts (about four weeks in man). About
3 months are required for the whole life cycle (RIM,
1982a).
The longevity of the parasite is very dependent on the
host-parasite
compatibility
and the tolerance of the host.
In general, the adult stage can survive 15-25 years in humans, but an extreme longevity of over 26-40 years may
also be deduced, judging from patients who have long
resided away from endemic areas (CALERO, 1967; ATTWOOD & CHOU, 1978; OOSTBURG & SMITH, 1981; LEITE
et al., 1989; ISHIOKA & 001 ELLY,1990).
Up to nine species of fresh water snails have been reported as being able to develop the role of first intermediate host for C. sinensis: Fam. Hydrobiidae:
Parafossarulus manchouricus (= P. striatulusi, P. anomalospiralis,
Bithyniafuchsiana, B. chaperi and Alocinma longicornis;
Farn. Thiaridae: Thiara granifera and Melanoides tuberculata; Fam. Assimineidae:
Assiminea lutea; Fam. Pleuroceridae: Semisulcospira libertina.
The hydrobiid
snail P. manchouricus, 7-10 mm in
height, is the main first intermediate
host in all the endemic regions where full transmission
of the parasite is
accomplished,
such as in China, Taiwan, Korea, Japan,
Vietnam and the Far East of Russia (RIM, 1982a; PO·
SOKHOV, DOVGALEV & BRYUNETKINA, 1987; KORA·
BLEV & KOL·TSOV, 1992). All other snail species act as
intermediate
hosts in China (RIM, 1982a; LJ et al.,
1985). In China, B. fuschsiana is the host in the northern part and A. longicornis is also a host in some
areas, but to a lesser extent than P. manchouricus and
B. fuchsiana. Outside China, S. libertina and T. granifera may also serve as intermediate
hosts in Taiwan
(CROSS, 1984; CHEN & HSIEH, 1984; CHEN, 1991). B.
chaperi has been reported as the host in the delta of the
Red River in northern
Vietnam
(GAILLIARD, 1939).
Also in Vietnam,
M. tuberculata has been recently
found participating
in the life cycle of the parasite in
the Ha Nam Nin Province (KIE, BRONSHTEIN & FAN,
1990).
The two thiarid species, T. granifera and M. tubercula/a, have a markedly high colonization capacity, as deduced from their successful introduction
in North (southern USA, Mexico), Central (Panama, Caribbean area)
and South America (Venezuela,
Brazil), Europe, Africa,
Australia, and Pacific islands, as well as in Asian areas
other than those of the clonorchiasis
enderny (MADSE
& FRANDSEN, 1989; POINTIER & MC CULLOUGH, 1989;
POI TIER, pers. comm, 1995). The potentiality
of geographical spread of C. sinensis thanks to this phenomenon is evident.
From the ecological point of view, P. manchouricus is
common in ponds, including fish culture ponds, but also
inhabits lakes, swampy areas, and sluggish parts of rivers and small streams. The other species also have similar habitats. Studies carried out in Japan have shown that
temperature
affects the activity of the snails, so that at
low temperatures
(10° C), P. manchouricus crawls on
the mud, but as the temperature
rises, it adheres to the
aquatic vegetation for crawling and egg laying (SATO et
al., 1959).
In general, infection rates in the snail are low, and
they show seasonal variation. Of 535 P. manchouricus
examined
from Sun Moon Lake in Taiwan,
only 7
(1,3%) released C. sinensis cercariae (CLARKE, KHAW
& CROSS, 1971). In South Korea, in a study from
March 1979 to September
1980, P. manchouricus was
collected
in summer (May to August) from localities
along the river Taewha, Kyungnam
Province, snail population
density
ranging
10-500/m2
and only 3
(0,059%)
of 5075 snails (I from each of 3 localities)
harboured
C. sinensis cercariae
(100, 1980). Worth
mentioning
is the high prevalence 25,8% of the parasite
detected in M. tuberculata in Vietnam (KIE, BRONSH·
TEIN & FAN, 1990).
152
A wide variety of species of freshwater fishes serve as
the second intermediate hosts, carrying encysted metacercariae of C. sinensis. A total of 113 fish species belonging to several families, mostly Cyprinidae, has been
reported so far (RIM et al., 1994).
YOSHIMURA(1965) already listed more than 80 fish
species so far incriminated as second intermediate hosts
of C. sinensis. Among them, a majority of 71 species are
confined to the family Cyprinidae, two belong to the family Elotridae, and one to each of the families Bagridae,
Cyprinodontidae, Clupeidae, Osmeridae, Cichlidae, Ophiocephalidae, and Gobiidae. In addition to these fish
species, certain freshwater shrimp (the crustaceans Caridina nilotica gracilipes, Macrobrachium superbum, and
Palaemonetes sinensis) have been incriminated as a
source of infection in Nanan, Fukien Province, China
(TA Get al., 1963). The species shown to be infective in
China, Taiwan, Korea and Japan were critically analysed
by KOMIYA(1966).
In China, about 70 species have been listed, the most
heavily infected species Ctenopharyngodon idellus, Mylopharyngodon aethiops, and Culter alburnus being
used in raw fish dishes as the important food among Chinese population (YOSHIMURA,1965; RIM, 1982a).
In Taiwan, 13 species of the members of the family
Cyprinidae and one of the family Ophiocephalidae are
known as intermediate hosts, among which Pseudorasbora parva and Hemiculter kneri (= Cultriculus kneri)
are commonly found infected with large numbers of metacercariae but they are seldom eaten (KIM & KUNTZ,
1964). In the transmission to humans, Mugil cephalus
and Ctenopharyngodon idellus are the most important
ones with above 80% infected, and they are frequently
consumed raw by the inhabitants in endemic areas
(CROSS, 1984; CHE & HSIEH, 1984; CHE ,1991).
In Japan, 27 species of fishes belonging to the family
Cyprinidae (25 species), Gobidae (I species), and Osmeridae (1 species) have been found naturally infected (Ko
MIYA& SUZUKI, 1964), metacercariae being found most
frequently in the small fishes, such as Pseudorasbora
parva, Sarcocheilichthys
variegatus, Acheilognathus
lanceolata, and Tribolodon hakonensis (RIM, 1982a).
In Korea, about 30 fish species were implicated, most
frequently Pseudorasbora parva. Sarcocheilichthys sinensis, Hemibarbus /abeo, Acanthorhodeus
gracilis,
Acanthorhodeus asmussi (= Acanthorhodeus taenianalis), Pungtungia herzi, Pseudogobio esocinus, Gnathopogon atromaculatus, Cultriculus kneri, Macropodus
chinensis and Opsariichthys bidens (RIM, 1982a).
Epidemiology
The geographical distribution of clonorchiasis is pronouncedly marked by that of the intermediate snail host
species, mainly the species Parafossarulus manchouricus. This snail inhabits various types of bodies of water
S. MAs-CoMA
& M.D. BARGUES
such as ditches, streams, ponds, and reservoirs in the low
flat area. C. sinensis prevalences in large populations of
this snail species in many water bodies appears to be
low, but the parasite develops a high intensity of cerearial liberation from the few infected snails, thus ensuring
propagation. Cercariae are shed in the May-October period in Korea, and in March-October in the more southern latitudes, as in Taiwan. In Japan, the parasite appears to be able to survive the hibernation period of the
snail under redial stage, cercariae being liberated around
April at the time the snail resumes its spring activity.
Contrarily, in Korea, cercariae and rediae are fatally damaged by the low temperature, so that in such a cold climate snails acquire a new infection each year, since the
resumption of the snail's activity starts in early spring
and the cercariae do not start to emerge until late spring
(RIM, 1982a). The geographical distribution of human
endemy is evidently related to that of the intermediate
fresh water snail hosts. Infected people are found more
or less concentrated around fresh water collections
where transmission takes place. Definitive host prevalences decrease with the increase of the distance from
these water bodies, although these concer.trations are
masked because infected fish can be found quite far
away from the snail's habitat and the long viability of
metacercariae in dead fish for human consumption makes human infection possible even farther away, not only
from snail habitats but also from fresh water collections.
The long viability of metacercariae also masks the seasonality of cercarial transmission, which is not clearly
transmitted to mammal incidence, although this seasonal
variation must evidently influence the infection of fish,
so that a risk period for the infection of humans and other mammals can be deduced for summer and autumn.
The infection of the definitive mammal hosts takes
place by the ingestion of metacercariae together with
fish food. Every region has one or a few species that are
more infected than all others, and concerning the transmission to the definitive hosts not all of the fish species
are of the same importance. The species Pseudorasbora
parva, owing to its large populations and wide distribution as well as to the very high infection prevalences by
metacercariae it is able to support, appears to be the most
important fish in the transmission of the disease, considering all the endemic regions as a whole.
With regard to clonorchiasis in mammals, fish species
involved in the transmission to domestic animals are not
necessarily the same as those mainly reported for the infection of wild mammals. Concerning domestic cats and
dogs, small fish such as Pseudorasbora parva, Pseudogobio rivu/aris and other species, are mainly responsible
for transmitting the disease, because they are cheap and
consequently used as food for cats and dogs (YOSHIMURA,1965).
Animal reservoir hosts, including hogs, dogs, cats,
rats, and other hosts are found naturally infected, and
their infection intensities do not always coincide with
the prevalences in man in the same localities, the inten-
Human
liver flukes:
153
a review
sity of human infection being largely dependent upon
the eating habits of the population in the place in question. Sometimes similar prevalences appear in animals
and in man, such as in two endemic areas of Korea. In
Gimhae Gun prevalences were high in humans (68,8%)
and also important in hogs (18,5%), dogs (50%) and
house rats (10,9%), whereas in Goyang Gun prevalences
were lower in humans (15,2%) and also lower in hogs
(2,4%), dogs (21,6%) and house rats (3,8%) (KIM,
1974). However, sometimes the situation is quite the opposite. In northern China, where little or no raw fish is
eaten except in Cantonese restaurants, prevalences in humans are very low (0,4%) but important in cats and dogs
(25-30%). Tn central China prevalences in humans are
uncommon but very high in cats and dogs (75-100%).
And in southern China prevalences in humans are high
but not so much in cats and dogs (45%). From all these
and many other data it is evident that reservoir hosts,
such as cats and dogs as well as pigs and rats, play a significant role in spreading the eggs and thus in the transmission of the parasite in given areas. However, the intensity of human infections is usually heavier than the
infection of reservoir animals, indicating that human infections play a major role in the epidemiology of the disease rather than that of the reservoir hosts (RIM, 1982a,
1986).
Human infection is acquired by ingesting raw, inadequately cooked, dried, salted, or pickled freshwater fish
flesh which harbours the encysted metacercariae, Concerning the transmission to man the importance of the
fish species differ, depending from local human diet traditions. The intensity of human infection is also dependent upon the eating habits of the population in each
area. Tn most areas, the fish are even raised in fish ponds
that are commonly fertilized with human and animal faeces. This provides excellent nutrient for the growth of
plant and animal life upon which the snails and fish feed,
and also provides an opportunity for perpetuating the life
cycle of the parasite (BUNNAG& HARINASUTA,1984).
Fish harbouring metacercariae are frequently small in
size and have little or no sale value, depending on the
species. For instance, the small species Pseudorasbora
parva shows extremely high infections, with 4,44 metacercariae per g and usually hundreds to thousands (a maximum of 31516) metacercariae in a fish (KIM, 1974;
RHEE et al., 1984).
In Japan and Korea, people like to eat raw fish prepared in various ways. Large fish such as Cyprinus carpio
and Carassius carassius are preferred, but sometimes
also Tribolodon hakonensis. The first two fish species
should be considered as the main source of infection, although they contain only a few cysts. Similarly in Taiwan, species such as Tilapia mossambica and Ophiocepha/us maculatus are commonly consumed raw, but the
metacercarial infection rates are low. However the repeated consumption of raw fish may lead to heavy infections and high incidence caused by accumulated light infestations due to frequent exposure for several years.
Heavily infected small fishes are not generally eaten
raw, but they may be eaten after undercooking and may
transmit infection (KOM1YA& SUZUKI, 1964; KOMIYA,
1966). In China, Cantonese people with a marked preference for raw fish in their diet are notably infected. In
central and northern China, however, fish is not eaten
raw and there is little or no infection except in certain
endemic areas, although fish and reservoir hosts may be
heavily infected (RIM, 1982a). In the endemic area of
south Fujian Province, China, the residents eat raw shrimp which is considered to be the only source of infection (TANG eta!., 1963; RIM, 1982a, 1986).
When analysing human infections, three aspects are
worth mentioning: the existence of a social factor, the
age distribution and the sex distribution.
The social factor refers to the custom of eating raw fish
among the different racial or social groups, this habit explaining marked differences of infection among groups,
such as for instance immigrants with this dietary custom
in areas where authochtonous people do not have it (KOMIYA, 1966). This social factor is also related to the family as an epidemiological unit, there being a tendency
towards familial aggregation (KOMIYA& SUZUKI,1964).
Concerning age distribution, in various endemic areas
of Japan, Korea and Taiwan as well as in Hong Kong,
the incidence of infection is greater in the higher age
groups and greatest in persons of 30-50 years old, because clonorchiasis is contracted through eating raw fish
and the latter represents an adult diet (HoU & PANG,
1964; Joo & CHOI, 1974). Contrarily, in some endemic
areas in China where infection is due to the ingestion of
fish roasted for about 10 min only, clonorchiasis occurred mainly in children under 15 years of age (Wu,
1963; SUNG, 1963; KOMIYA, 1966; RIM, 1982a).
Concerning sex distribution, whereas in given areas
there is no apparent difference in the incidence of infection in males and females in Japan (KOMIYA, 1966), in
other areas males have been shown to be more highly infected than females, as in Korea (W ALTON & CHYU,
1959), China (FAUST & KHAW, 1927; RIM, 1982a), or
Taiwan (CHOW, 1960). This higher infection rate in men
is directly related to the habit and frequency of eating
raw fish, which in turn is probably related to some social
customs. For instance, the Korean people have a traditional custom of eating raw fresh water fish after soaking
them simply in vinegar or red-pepper mash as an appetizer for the drinking of rice wine at social gatherings.
Since women infrequently participate in such gatherings,
they have much less exposure to infection (RIM, 1982a).
Human pathology is in the liver, pancreas and spleen.
Complications are also worth mentioning.
In the liver, parasites lodge and mature in the medium
and large intrahepatic ducts, especially those of the left
liver lobe. Early changes seen in the biliary ducts are ex-
S. MAs-CoMA& M.D. BARGUES
154
cessive mucin formation, desquamation, and adenomatous hyperplasia of the duct epithelium with goblet cell
metaplasia. In the chronic stage, progressive bile duct
thickening dilatation and tortuosity, and ductal and periductal fibrosis are noted. Biliary stasis results in secondary infection leading to pericholangitis, cholangiohepatitis, pyelophlebitis, and multiple abscesses. Fibrosis
rarely appears in the portal tracts, and portal cirrhosis
has been described only infrequently. Not uncommonly,
the flukes may cause dilation and fibrosis (MARKELL&
GOLDSMITH,1984). Principal gross changes are encountered in the liver. In massive infections, the organ may
be enlarged to 2 or 3 times normal size. The external surface of the liver may show pale cystic areas. Linear whitish streaks corresponding to dilated bile ducts may be
observed. The cut surface reveals a normal parenchyma
punctuated by ectatic bile ducts with walls 2 to 3 times
their normal thickness (DOOLEY& NEAFIE, 1976). Localized dilation of the bile ducts, usually near the free edge
of the liver and especially in the left lobe, is a common
manifestation, whereas generalized dilation of the bile
ducts is uncommon (GLBSON& SUN, 1971). Parasites do
not invade tissue and thus elict little or no inflammatory
reaction. There is a marked increase in mucus production (DOOLEY& NEAFIE, 1976).
The pancreas is sometimes also affected. The pancreatic ducts, filled with worms, become thickened and dilated and exhibit mucinous and squamous metaplasia.
Pancreatitis, usually mild, is however not common (DOOLEY& NEAFIE, 1976). Splenic congestion is seen in the
early phase of the infection. The spleen may be enlarged,
showing an increase of fibrous connective tissue especially in the red pulp in chronic infection with hepatic
changes (OOSTBURG& SMITH, 1981).
As for the complications of clonorchiasis, the occurence of intrahepatic gall stone is one of the most characteristic pathological features. Cholangitis and cholecystitis are caused by bacillary infection during the
obstructive disturbances of the bile ducts. Liver cirrhosis
and carcinoma of the bile ducts are often observed in
close association. The evidence for a carcinogenetic effect of clonorchiasis is strongly suggestive. The flukes
provoke hyperplasia and, in some subjects, neoplasia leading to cholangiocarcinoma. The association between
C. sinensis and cholangiocarcinoma has been documented epidemiologically for many years (RIM, 1986; SHER
et al., 1989; ONA & DYTOC, 1991).
Only one case of adenocarcinoma of the pancreas associated with C. sinensis has been reported recently
(COLQUHOUN& VISVANATHAN,1987). Biopsy of the
pancreatic lesion revealed well-differentiated ductal adenocarcinoma. C. sinensis was detected in the common
bile duct. Following cholecystectomy and choledochoduodenostomy the patient made an uneventful recovery.
Concerning symptomatology, most patients, even in
endemic areas, are asymptomatic and harbour few parasites. Among symptomatic patients, both acute and chronic syndromes occur. Symptoms and signs may appear
and persist for several months, including malaise, lowgrade fever, high leukocytosis and eosinophilia, an enlarged and tender liver, and hepatic or epigastric pain.
The acute phase is infrequently recognized, and the diagnosis is difficult to make because eggs may not appear in
the faeces until 3 or 4 weeks after the onset of symptoms
(MARKELL& GOLDSMITH,1984).
In chronic clonorchiasis, clinical findings vary according to the worm burden and duration of infection. The
clinical manifestations appear to increase in severity progressively as the infection becomes older and as the flukes are gradually acquired. The infection may persist for
15-20 years or more. Lightly infected persons usually
show no symptoms, but in moderate or progressive cases
the clinical symptoms show loss of appetite, indigestion,
fullness of abdomen, epigastric distress unrelated to meals, discomfort in the right upper quadrant, diarrhea,
edema, and some hepatomegaly. In heavy infection cases the symptoms show weakness and lassitude, epigastric discomfort, paresthesia, loss of weight, palpitation of
heart and tachycardia, diarrhea, vertigo, tetanic cramps
and tremors, and toxemia from liver impairment. In the
later stage of heavy infection or severe cases the symptoms include marked GI disturbances, with a syndrome
associated with portal cirrhosis, splenomegaly, ascites,
and edema (BELDING, 1965).
Diagnosis
The parasitological diagnosis is based on coprological
methods for the finding of the characteristic eggs in the
faeces or biliary drainage. Care must be taken because of
their small size, and the need to differentiate them from
eggs of other opisthorchiid and heterophyid fl ukes
which may be present in the same area. Concentration
techniques are therefore recommended. The method of
formalin-ether sedimentation or other centrifugation
techniques are more reliable for detecting the eggs in faeces. The direct smear method of recovering eggs from
the faeces can be applied in cases of heavy infection, but
in light infections eggs may not be encountered by this
method (RIM, 1982a).
Quantitative methods can be applied to evaluate the clinical severity. Patients were divided into four groups according to the results obtained with the Stoll's dilution
egg counting method: light infections (1-999 eggs/g of
faeces), medium infections (1000-9999 eggs/g of faeces),
heavy infections (10000-29999 eggs/g of faeces), and
very heavy infections (30000 eggs/g of faeces and over)
(RIM, LEE & SEO, 1973). Another quantitative technique,
the Kato faecal thick smear technique, has also been used
because of being simple, of low cost and of reproducible
results, although it is recommended to use it in combination with other techniques, like the formalin-ether technique (CHAI et al., 1982; LEITEet aI., 1989).
In patients with biliary obstruction, eggs are not passed in stools but may be found in the bile duct by percutaneous needle aspiration. If the patient undergoes sur-
155
gery, adult flukes and eggs are found in the biliary system or pancreatic duct (RIM, 1982a).
The immunological
tests used for clonorchiasis
(indirect fluorescent
antibody test, enzyme-linked
immunosorbent assay, indirect haemagglutination
test, complement fixation test, counter-immunoelectrophoresis,
and
others) have been reviewed by HILLY ER (1986). ELISA
has proved to be useful as a screening test, but cross-reactions with other trematodes
(Fasciola, Paragonimus,
Schistosoma) occur (RIM, 1986). Applied serologic tests
appear to be generally
nonspecific
and of little value
(Bu
ANG & HARI ASUTA,1989).
In endemic areas where uncooked fish is eaten, clinical diagnosis
is suggestive
in patients with an enlarged
liver and symptoms
of hepatitis.
Advanced
infections
require differentiation
from malignancy,
cirrhosis
of
the liver, or other causes of hepatic enlargement
(RIM,
1982a).
Haematology
can be helpful. Leukocytosis
varies with
the intensity of infection, and eosinophilia
may be present. Eosinophilia
and liver fuction test in clonochiasis
were studied by KIM & KIM (1979).
On transhepatic
cholangiograms
of the large and medium-size
intrahepatic
ducts, the worms appear as curved filling defects within dilated bile ducts or as mounds
attached to the duct walls (BUNNANG & HARINASUTA,
1989). Several cholangiography
types have been applied
(LEUNG et al., 1989; LIM, 1990), although they are decreasing in use because of the introduction
of ultrasonography and computed
tomography
in the diagnosis
of
hepatobiliary
diseases. Ultrasonography
is now considered of great use for the diagnosis of clonorchiasis,
allowing us to determine the parasites in the bile ducts and
to analyze the extent of the disease at the level of the hepatobiliarry
tract. It is also useful for the evaluation
of
the effectiveness
of a treatment. Ultrasound
features of
biliary clonorchiasis
have been reported by LIM et al.
(1989). Because the majority of North American cases
will have light infections
and be asymptomatic
at the
time of presentation,
the abdominal
ultrasound
is invariably normal as are liver function tests (HARINASUTA,
PUNGPAK & KEYSTONE, 1993). Imaging techniques are
most important in the evaluation
of patients with recurrent pyogenic cholangitis,
an entity that is often seen in
association
with clonorchiasis.
The condition is characterized by dilation and structure of second-order
biliary
radicals and the presence of intrahepatic
pigmented
biliary stones or sludge. Although endoscopic and percutaneous cholangiography
and ultrasonography
readily
highlight these findings, computed tomography
appears
to be the most sensitive diagnostic modality (FEDERLE,
CELLO & LAING, 1982; LIM, 1990).
The prognosis
is good in those with light infections.
Patients rarely die of this infection alone. Death can occur, however, in heavy infections of long standing when
the parasites have caused serious impairment
of function, especially in cases with relapsing pyogenic cholangitis (BUN AG & HARINASUTA, 1989).
Treatment
The drug of choice is praziquantel.
Doses of 25 mg/kg
three times daily after meals for 1 or 2 days or 20 mg/kg
body weight for 3 days gi ve cure rates of 85 to 100%
(RIM et al., 1982: LOSCHER et al., 1981; WEGNER,
1984). The tablets should be taken after a meal, and the
interval between individual doses should not be less than
4 hours or more than 6 hours. The cure rate of praziquantel is related to the intensity of the infection. The cure
rate of a single dose of 40 mg/kg was only 22,7-33,3%
according to the intensity of the infection, although egg
reduction rate was high in the patients who were not cured (RIM, 1982b). In large scale treatment programmes,
RIM (1982b) and RIM et al. (1982) proposed a single
dose of 40 mg/kg for light infections « I000 eggs/g of
faeces), 2 x 30 mg/kg for moderate infections (100010000 eggs/g) and 3 x 25 for heavy infections (> I0000
eggs/g). Adverse effects of praziquantel
were transient
and included nausea and vomiting (15%), vertigo (12%),
hepatomegaly
(4,5%), headache
(1,5%), rash (1,5%),
and hypotension
(1,5%) (YANGCO et al., 1987). Because
the drug is also effective in cysticercosis
and paragonimiasis infections of the brain, death of these parasites
may result in larish-Herxheimerlike
reactions and serious cerebral symptoms, including convulsions,
paralysis, coma, or death. Therefore, in areas endemic for both
clonorchiasis
and cysticercosis
or paragonimiasis,
cerebral involvements
must be ruled out before administration of praziquantel
(BUNNAG & HARINASUTA, 1989).
The therapeutic effect of albendazole
is comparable to
praziguantel.
It has the advantage of clearing various intestinal helminthic
infections simultaneously,
very low
toxicity, excellent tolerance and relatively low cost, although its treatment
course for clonorchiasis
needs 7
days (LIu et al., 1991).
Chloroquine,
widely used in the past in treatment, appears to inhibit fluke egg-laying only temporarly and is
no longer
recommended.
Hexachloroparaxylene
has
been used in China but is poorly tolerated by many patients (BUNNAG & HARINASUTA, 1989). Niclofolan has
also been used and observed to be effective, although the
serious side effect affecting the optic nerve indicate that
it cannot be recommended
(RIM, 1990).
In late or severe clonorchiasis,
with gallbladder enlargement and obstruction
of the biliary passage, surgery
may be useful. In cholangitis with superimposed bacterial
infection, antibiotics should be given. Supportive measures such as nutritious diet and fuid and electrolyte control
may help in recovery (BUNNAG & HARINASUTA, 1989).
Measures to control clonorchiasis
are directed to reduce or eliminate the transmission
of the disease, in order to prevent new human infections. There are several
ways of control to be applied, according to the different
phases of the life cycle: A) control of snail hosts; B) he-
156
alth education; C) treatment of infected persons and domestic animals; D) elimination of human and animal faeces; E) protection of fish ponds from contamination.
The choice of the methods must take into account the
characteristics of the transmission foci, the habits and
customs of the people, the pattern of transmission, and
the resources of the country and endemic area (RIM,
1982a).
Measures to control snail hosts in water collections
such as rivers in endemic regions appear to be feasible
with difficulty, but several actions can be applied in manmade water collections such as fish-farming ponds. The
extermination of snails by engineering measures is too
expensive to be practical, and the molluscicides capable
of destroying the snails may also destroy fish and other
aquatic life. However, biological methods could be implemented, such as the introduction of mollusc competitors or animal predators of the snail host species, trematode competitors of C. sine/His such as digenean species
able to effectively compete in using the same snail host
species, and sterilizing or pathogenous parasites of the
snail host species. However, it is still too early to tell. In
Japan, among the factors responsible for the marked reduction of incidence is water pollution from factories, insecticides, and land development with drainage of
swamps, all factors directly affecting snail populations,
as well as public health education (KOMIYA & SUZUKI,
1964). Similarly, in Korea, traditional ways are changing,
and the mechanization of farms, the use of chemical fertilizer, pesticides, and insecticides may have affected the
parasite or its intermediate hosts (RIM, 1979, 1982a).
The measures to prevent stools containing viable eggs
from reaching bodies of water containing the snail intermediate host would apply only to the human population,
since water pollution by reservoir animal hosts cannot be
controlled. To prevent or reduce infection of the snail
host, the treatment of the definitive host, mainly humans,
to destroy the adult worms would be of value as a control measure and appears to be the most feasible in endemic areas.
At human level, control is evidently related to measures taken to avoid the ingestion of metacercariae with
raw, freshly pickled or insufficiently cooked fresh water
fish. Although complete protection is achieved simply
by cooking fish, it would be a futile exercise to try to get
millions of people to change centuries-old eating habits.
Even so, to educate these people to cook their fish would
not change matters, since fuel is commonly a luxury that
many cannot afford. At any rate, in the districts where
eating raw fish constitutes a custom, educational activities stressing the importance of thoroughly cooking all
freshwater fish appears to be the most effective means of
preventing clonorchiasis (RIM, 1977). When comparing
the prevalence rate of clonorchiasis in a certain area in
Korea between 1964 and 1976, a marked reduction in
the prevalence was encountered in the youngest age
group, but there was no significant difference in the older age groups. The overall prevalence rate for clonor-
S.
MAs-CoMA
&
M.D.
BARGUES
chiasis was reduced from 27,7 to 19,6% in a period of
about 10 years, health education, as well as cultural, dietary, and economic changes, appearing to have assisted
in the general decrease of infection (CHOI et al., 1977;
RIM, 1979, 1982a).
OPISTHORCHIS
VIVERRINI
Morphology
The adult stage is flat, elongate, lanceolate, rounded
posteriorly and attenuated anteriorly, thin, transparent,
5,5-9,5/0,77-1,65 mm (mean 7,4/1,47 mm) in size, with
a smooth outer tegument in mature worms. Both suckers
are similar in size. The oral sucker is subterminal and the
acetabulum is about one-fourth the body distance from
the anterior end. The pharynx is small, a short oesophagus is present, and the caeca reach almost the posterior
extremity. The excretory bladder is a long saccular tube
extending up to ovary level. The two testes are markedly
lobed, in oblique tandem in the posterior body. The long,
slightly coiled seminal vesicle terminates in a weakly
muscular ejaculatory duct, which opens through the genital pore immediately in front of the acetabulum. Cirrus
pouch and cirrus are lacking. The ovary is oval or
slightly lobed, median, directly pretesticular. The numerous vitelline follicles vitellaria are aggregated in a few
clusters and disposed in two lateral fields in the middle
third of the body. The uterus proceeds anteriad as an intracaecally coiled tubule which terminates with a metraterm opening in the genital pore. The eggs are elongate
ovoid, light yellowish-brown, 22-32111-22 urn (mean
28/l6 urn; length/width ratio = 1,75) in size, with an
operculum that fits into a thickened rim of the shell proper and a minute tubercular terminal thickening (not visible in all eggs).
Worth mentioning are the difficulties in differentiating O. viverrini from O. felineus, both at adult and egg
levels. Although differences between adults and between eggs of both species have been found (SADUN,
1955; RIM, 1982; DITRICH, GIBODA & STERBA, 1990;
HARI ASUTA, Pu GPAK& KEYSTONE,1993), WYKOFF
et al. (1965) were unable to distinguish O. viverrlni
from O. felineus on the basis of morphological characteristics of adult worms or eggs owing to their overlapping intraspecific variability (see chapter on O. felineus
for more detai I). At any rate, both Opisthorchis species
are distributed very far away from each other, so that
the possibility of confusion does not become a problem.
This is not the case with C. sinensis, another human liver fluke whose geographical distribution overlaps with
that of O. viverrini in several countries of southeastern
Asia and whose eggs closely resemble those of O. viverrini in size and shape (RIM, 1982; DITRICH et al.,
1992a), so that the possibility of confusion in overlapping endemic regions must always be taken into account.
The adult fluke is a parasite of the distal bile ducts and
also, but less intensively,
the gall bladder of man and
animals. The civet cat, domestic cat and dog, as well as
other fish-eating
mammals,
are definitive
hosts other
than man, which are often found infected with O. viverrini, even in regions where the infection is not known to
occur in humans. In human endemic areas of Thailand,
approximately
60% of the cats and 40% of the dogs were
found to be naturally infected, whereas studies on many
types of non-domesticated
animals never showed parasitation by O. viverrini (WYKOFF et al., 1965).
Cats, rabbits, guinea pigs and albino rats are used in
the laboratory for experimental
purposes. These animals
are of additional
interest because in them the general
pathological
changes in the liver are more or less similar
to those in man (RIM, 1982). Rabbits seem to be the best
host in the laboratory (WYKOFF & ARIY APRAKAI, 1966).
Dogs can also be experimentally
infected, but the worms
in the liver usually disappear spontaneously
after a short
period of time if the metacercariae
are not fed repeatedly
(RIM, 1982). Monkeys could not be successfully
infected
(HAR! ASUTA, 1969). Hamsters are easily infected and
are used for immunological
studies (SIRISI HA et al.,
1983; CHAWE GKIRTTIKUL & SIRISINHA, 1988), but the
flukes produce relatively few eggs (85 eggs/worm/day)
(WYKOFF & ARIY APRAKAI, 1966), and the pathological
changes revealed that the liver tissue responses seemed
to be more destructive
and more inflammatory
than
those in other animals (HARI ASUTA, 1969).
Reports in humans
O. viverrini infection
has been reported in persons
from southeastern
Asia, namely Thais, Laotians, Malaysians, Vietnamese,
Cambodians
and Chinese, prevalences and intensities being mainly related with traditions
of eating raw or undercooked
fresh-water fish.
In Thailand, human infection by O. viverrini appears
to be widespread
only in the northeastern
part and in
some provinces of the northern part of the country (RIM,
1982). This progressive
and slowly disabling disease is
considered
a public health problem, O. viverrini infection remaining the leading human parasitic disease in the
northeastern
part of the country, with prevalences
reaching up to 90% in highly endemic areas (HARI ASUTA,
1986). A survey by the Ministry of Public Health in
1984 found an average prevalence of 34% and estimated
that 7 million of the 19 million people in this region
were infected (PREUKSARAJ, 1984). A more recent survey by the Ministry reported a prevalence of 15,2% nationwide, and 24% for the northeast (JONGSUKSANTIGUL
et al., 1992), showing a regional drop of 10% over a decade. However, this survey also detected a pronounced
increase of the prevalence
in northern Thailand
from
5,6% to 22% in the period 1982-1992,
so that consequently the national prevalence did not decrease. A third
157
major survey in seven provinces in the northeast conducted in 1992 indicated that 34% of the human population
harbours this parasite. When taking into account local situations, prevalences
and intensities vary markedly from
one community
to another. In a very recent survey on 60
villages from 7 Northeast
Thai provinces,
prevalences
detected ranged more or less between a minimum of 8%
and a maximum of 68%, depending on villages and communities. The factors responsible
for this variation probably include microgeographical
characteristics
which
determine snail and fish availability as well as recent treatment programmes
and changing eating habits resulting
from Thailand's
extensive public health efforts (SITHlTHAWORN et al., 1994). In central and south Thailand, human opisthorchiasis
does not appear to be an important
health problem, prevalences
ranging only 0-5% (RIM,
1982; PREUKSARAJ, 1984; HARINASUTA & HARINASUTA, 1984).
In the neighbouring
Laos, the parasite also appears to
be common. Because of geographical
location and similar eating habits, a large number of people are likely to
be infected (WYKOFF et al., 1965). According to the latest knowledge, an estimated 1,7 million Loatians are infected with O. viverrini (RIM et al., 1994). However,
there have been fewer studies in this country. Surveys
carried out in the Vientiane province and its immediate
surrounding
areas showed prevalences
up to 54,4% and
even nearly 100% (BEDIER & CHESNEAU, 1929; SEGAL
et al., 1968; PATHAMMAVONG, 1971, 1973; SORNMANI
et al., 1974; GIBODA et al., 1991; PHOLSENA et al.,
1991). In Laos, moreover,
high prevalences
of minute
intestinal flukes (Haplorchis
spp.), whose egg morphology is similar, complicate
diagnosis
(GIBODA et al.,
1991). An exact knowledge on the distribution of human
infection by O. viverrini in the interior of Laos is today
lacking.
In Malaysia, reports on human infections by O. viverrini are limited to the study of BISSERU & CHONG
(1969) in the western part of the country. More studies
are needed in Malaysia to assess the exact distribution of
human opisthorchiasis.
It is evident that specifically directed surveys are needed to know if human infection by O. viverrini is present
or not in neighbouring
countries such as Vietnam, Karnand southern China. in which the
puchea (= Cambodia)
well-known
existence of human infection by C. sinensis
can give rise to confusion due to the difficulties of differentiating the eggs of both species. In the neighboring
areas of Vietnam, at least some of the O. felineus human
infections
reported are thought to represent cases in
which O. viverrini and O. [elineus have been confused
because of the similarity
of their eggs (MARKELL &
GOLDSMITH, 1984). Concerning
Kampuchea (= Cambodia) and China, no report on human infection by this species could be found in the literature. There are however
several reports on O. viverrini infection in Cambodians
and Chinese detected in the territory of Thailand. In this
country, Cambodians
and Chinese very rarely eat raw
158
fish in the traditions of Thais, which explains the low
prevalences
by O. viverrini detected in them. SADU
(1955) found in Udorn that only 2,9% of the Chinese
passed O. viverrini eggs with their stools, whereas
50,4% of the Thais did. KEITTIYUTI et al. (1982) found
0. viverrini eggs in 19% of 5085 Cambodian
refugees
hosted in a holding center of the Prachinburi
Province,
Thailand.
Worth mentioning
also is the frequency
of O. viverrini infection as reported in studies on human emigrants from these endemic countries and carried out in
other parts of the world, such as Thais in Japan (TANAKA et al., 1988), Laotians and Thais in the U.S.A.
(HOFSTETTER et al., 1981; WONG et al., 1985; DAO,
BARNWELL & ADKINS, 1991), Laotians
in Germany
(ZIEGLER et al., 1983), Laotians, Vietnamese
and Cambodians in France (AMBROISE-THOMAS et al., 1985),
Thais, Laotians and Vietnamese
in the Czech Republic
(DITRICH, GIBODA & STERBA, 1990), or Thais in Kuwait (HIRA et al., 1987).
The present knowledge
on the geographical
distribution of O. viverrini shows that it almost overlaps the distribution of the known human infection by this species,
which can be obviously understood owing to the largely
more numerous studies made on the human host. Accordingly, O. viverrini appears to be confined to southeastern Asia, with at least three different countries, in which
undercooked fish eating is a more or less usual tradition,
being involved. Reports on this species have been made
mostly in Thailand and only sporadically
in Laos and
Malaysia.
Unfortunately,
however,
in these countries
there is an evident scarcity of studies on reservoir hosts
such as cats and dogs, as well as on the snail and fish intermediate hosts, which could make possible a more accurate delimitation of the boundaries of the geographical
distribution of this parasite.
In Thailand, studies have been numerous because of
the recognized medical importance of opisthorchiasis
in
this country. It has been observed that in the areas of
high endemicity,
man is the most common definitive
host and thus undertakes
the main responsibility
for
maintaining the parasite life cycle in nature. Surveys on
humans have shown that O. viverrini is more prevalent
in the northeast and the north of Thailand. In the northeast, the reservoir hosts, normally cats and dogs, have an
infection rate of 40-90%, corresponding
with the rates in
man (HARI ASUTA, 1969). But studies on cat and dog
reservoir hosts have demonstrated
that the geographical
distribution
of O. viverrini is considerably
greater than
in man. In central Thailand, the life cycle is maintained
with snails, cats and dogs, although human infection is
not present or found only occasionally
at rates of 0-5,0%
(RIM, 1982). In the south of Thailand, human infection is
only sporadically found, with a 0,0 I % prevalence (HARINASUTA & HARINASUTA, 1984).
S.
MAS-COMA
& M.D.
BARGUES
In Laos, up to the present all reports on O. viverrini
concern the same zone, the Vientiane province and its
immediate
surrounding
areas (BEDIER & CHES EAU,
1929; PATHAMMAYONG, 1971, 1973; SOR MANI et al.,
1974; GIBODA et al., 1991; PHOLSENA et al., 1991), in
which the parasite has even been found at larval stage level in snails, as metacercariae
in fish and at adult level in
cats (GIBODA et al., 1991). Studies are needed to know if
O. viverrini is present in other areas of Laos.
In Malaysia, 0 viverrini has been found in cats (RrM,
1982) as well as in humans (BISSERU & CHONG, 1969)
in west Malaysia. BISSERU & CHONG (1969) also studied
the whole life cycle with naturally infected snails in this
country, although verification
of their result are needed
(DITRICH et al., I992b). Prospections
at all levels (snails,
fish, humans, reservoirs)
in other parts of this country
are needed to verify if the parasite has a wider distribution or not.
In other neighbouring
countries in the same area, such
as Vietnam, Kampuchea (= Cambodia) and the southern
bounderies of China, the presence of O. viverrini has never been reported, except probably the confused determinations
of O. felineus in Vietnam
(MARKELL &
GOLDSMITH, 1984), but cannot be excluded a priori. In
the latter three countries,
the marked similarity of the
egg of O. viverrini with that of C. sinensis, a well-known
human parasite in Vietnam, Kampuchea and China, does
not make the studies at human level appropriate to disentangle the possibility
of the presence of O. viverrini.
Specifically
directed studies on reservoir hosts such as
cats and dogs (with the possibility
to obtain parasite
adults for specific determination
after dissection) would
initially be more convenient.
Life cycle
The life cycle of O. viverrini has been reviewed by
WYKOFF et al: (1965), RIM (1982), HARINASUTA (1969,
1986), HARINASUTA & HARINASUTA (1984), UPATHAM
(1988)
and HARINASUTA, PUNGPAK & KEYSTONE
(1993). The development
pattern is typical of opisthorchiids and thus similar to that of C. sinensis and O. felineus. O. viverrini follows a trihetroxenous
life cycle
which develops in fresh-water.
Eggs already contain ciliated miracidia
when laid by the adults. Thus, fully
embryonated
eggs are excreted with the faeces of the definitive host, man and other fish-eating
mammals. The
egg-laying
capacity of adult flukes in cats is 160-900
eggs/adult/day
(RIM, 1982) and in humans 2000-4000
(average 3 I 60) eggs/adult/day
(WYKOFF & ARIYAPRAKAI, 1966) or an average of 180 eggs/adult/g
of faeces
(ELKINS et al., 1991). Thus, the number of faecal eggs
per gram correlates with worm burden (ELKI S et al.,
199 I; SITHITHAWOR et al., 199 I). Studies in humans
have suggested density-dependent
constraints
on fecundity which could operate to restrict the faecal egg output
in heavy infections (RAMSAY et al., 1989; ELKINS et al.,
199 I; SITHITHA WORN et al., 1991).
159
Only those eggs reaching a fresh-water collection, in
which appropriate aquatic snails are present, will have
the opportunity to continue their development. Once in
water, the inner miracidium must fully mature before
being ingested by a snail belonging to a specific species
(CHANAWO G & W AlKAGUL, 1991). After ingestion,
the miracidium hatches and penetrates the wall of the
snail digestive tract to metamorphose to the following
larval stage of sporocyst in the peridigestive regions of
the mollusc. The mature sporocysts are extremely thinwalled, generally coiled, 1100/650 urn in average size.
This sporocyst stage is already rediagenous. Inner rediae which have finished their development to mature
stage, escape from the sporocyst. Rediae measure 1801100/80-280 urn (mean 540/120 urn), Mother rediae are
very long, narrow and sac-like, whereas daughter rediae
are spindle-shaped or elongate (SCHOLZ,DITRICH& GIBODA, 1992). Rediae migrate to the region of the hepatopancreas or digestive gland of the snail and begin the
production of cercariae. Cercariogenous rediae appear
in about 1 month. About 15 developing cercariae can be
simultaneously observed within a mature redia (WYKOFF et aI., 1965). The prepatent period is approximately 8 weeks (CHANAWONG& WAIKAGUL,1991).
Cercariae escape from the rediae while still immature
(average length about 200 urn), to continue development
up to the cercarial mature stage, which leaves the snail in
about 2 months. Cercariae shed by the snail are 490565 urn in total length, with a body measuring 140183/61-96 urn and an unforked tail 350-437 urn long and
26 urn wide on average (WYKOFF et aI., 1965). The body
of the cercaria is covered with minute spines and at least
ten long cilia on each side. It presents a conspicuous pair
of eye spots located anterolaterally to the pharynx, brownish pigment scattered in a bilaterally symmetrical pattern throughout the body, five pairs of penetration glands
with ducts opening dorsal to the mouth, and an excretory
system of 2 [(3 + 3) + (3 + 3 + 3)] flame-cell pattern
which remains constant from the time of its emergence
from the snail up to its transformation into metacercarial
stage. The margins of the tail are drawn out into a thin
finlike membrane (WYKOFF et aI., 1965; DITRICHet al.,
1992b; SCHOLZ, DITRICH & GlBODA, 1992). Cercariae
appear to be both positively phototactic and geotropic,
tending to settle and live at the bottom with intermittent
periods of swimming.
When the mature cercariae come in contact with a suitable species of fish, they attach themselves to the scales,
lose their tails, and penetrate the tissues, where they
encyst between the muscle bundles. The metacercarial
cyst is oval in shape, measures 190-250/150-220 urn and
is surrounded by a thick layer of host tissue (SCHOLZ,DITRICH& GrnODA, 1990). The metacercariae when removed from the cyst appear to be oblong in shape, with a
size of 310-820/80-210 urn (VAJRASTHlRA,HARINASUTA
& KOMIYA, 1961; SCHOLZ, DITRICH & GrnODA, 1990,
1992). In fish, the metacercariae mature in approximately
6 weeks at 18-20° C. The survival of metacercariae
encysted in cyprinoid fish is probably not longer than one
year (BROCKELMANet aI., 1986). When ingested by humans or other fish-eating mammals, the metacercariae
excyst in the duodenum or jejunum and migrate through
the ampulla of Vater to the distal bile ducts, where they
attach to the biliary epithelium, mature within 3-4 weeks,
and begin to produce eggs (HARlNASUTA,1969). In cats,
rabbits, guinea pigs, and albino rats experimentally infected with metacercariae, parasites grow to adult worms in
the liver within about 30 days, the size of the worms
found in each host species being slightly different depending on the size of the experimental animals (RIM, 1982).
The entire life cycle requires 4-4,5 months, adult worms
having a life span of 10 years or longer (HARlNASUTA,
PUNGPAK& KEYSTONE,1993).
O. viverrini appears to be stenoxenous at first intermediate host level, with a marked specificity for aquatic
snails of the Fam. Hydrobiidae, Subfam. Bithyniinae belonging only to the genus Bithynia (subgenus Digoniostoma) (HARINASUTA,PUNGPAK & KEYSTONE, 1993).
Four closely related species or subspecies of this genus
have been so far recorded as first intermediate hosts: B.
siamensis siamensis, B. siamensis goniomphalus, B. siamensis laevis and B. funiculata. B. funiculata is easily
distinguished from B. s. goniomphalus by its more open
umbilicus and having a sharp basal keel, whereas B. s.
siamensis and B. s. laevis are mainly distinguished by
their ecological characteristics. These subspecies of B.
siamensis should be considered as ecological forms of
this snail species (WYKOFFet aI., 1965; DITRICHet aI.,
1992b). Each one of these snails act as first intermediate
host of O. viverrini in Thailand: B. s. goniomphalus in
the northeast, B. funiculata in the north and northwest,
and B. s. siamensis and B. s. laevis in the central area of
the country (WYKOFF et al.,1965; HARINASUTA,1969;
RIM, 1982; UPATHAM,1988; DITRICHet aI., 1992 b).
In Laos, B. siamensis goniomphalus has also been found
to be the snail species involved, whereas no infected specimen of B. s. siamensis and B. s. laevis could be found (GIBODAet aI., 1991; DITRJCHet al., 1992b), despite CHANAWONG& WAlKAGUL(1991) who demonstrated that B. s.
goniomphalus is 4-7 times less susceptible to O. viverrini
infection than B. s. siamensis and B.funiculata.
In Malaysia, BISSERU& CHONG (1969) described the
natural and experimental infection of a snail species belonging to the family Thiaridae, Melanoides tuberculata,
but, as already discussed by DITRICHet al. (1992b), their
parasite identification offers serious doubts (the cercaria
they described do not fit into the characteristics of O. viverrini cercariae).
Several species of fish act as second intermediate
hosts harbouring the metacercariae of O. viverrini.
160
In Thailand studies carried out have demonstrated that
there are not many fish species involved in the parasite
transmission in nature. The most important species are
Cyclocheilichthys siaja, Hampala dispar and Puntius
orphoides, which are prevalent in many provinces. The
other less important species of infected fish are Esomus
metallicus, Barbodes gonionotus, Puntius proctozysron,
P. viehoever, Labiobarbus lineatus, and Osteochilus sp.
(WYKOFFet al., 1965).
In Laos, recent studies in Vientiane province have detected up to seven different cyprinid species harbouring
metacercariae: Hampala dispar, H. macrolepidota, Barbodes gonionotus, Puntius brevis (= P. leiacanthusi,
Puntius sp. 1, Puntius sp. 2, and Cyclocheilichthys repasson (SCHOLZ,DITRICH& GIBODA, 1990; GIBODAet
al., 1991).
Epidemiology
The transmission of the parasite to the fresh-water
snail hosts is related to the defaecating habits of the definitive hosts, mainly man but also other fish-eating mammals, especially cats and dogs, in or near fresh-water collections where the appropriate snail and cyprinid fish
species are present. In highly endemic areas of Thailand,
Bithynia snails, especially B. goniomphalus, are always
available in water bodies. In these endemic areas, the absence of latrines in villages constitutes an important factor responsible for the propagation of the parasite, owing
to the habit of these people of defaecating on the ground
in the bush not far from their houses, many of which are
situated around the lakes, water beds, or on the banks of
the streams, so that contamination of the water by the faeces containing O. viverrini eggs takes place in the rainy
season (HARINASUTA,1969; RIM, 1982).
Man and other animals acquire the infection by ingestion of fish containing metacercariae. In northeast Thailand, for example, cyprinoid fish are an important source
of protein since they breed naturally and are available in
most water bodies, including flooded rice fields (SITHITHAWORNet al., 1994). The studies by WYKOFF et al.
(1965) already demonstrated that there are gi ven fish
species which develop a more important role in the
transmission to the definitive host than others. C. siaja,
H. dispar and P. orphoides are always available in water
collections in the highly endemic areas. Fish species
containing the largest average number of metacercariae
were P. orphoides (79 metacercariae per fish), followed
by C. siaja (26 per fish) and H. dispar (22 per fish). The
highest frequency of infection was in H. dispar (74%
prevalence), followed by P. orphoides (65%), C. siaja
(51 %) and P. viehoever (22%). In Laos, Cyclocheilichthys repasson appear to be the fish species most frequently involved (63%) and which carries the largest
metacercariae number (1-66; mean 15) (SCHOLZ, DITRICH& GIBODA, 1990).
Despite the low specificity of O. viverrini at definitive
host level, in nature man proves to be the most important
S.
MAS-COMA
& M.D.
BARGUES
definitive host species at least in endemic areas, and cats
and dogs appear to be the main mammal species assuring the maintaining of the parasite life cycle in areas
with little or no human infection.
Although transmission to man may occasionally result
from drinking water containing metacercariae from decomposed fish or from eating dried and salted fish, the
bulk of human infection is acquired through the consumption of raw or imperfectly cooked fresh-water fish,
which is a common food in all areas of heavy endemicity. Thus, culinary traditions are clearly related to human infection and explain differences of incidences and
prevalences which are detected among people from different origins. For instance, Thais, Laotians, Cambodians and Chinese inhabiting the northern portion of
northeastern Thailand (Udorn) exhibit different eating
habits which translate into marked prevalence differences. SADUN (1955) found that 50,4% of the Thais were
infected, whereas only 2,9% of the Chinese passed
Opisthorchis eggs with their stools. The Laos descendent people of northeastern Thailand and of lowland
Laos enjoy traditional dishes prepared from raw or undercooked cyprinoid fish, such as «Koi-pla», «Pla-sorn»
and «Lop-pia». This eating habit constitutes the main
mode of human infection by O. viverrini in both Thailand and Laos. The dish «Koi-pla», the most common
raw fish food eaten and a consuming habit practiced for
generations in that area, is eaten immediately after being
prepared and usually forms a part of the menu of any celebration, many of which are held by the local people.
This dish is sold in most markets of northeast Thailand
and consumed as often as three times a week (SADUN,
1955). Another popular food, eaten daily, is raw fermented fish «<Pla-ra»), which may also contribute to infection, but the ability of the infective stages to survive in
high salt concentrations remains unclear (SITHITHAWORNet al., 1994). Other raw fish food such as «Plalap», «Sorn-fak», and «Pla-kaw» are also consumed in
this region (SADUN, 1955). Contrarily, in another part of
Thailand, such as in Korat, people like to boil fish before
eating and, accordingly, very low infection rates are
found among them in spite of the fact they are near the
most endemic areas of the country.
At the present, in Thailand there are well-documented
data on the pattern of infection with 0. viverrini both
from hospital and community-based studies. The marked
prevalence and intensity differences which appear between different regions (northern and northeastern Thailand / central and south Thailand), as well as between
different villages and communities among a same endemic area, are related to local characteristics concerning
snail distribution (the discontinuous distribution of the
transmission foci is determined by the dependence of the
first intermediate snail hosts on fresh-water collections,
and consequently to the greater or lesser proximity to
such water bodies) and fish availability (transmission to
humans depending on eating habits), but also to treatment programmes carried out in recent years and to culi-
Human
liver flukes:
a review
nary changes introduced thanks to public health campains (SITHITHAWOR et al., 1994). Interestingly, studies mostly on agriculturalists showed that prevalence of
infection among people residing in villages far from rivers was higher (52,6% and 51,7% in males and females,
respectively) than those residing in villages on the banks
of the rivers (27,9% and 21,7% in males and females,
respectively), the infection level increasing sharply in
the 6-10 year-old age-group among people residing far
from the rivers, even despite the higher recording of raw
fish consumption in villages on the banks (TESA A et
al., 1991).
Within a given human community, the distribution of
o. viverrini is highly aggregated or overdispersed, so
that a majority of people harbour relatively light infections while a minority carries most of the worm population within heavy infections (HASWEEL-ELK1NSet al.,
1991; SITHITHAWORNet al., 1991). A maximum burden
of up to 7900 O. viverrini individuals has been found during autopsy in northeast Thailand, but infections with
less than 100 worms are much more common (SITHITHAWORNet al., 1994). In the future, light infections will
probably increase in frequency as praziquantel treatment
is applied more widely. Although infection can occur rapidly (UPATHAMet al., 1988), the accumulation of heavy infections may take much longer than in the past, as
a consequence of environmental constraints and behavioural change discouraging raw fish consumption (SITHITHAWORNet al., 1994).
Observations have been made concerning relationships of human infection by O. viverrini and year season,
human sex and age.
Transmission of O. viverrini from humans to fish via
snails is the net result of a complex interplay between
hosts and parasites that is invariably regulated by seasonal environmental conditions, especially water temperature and the duration and amount of rainfall (BROCKELMANet al., 1986). According to WYKOFF et al. (1965),
in Thailand the season appears to have definitive influence on infection intensity. During the dry season
(November-May), the ground becomes increasingly parched, wells go dry, and water becomes a valuable commodity. Whereas during the rainy season water bodies
act as convenient latrines, in the dry season the faeces
are deposited on the ground and the eggs fail to come in
contact with the snails. In the few remaining ponds, as
the water level falls, fishermen use large nets to remove
the confined fish. As the end of the dry season approaches, extremely few fish are left and most snails have
either died or have buried themselves beneath the surface. The trematode eggs die without reaching the water.
In May, when the rains start again, the drainage ditches,
ponds and canals begin to fill. The snail population increases quickly and fish soon refill the ponds. At this
time fresh faeces are washed or deposited into the water,
and the snails eat the eggs. For a period of at least a
month, while the cercariae begin to develop in snails, the
only source of human infection is the few fish which
161
may have been previously infected with metacercariae
and which may have survived the drought. After this
time, cercariae penetrate new fish and again a period of
at least 21 days is required for the full maturation of the
metacercariae. As soon as the metacercariae become infective, human reinfection commences. In addition to
those eggs already being passed from old infections, the
newly developed worms also begin passing ova. By the
end of the rainy season, large numbers of eggs are reaching the aquatic snails, thousands of cercariae are being
shed, and numerous fish are being infected. As the waters recede, fish are more easily caught and the number
of metacercariae being eaten by the human host is at a
seasonal high. Thus, most human infections are acquired
toward the last third of the rainy season and the first
third of the dry, for it is during this time (September to
February) that the fish harbour the largest number of metacercariae and toward the end of this season that they
are most easily caught. A similar seasonal pattern of metacercarial infection in cyprinoid fish occurs in both low
and high transmission areas: high burdens in the late
rainy season and winter (July to January) and low burdens during the summer (March to June) (SITHITAWORN
et al., 1997). Snails shed increasing numbers of cercariae
until the ponds once more become dry, in March.
In Laos, a similar seasonal character at snail level was
found in rice fields around the Vientiane capital, in
which there is a lack of water during the dry season,
snails appearing positive (shedding cercariae) from the
end of August to September and being negative in June
to the beginning of July. Contrarily, in water reservoirs
around Nam Ngum snails can be active thoughout the
whole year and cercarial development probably has not a
seasonal character (DITRICHet al., 1992b).
Concerning sex, BUNYARATVEJet al. (1981) found in
a nationwide survey that O. viverrini infection occurred
5 times more frequently in males than in females, and
UPATHAMet al. (1985) detected that the incidence was
also higher in males than in females, especially in children under 5 years of age. However, in epidemiological
studies there is often no difference in prevalence and
average intensity of infection between the sexes, although heavy infections are often more frequent among
males than among females (HASWEEL-ELKINSet al.,
1991; SITHITHAWORNet al., 1994).
In endemic areas, both prevalence and intensity of infection invariably increase with age, so that people contract the infection in early childhood (a 22% incidence
was already found among 1-4 year-old children by SADU , 1955) and afterwards the reinfection of the individual takes place repeatedly, leading to the accumulation
of heavy infections (RIM, 1982), reaching a plateau in
the age group 20 years old and older (UPATHAMet al.,
1982, 1984; HASWEEL-ELKINSet aI., 1991; SITH1THAWOR et al., 1991). But if this was the usual situation in
the past, more recently, however, infection patterns often
show a drop in prevalence and intensity among age
groups over 30, but these remain higher among the teens
162
and early 20s. These changing patterns may reflect lower
levels of participation
in treatment programmes
and in
heeding health education
messages
(SITHITHA WORN et
al., 1994).
Declines in average worm burden in the oldest age
groups (50 years plus) have been observed (HASWEELELKI S et al., 1991; SITHITHA WORN et al., 1991). This
may result from slowly-acquired
protective immunity or,
more likely, parasite-associated
mortality, since individuals with long-standing
heavy infections frequently develop cholangiocarcinoma
(ELKINS et al., 1990; MAIRIANG et al., 1992). Worth mentioning
is that declines in
egg output in older age groups are not usually observed,
suggesting that parasites in older individuals
tend to be
more fecund than those in younger people. This may be
in part due to density-dependent
constraints on egg production observed in heavy infections (SITHITHA WORN et
al., 1991; ELKINS et al., 1991). In addition, the pathological consequences
of infection,
which are associated
with age and parasite-specific
antibody level, may be advantageous
to the parasite,
increasing
egg production
and output (SITHITHA WORN et al., 1994).
Pathological
changes occur in the extra- and intrahepatic bile ducts and the gall bladder. The movement of
parasites along the biliary ducts results in adenomatous
hyperplasia
of the biliary epithelium
and thickening
of
their walls with fibrous connective
tissue, bile ducts becoming hypertrophied
and dilated. The worms themselves and their metabolic products cause mechanical
and
chemical irritation of the biliary epithelium
leading to
inflammation
and pathogenesis
of the biliary tract. Inflammation tends to be distributed extensively
in the gall
bladder, extrahepatic
duct, and in areas of the biliary
epithelium (TANSURAT, 1971; KLM, 1984).
Enlargement
of the liver is observed in most cases, especially in massive infections or malignant transformations. A large number of liver flukes will produce considerable hepatic changes. The gross hepatic pathology in
heavy infections
is characterized
by subcapsular
bile
lake dilatation on the liver surface (RIGANTI et al., 1989;
PAIROJKUL et al., 1991). The predominant
histopathological feature is a desquamation
of the epithelial cells of
the secondary bile ducts with inflammatory
cell infiltration. This leads to epithelial hyperplasia,
goblet cell metaplasia and gland formation, followed by adenomatous
hyperplasia
and periductal
fibrosis (TANSURAT, 1971;
BHAMARAPRAVATI, THAMAVIT & VAJRASTHIRA, 1978;
FLAWELL, 1981; KIM, 1984; RJGA TI et al., 1989; PAlROJK L et al., 1991).
Obstructions
of the biliary tracts by the worms cause
marked dilation at the distal ends, extensive hyperplasia
of the biliary system, and multiplication
of ducts with
glandular proliferation
of papillomatous
and adenomatous type. Bile retention in the liver cells is also seen. In
S. MAs-CoMA
& M.D. BARGUES
marked cases, necrosis and atrophy of the hepatic cells
and extensive formation of portal fibrous connective tissue are observed (RIM, 1982).
In early infections, however, there is no hyperplasia of
epithelium,
no proliferation
of fibrous connective
tissues, and the ducts are lined by a single layer of columnal epithelium.
The cellular infiltration
is secondary to
superimposed
bacterial infection. Suppurative
cholangitis is frequently
the end, and the infection may extend
into the parenchyma
of the liver tissue, causing hepatitis
with the formation of micro- and macroabscesses.
Macroabscesses
vary in size, ranging from 5 to 10 mm in
diameter.
In some cases, rupture of an abscess at the
right dome of the diaphragm into the right pleural cavity
and subsequent infection involving the lower lobe of the
right lung have been described (PRIJY ANONDA & TANDHANAND, 1961; TANSURAT, 1971; RIM, 1982).
O. viverrini can stimulate both systemic humoral and
cell-mediated
immune responses. Although flukes lodge
within the biliary mucosa and despite the absence of a tissue migration stage, vigorous parasite-specific
antibody
responses are stimulated
during infection (WONGRATANACHEEWIN et al., 1988; ELKINS et al., 1991). Immune
responses also appear to be associated
with pathology.
Lymphocyte
cell infiltration has been observed in some
areas of second-order
bile duct inflammation
in infected
individuals (PAIROJKUL et al., 1991). Recent studies have
found that gall bladder size and severity of hepatobiliary
disease are closely associated with levels of parasite-specific serum IgG (HASWELL-ELKINS, SATARUNG & ELKINS, 1992; MAIRIANG et al., 1992). T cell proliferative
responses are more frequent and marked among infected
people with accompanying
gall bladder abnormalities
than among those with no detectable damage (SITHITHAWORN et al., 1994). These immune responses do not lead
to parasite death nor confer substantial protection against
reinfection (FLAWELL, PATTANAPANYASAT & FLAWELL,
1980; SIRISINHA et al., 1983). The absence of protective
immunity may be attributed to several factors, such as
immunosuppression
by parasites and their metabolic products, as well as the resistance or evasion of parasites
from the host's immune responses. The resulting tissue
damage may even be beneficial to the parasite, causing
enhanced leakage of nutrients from the tissue into the biliary tract. Moreover, the damage may facilitate the uptake of parasite antigens and toxic products into the host
tissue circulation. The finding that high parasite-specific
antibody levels are associated with gall bladder enlargement as well as increased parasite fecundity supports the
suggestion
that immune responses benefit the parasites
(ELKI S et al., 1991).
It is becoming increasingly
clear that the immune response plays a role in the hepatobiliary
disease caused by
O. viverrini. It is possible that the parasite benefits from
the immunopathology,
since it may result in the crossing
of serum proteins or other nutritional
components
into
the bile for the parasite's
usage. The immune response
does not appear to effectively
eliminate the flukes, and
the non-malignant diseases, since they are asymptomatic, do not appear to affect host activity. The fact that
these immunological pathways may lead to the development of cholangiocarcinoma (see below) and subsequent
death after 20-40 years of infection may not be a high
price for the parasite population, but a tremendous human price in both social and economics terms (SITHITHAWORNet al., 1994).
The liver function test, blood examinations, and biochemical analysis do not give any significant information in connection with the diagnosis, severity, and prognosis of this infection (HARINASUTAet al., 1966). From
the haematological and biochemical points of view, O.
viverrini infection does not cause any specific symptoms
in endemic regions (WYKOFF, CHITTAYSOTHORA &
WINN, 1966).
The clinical involvement depends upon the number of
the worms present in the liver and the duration of infection. The majority of cases are symptomless. Clinical
manifestations are seen in patients over 30 years of age
(HARINASUTA,PUNGPAK& KEYSTONE,1993). Mild infections (less than 100 worms) are usually asymptomatic
or with a few symptoms, occasional flatulent dyspepsia
being, in some instances, the only complaint. There are
episodic symptoms of dull pain and discomfort in the
right hypocondrium, with occasional spread to the epigastrium and left costal region. These pains usually last
for several days to weeks and recur over months or years. Liver function is generally normal (PUNGPAK,BUNNAG& HARINASUTA,1983). As the disease progresses,
pain becomes persistent. In moderate infections there are
diarrhea or loose stools, dyspeptic flatulence after meals,
pain over liver region and moderate fever (37,5-38,5° C)
in many patients, jaundice in a moderate degree found
frequently, and enlarged liver of firm consistency in
most cases. The gall bladder also is enlarged and is
found infrequently on palpation. Blood examination
shows no anemia. Frequently a peculiar hot sensation is
felt on the skin of the abdomen, which bears no relationship to segmental nerve supplies. It is often felt in a
small area overlying the liver, the back, or sometimes
the whole abdomen. Other symptoms include loose bowel movements, poor appetite, lassitude, and weight loss
(HARINASUTA,PUNGPAK& KEYSTONE,1993). Ultrasonographic examination revealed PUNGPAKet al. (1989)
normal findings in 80,6% of subjects and abnormalities
at the following rates: liver enlargement in 14,8%, dilation of the gall bladder in 3,5%, sludge formation in
2,1 %, thickening of the wall of the gall bladder in 1,0%,
gallstones in 1,0% and dilation of the intrahepatic bile
ducts in 0,1 %. While gallbladder enlargement is not sexspecific, the prevalence odds of sludge presence, irregular gallbladder wall, liver enlargement, and enhanced
portal vein radicle echoes (the latter suggesting chronic
inflammation and fibrosis of bile ducts) appear 2-3 times
more among males than females (ELKINS et al., 1996).
In heavy, long-standing infections there are hepatic cirrhosis, ascites, edema of the legs, prominent abdominal
163
pains, and occasionally carcinoma (HARlNASUTA& VAJRASTHIRA,1960, 1962; WYKOFF, CHITTAYSOTHORA
&
WINN, 1966). A study by PUNGPAKet al. (1985) on patients with severe O. viverrini infection showed that
there was no correlation between severity of the disease
and the faecal egg output and that the clinical manifestations were: severe jaundice (46,6%), mild jaundice
(4,5%), associated secondary infection of the biliary system (25,0%), cholangitis (29,5%), intraabdorninal mass
(53,4%), enlarged liver (42,0%), liver adenocarcinoma
(18,2%), high bilirubin transaminase (78,0%), and low
serum albumin (62,9%).
Morbidity in O. viverrini infection is almost paradoxical. Few infected people, even among those with heavy
infection, suffer detectable signs or symptoms by physical examination. Thus, the actual rate of «morbidity» or
illness caused by infection is quite low, but this does not
mean that the parasite is non-pathogenic. Unfortunately,
the asymptomaticity of O. viverrini infections becomes
extremely dangerous and, via its enhancement of carcinogenesis, a leading cause of death among northeast
Thais. The frequency of hepatobiliary abnormalities, e.g.
gall bladder enlargement and poor function, and simultaneously the odds of cholangiocarcinoma, rise sharply
with intensity of infection. The true impact of this increased risk is clear from the Khon Kaen Cancer Registry,
which reports the highest incidence of liver cancer in the
world (SITHITHAWORNet al., 1994).
As already stressed by SITHITHAWORNet al. (1994),
worth mentioning in Khon Kaen, northeastern Thailand,
is the elevated incidence of cholangiocarcinoma or bile
duct cancer, which usually accounts for only a minority
of liver cancers (most of which are hepatocellular): 89%
of liver cancers are cholangiocarcinoma, its age standardized incidence rate being 84,6 and 36,8 per 100.000
males and females, respectively. In the northern province of Chiang Mai, Thailand (second highest incidence area, possibly associated with northeastern migrants), where O. viverrini infection is comparatively
rare, reported age standardized incidence rates are 6, I
and 4,8 per 100.000. In Hong Kong (third highest incidence area), where Clonorchis sinensis is present, rates
are 5,4 and 3,1 per 100.000. In other regions incidences
are below 2 per 100.000. This means that Khon Kaen experiences a 20- to 90-fold increase in the frequency of
cholangiocarcinoma,
compared to areas without liver
fluke infection.
Since cholangiocarcinoma and O. viverrini are concurrently prevalent in northeastern Thailand, the geographical relationship is clear and has been recognized for
many decades. Moreover, additional support on this relationship has been recently obtained. Concerning the
relationship between serological evidence of infection
and cancer, PARKIN.et al. (1991) found a significanlty
higher frequency of elevated liver fluke antibody among
their cases with cholangiocarcinoma compared to controls. Concerning the relationship between infection intensity and cancer risk, studies have demonstrated that
164
the frequency of cholangiocarcinoma is so high within
heavily infected communities that pre-symptomatic cases could be detected even within small villages. Larger
cross-sectional studies were therefore undertaken by research groups to identify cases of cholangiocarcinoma
prior to obstruction, when egg output can be accurately
measured (eggs cannot pass through a bile duct completely obstructed by the presence of a tumour). Ultrasound
and endoscopy were used to diagnose asymptomatic
cholangiocarcinoma and measure cholangiocarcinoma
prevalence among groups with differing intensity of infection. A number of cases were identified prior to the
onset of obstruction and jaundice, and therefore levels of
exposure to the fluke were measurable among those with
cancer and those without (SITHITHAWORNet al., 1994).
Worth mentioning are the sex- and age-related studies
which have demonstrated a much higher prevalence of
cholangiocarcinoma among people with heavy infections (> 6000 eggs/g) compared to those not excreting
eggs. The frequency was moderately elevated among
those excreting 1000-6000 eggs/g. Interestingly, males
were more likely to have cholangiocarcinoma than females, which confirms a sex-associated difference in cancer
susceptibility given equivalent exposure. Not surprisingly, older individuals (>50 years) were more frequently affected than middle aged (35-49 years) and
those aged 24-34 (SITHITHAWOR et al., 1994).
But if it appears clear today that O. viverrini infection
leads to cholangiocarcinoma, the question arises as to
why such closely related flukes as O. felineus or C. sinensis are not similarly carcinogenic. Possible reasons
could perhaps be found in aspects such as genetic variation in the parasites themselves, varying parasite distribution patterns, duration of the infection, differences in
praziquantel treatment application, other environmental
factors and host-associated factors such as nutritional
status and genetics. Comparative studies are needed on
these questions (SITHITHAWORNet al., 1994).
Diagnosis
In the endemic area of southeastern Asia, all patients
complaining of flatulent dyspepsia, pain over the liver
region or enlarged liver, and diarrhea or loose stools are
clinically suspected to present O. viverrini infection. The
definitive diagnosis is made by finding the characteristic
eggs in the faeces or duodenal aspirates: Worth mentioning is the necessity of a differential diagnosis with C.
sinensis, whose eggs closely resemble those of O. viverrini in size and shape (RIM, 1982; DITRICH et al.,
1992a) and whose endemic region largely overlaps with
that of O. viverrini in southeastern Asia, so that the possibility of confusion in specific determination through
eggs is evident. Fortunately this is not the case with O.
[elineus, from which it can be differentiated by the geographical separation of the endemic region (human infection by O. felineus is known from countries of the old
USSR) and by the ratio of the mean length over the
S.
MAs-CoMA
&
M.D.
BARGUES
mean breadth of the eggs (1,75 in O. viverrini; 2,75 in O.
felineus) (RIM, 1982, HARINASUTA,Pu GPAK & KEYSTO E, 1993) although not differentiable by their morphology and absolute measures (WYKOFFet al., 1965).
The sensitivity of the coprological technique is of utmost importance, mainly because of the limitations of all
techniques to detect very light infections. A comparative
study of three major egg counting techniques indicated
that the formalin ethyl acetate concentration method and
Stoll's dilution technique were approximately equally
sensitive, while the Kato faecal thick smear technique
was markedly less effective in detecting light infections
(SITHITHAWOR et al., 1994). Furthermore, it has been
suggested that as much as 10-15% of infections may be
underdiagnosed by a single reading using even highly
sensitive techniques such as the formalin ethyl acetate
concentration method and Stoll's method (SITHITHAWORNet al., 1991). This lack of sensitivity is particularly pronounced when the worm burden is less than 20
and hence egg output in the faeces is not detectable.
Coupled with the nature of fluke distribution in the human population, whereby most infections are light, this
lack of sensitivity may cause considerable underestimation in prevalence surveys (SITHITHAWOR et al., 1994).
Interestingly, the quantitative faecal egg count by Stoll's
technique shows a strikingly close positive correlation
with the number of worms recovered in autopsies, indicating a strong linear association between eggs/g of faeces and worm burden and thus being useful for the determination of infection intensity (SITHITHAWORNet al.,
1991). Flotation techniques appear to be inappropriate
for the detection of O. viverrini eggs in faeces or contaminated soil (HARNNOlet al., 1998).
Although immunodiagnosis would be useful in situations in which eggs may not be present in the stool, such
as in light infections, biliary obstruction or during the
prepatent period, immunodiagnostic techniques are not
generally available (HARINASUTA,PUNGPAK & KEYSTONE, 1993). The indirect immunofluorescent antibody
technique gave only relatively satisfactory results (BOONPUCKNAVIG,KURATHONG& THAMAVIT,1986). New
advances utilizing faecal-based antigen detection are likely to facilitate diagnosis in the future. ELISA, monoclonal antibody-based ELISA, and DNA hybridization
are techniques being developed and evaluated for their
potential in the detection of O. viverrini infection in humans (SRIVATANAKULet al., 1985; WONGRATANACHEEWI et al., 1988; POOPYRUCHPOG et al., 1990; SIRISI HA et al., 1991; CHAICUMPAet al., 1992). Care must
be taken with possible cross reactions with other humaninfecting flukes present in the O. viverrini endemic zones, as already observed by ELKI S et al. (1991) who
found significant associations between antibody levels
measured by ELISA and echinostome infection.
To determine whether certain tumor markers are elevated in Thai patients with cholangiocarcinoma,
and
thus might be useful in the diagnosis of cholangiocarcinoma associated with O. viverrini infection in Thailand,
the tumor markers CA 125 and CA 19-9 were measured
by radioimmunoassay
in serum samples (PUNGPAK et
al., 1991). These preliminary results suggest that the measurements of CA 125 and CA 19-9 may be useful in the
early detection of O. viverrini-associated cholangiocarcinoma.
Actually, cholangiography,
bile examination
and ultrasonography
are additional
techniques
employed
for
the diagnosis of O. viverrini infected patients (PUNGPAK
et al., 1989; DAO, BARNWELL & ADKINS, 1991; MAIRIANG et al., 1992; HARINASUTA, PUNGPAK & KEYSTONE, 1993). Portable ultrasonography
has proved to be
a reliable noninvasive
technique in the evaluation of the
morbidity
due to O. viverrini infection in rural areas
(Pu GPAK et al., 1997).
Treatment
Trials on Hetol (1,4-bis-trichloromethylbenzole)
in
humans showed that the eggs disappeared
within 3 weeks, suggesting
that Hetol was highly effective against
O. viverrini (HARI ASUTA et al., 1966; Bu
AG et al.,
1970), but this drug was later withdrawn for human use
by the manufacturers
following reports of chronic toxicity on dogs and sheep (RIM, 1982). Later, dehydroemetine showed to be significantly
effective. Oral administration of late release tablets of dehydroemetine
at a dose
of 2,5 mg/kg on alternate days over a 2-month period
gave 84,9% mean egg reduction rate at the follow-up 6
months after treatment (MUANGMA EE et al., 1974). Niclofolan, which has a remarkable therapeutic effect on C.
sinensis (RIM, 1972; RIM & LEE, 1979), appears to be
ineffective against O. viverrini infection (RIM, 1982).
In recent years, praziquantel
has become the drug of
choice for the cure of O. viverrini infection. Praziquantel is very effective. A 100% cure rate can be obtained
with a dosage of 25 mg/kg three times in a single day
(BUNNAG & HARINASUTA, 1980; AMBROISE-THOMAS,
WEGNER & GOULLIER, 1981). A single dose of 40 to 50
mg/kg is more convenient
for mass therapy and yields a
91-95% cure rate (Bu NAG & HARINASUTA, 1981). A
single dose of 50 mg/kg gave a cure rate of 97% in heavy infections (10800-139000
eggs/g of faeces) (PUNGPAK, Bu
AG & HARINASUTA, 1985). A transient but
important
rise of faecal egg output after praziquantel
treatment
(from 180 eggs/ml of duodenal juice before
treatment
to 3486 eggs/ml
12 h after treatment)
has
been observed (RIGANTI et al., 1988). Side effects with
praziquantel
are mild and transient and include diarrhoea (54,5%),
dizziness
(36,4%),
sleepiness
(27,9%),
epigastric
pain
(25%),
headache
(16,2%),
nausea
(13,2%) and anorexia (Pu GPAK, Bu
AG & HARINASUTA, 1985). Although eggs disappear in a week, symptoms and signs may take a few months to subside
(DHIENSIRI et al., 1984). An ultrasonographic
study earried out by Pu GPAK et al. (1989) in O. viverrini infected patients who had been treated with praziquantel
(40
mg/kg) during 1981-1896 (treatment being repeated an-
165
nually in those reinfected),
demonstrated
that the reinfection rate was 53,9% in the first year and gradually
declined. The findings by MAIRIANG et al. (1993) suggest that gall bladder abnormalities
are reversible following elimination
of liver fluke infection
with praziquantel (40 mg/kg), but malignancies,
once initiated,
are not likely to be affected by treatment.
Patients recently treated with praziquantel
had higher odds of abnormalities
compared
with others with the same infection status who were untreated (ELKINS et al., 1996).
Satisfactory
resolution
of morbidity was observed during two years follow-up after treatment with praziquantel, with significant
clinical improvement,
normalization of laboratory
parameters,
and downgrading
of
ultrasonographic
abnormalities
(PUNGPAK et al., 1997).
According to SITHITHA WORN et al. (1994), praziquantel utilized in community-based
treatment programmes
can help reduce prevalence and intensity of infection, as
well as the frequency of gall bladder disease, but, despite
its widespread use, the frequency of cholangiocarcinoma
do not appear to decline and it may be decades before a
decline is realized. The recent findings that younger people, teenagers and those in their twenties, may not be cooperating in control programmes
as much as older individuals, is of great concern, taking into account evidence
suggesting that in some cases malignancy
becomes manifest 10-20 years after halting infection. If these age
groups maintain infection into their thirties and forties,
the upcoming generation may not escape the high mortality toll associated with this liver fluke.
Other drugs such as albendazole and mebendazole
are
also effective. Mebendazole
at 30 mg/kg for 20-30 days
yielded cure rates of 89-94% (JAROONVESAMA, CHAROat a doE LARP & CROSS, 1981), whereas albendazole
sage of 400 mg twice daily for 3 and 7 days cures only
40% and 63%, respectively
(Pu GPAK, Bu NAG & HARI ASUTA,1984)
In patients with obstructive
jaundice,
palliative surgery in the form of a choledocal
jejunostomy
is often
required. In cases with septicemia,
cholangitis,
or cholecystitis, appropriate
antibiotics
should be given (HARI ASUTA, PUNGPAK & KEYSTONE, 1993).
The prevention
and control measures to be taken in O.
regions are related to the characteristics of the life cycle and should include the control of
snail hosts, health education,
treatment of infected persons and domestic animals, elimination
of human and
animal faeces, and protection of fish-inhabited
water bodies from contamination.
In recent years, important efforts have been made within national control programmes
in Thailand, the prevalence by O. viverrini having been reduced from 34,6% in
1981 to 24, I % in 1991 in the northeastern
part of the
country (RIM et al., 1994). In these control programmes,
emphasis has been given and positive results have been
viverrini endemic
166
obtained with measures directed toward the changing of
the habits of eating raw fish food (especially «Koi-pla»,
a popular and common food everywhere in northeast
Thailand), teaching the villagers to build and use latrines, human treatment campaigns with praziquantel, health education and sanitation improvement.
SAOWAKO THA et al. (1993) studied the effecti veness
of the intervention measures of giving praziquantel treatment (40 mg/kg) to all infected people either once (village I) or twice (village II) per year with integration of
regular health education and sanitation improvement. A
control village (village III) received no intervention during the study. The incidence rate per 6 months in the
two treated villages was lower than that of the control village. Marked improvement in knowledge of opisthorchiasis, behavioural changes of eating raw fish and increased numbers of latrines was evident in all of the
villages. The study showed that the effectiveness of annual drug treatment is similar to that of 6-monthly treatments when combined with regular health education and
sanitation improvement. FUNGLADDAet al. (1989) already suggested that a primary health care approach can be
used, before and after treatment with praziquantel, as a
strategy to control liver fluke infection in rural areas.
An interesting one-year investigation on re-infection
rates was carried out by SORNMANlet al. (1984). In villages where selective population chemotherapy was
combined with improvements in sanitation and health
education aimed at changing food habits, the mean
monthly re-infection rate was 2,0% and the annual cumulative rate was 21,5% whereas in another village,
where only selective population chemotherapy was carried out, both rates were 5,0% and 55,5% respectively.
Another study on re-infection rates after chemotherapy
made by UPATHAMet al. (1988) showed that subjects
with high pre-treatment intensities of infection tended to
have heavier intensities of re-infection, about twice that
of those who were negative or had only light infection
before treatment, indicating that some people are predisposed to heavy infections. The re-infection rate was markedly higher than concurrently and previously measured
natural incidences of infection. These findings suggest
that chemotherapy would have to be applied several times a year in order to control opisthorchiasis, and that it
might be more cost-effective to preferentially treat heavily infected individuals.
Unfortunately, despite the decrease in prevalence and
intensity among age groups over 30 years owing to the
national control programmes, the infection levels still remain high among the teens and early twenties, which
suggests lower levels of participation in treatment programmes and in heeding health education messages.
Special attention should be focused on this group in future control efforts. Otherwise this age group may remain at high risk of developing cholangiocarcinoma later in life (SITHlTHAWORNet al., 1994).
As can be observed, up to the present all significant efforts have been made at human level. Much remains to
be done concerning additional but important control measures which can be implemented at snail, fish and mammal reservoir host levels.
OPISTHORCHIS
FELINE US
Morphology
Opisthorchis felineus is a species very close to O. viverrini from the morphoanatomical point of view. The
adult stage of O. felineus presents the same general
morphological characteristics as O. viverrini. However,
several differences have been distinguished by several
authors (see review in WYKOFFet al., 1965). O. felineus
adults are 8-18/1 ,2-2,5 mm in size and consequently larger than O. viverrini adults. Another difference can be
observed at the level of the oesophagus, which is prominent and more elongated in O. viverrini. Concerning genital organs, in O. felineus there is a longer distance between the anterior testis and ovary, a less marked
lobulation of the testes, the location of the posterior testis farther from the tip of the caecum, the longer and
more winding seminal vesicle, a less lobed ovary, and a
distribution of the vitelline follicles not being aggregated
in a few clusters.
Eggs can also be distinguished owing to their different
size and shape, those of O. felineus being of 21-36/1117 urn (mean 30/14 urn). These dimensions clearly overlap those of O. viverrini eggs, the difference being found
at the length/width ratio, which is 2,75 for O. felineus
and only 1,75 in O. viverrini (SADUN, 1955; RIM, 1982;
DITRICH, GTBODA & STERBA, 1990; HARINASUTA,
PUNGPAK & KEYSTONE, J 993). Recent studies using
electron microscopy have demonstrated that the eggshell has a musk-melon ultrastructure which appears to
be similar in both species (BEER, GIBODA & DITRICH,
1990; SCHOLZ,DITRICH& GIBODA, 1992).
It must be pointed out that WYKOFFet al. (1965) examined each character in a large sample and could confirm that these characters varied considerably, most likely representing the extent of contraction at the time of
fixation. These authors concluded that while some of the
characteristics (such as the nature of the seminal vesicle)
may tend to be present more frequently in one than in the
other species, the differences appeared to be neither consistent nor specific enough to permit a clear differentiation at adult stage level. Further comparative studies
with modern techniques (DNA sequencing, isoenzyme
electrophoresis, etc.) are evidently needed in this respect. Fortunately, there is apparently no danger of confusion thanks to the different, non-overlapping geographical distribution areas of both Opisthorchis species.
The adult stage lives mainly in the larger bile ducts,
gall bladder and pancreatic ducts. In humans it has an
Human
liver flukes:
a review
hepatic location, but in heavy infections worms are also
found in the pancreas (lMAMKULlEY,1971).
It is a natural parasite of fish-eating mammals, mainly
the cat, red, silver and polar foxes, and domestic and
wild hogs, but also dogs, wolverine, marten, beaver,
common otter (Lutra lutra), European polecat tMustela
putoriusi, Siberian weasel (Mustela sibiricay, sable
(Martes zibellinay, as well as rodents such as the Norway
rat (Rattus norvegicus) and Water vole (Arvicola terrestris), lagomorphs like the rabbit (Oryctolagus cuniculus), and pinnipeds such as three species of seals (Phocidae), the Grey seal tHalichoerus grypus), Caspian seal
(Phoca caspica) and Bearded seal (Erignathus barbaIUS); in captivity even the lion (Felis leo) has been mentioned (ERHARDT,GERMER& HbR ING, 1962; BOCHAROYA, 1976).
Reports in humans
Although man may be considered an accidental host
from the point of view of the life cycle of the parasite,
this liver fluke is now known to infect approximately
1,2 million people in Russia and 1,5 million in the former USSR, according to the latest estimates (RIM et al.,
1994).
In spite of the large geographical distribution of this
species, covering from central Europe (Italy, Switzerland, Germany, the etherlands), in the west, to the extreme northern regions, the western Siberian lowlands
and Kazakhstan up to the Lake Baikal, in the east (ARTAMOSHIN& FROLOYA, 1990; ZAYOIKIN, 1991), it is
worth mentioning that human infection is not known to
occur east of Poland and the Danube delta (ERHARDT,
GERMER& HbRNING, 1962; RIM, 1982), although sporadic isolated human cases cannot be disregarded in central Europe (BERNHARD,1985).
The disease is endemic with involvement of humans,
domestic animals, and wild animals in an area that covers nearly all the territory of the former USSR, with the
exception of the northern part of central and eastern Siberia, the far-eastern region, the Caucasus, and the former Republics of middle-east Asia (WHO, 1995). Up to
nine main human opisthorchiasis endemic regions, all in
the former U.S.S.R., can be distinguished:
I) Western Siberia: the basins of the rivers Ob and Irtysh
constitute a very large endemic zone in which the
prevalence of infection reaches 90-95% for man, and
50-100% in animals (ZAYOIKIN, 1991; ZAYOIKIN,
DARCHENKOYA& ZELYA, 1991);
2) Kazakhstan: several zones are endemic, such as the
Aktyubinsk, Dzhezkzgan, Karaganda, Pavlodar, Tselinograd, and Turgay districts; the population at risk is
227000 people, and of these the estimated number of
infected is about 49000 (WHO, 1995); human surveys
on opisthorchiasis along the Irtysh river in the Pavlodar region have shown prevalences up to 14% (GORBUNOYAet al.,1988); less important data were recorded in the Dzhangeldinsk Region (SMAILOYA,1990);
167
3) Eastern Siberia: human opisthorchiasis foci have been
detected from the Krasnojarsk Territory (GONCHAROYA, 1992; ZELYA& GERASIMOY,1992) to the AItai Territory (NIKITIN & KUIMOYA,1992) and the Irkutsk region, at the Lake Baikal (ZHITNITSKA
YA et
al., 1988);
4) The basin of the river Kama: situated west of the Central Ural Mountains, there is another endemic region;
a detailed statistical study of opisthorchiasis carried
out in the Komi-Permyak Autonomous Region, in
1985-87 by BRO SHTEI et al. (1989) showed high
prevalences: 58,3% in man, 79,7-85,5% in fish, 86%
in cats, and 2,5% in snails; Opisthorchis eggs were
present in 68% of soil and 57% of silt samples; in the
Kirov region, at the basin of the river Vyatka, a tributary of the Kama river, the parasite was found in 2951 % of the cats (burdens 1-519) and 5% of the first
intermediate snail host (MALKOY, 1991);
5) Central Ural Mountains: in the middle Urals, large
foci of human opisthorchiasis (humans: average
14,5%, in some foci up to 68%; cats: 83,4%) are
found in areas located in the basins of the rivers
Lozva, Sosva, Tavda, Tura and Pyshma (the Tobol river basin); human and animal infections are particularly high in Serov, Gari, and Tabory districts of the
Sverdlovsk region (CHURINA, 1973), which in fact
constitutes an endemic zone continuation of the river
lrthysh endemic area;
6) The basin of the river Volga: it appears that prevalence
of opisthorchiasis has increased on account of construction of dams and the creation of reservoirs suitable
for breeding both the snail and the fish hosts, as in the
Rybinsk, Gorky, and Kouybyshev reservoirs (IzyOUMOYA,1959); human infection is detected also in the
Volga delta (SEMENOYA& IYANOY,1990);
7) The Moscow region: autochtonous infection in inhabitants of the Moscow and Vladimir regions has been
reported by BRONSHTEI & BEER (1988);
8) Ukraine: there are different foci, the infection rates
varying between 0 and 82%; the Sumy region is a
well-known endemic area of opisthorchiasis, which
comprises the River Dnepr and its eastern tributaries:
Desna, Sejm, Sula, and Vorskla; another but less important endemic zone is the basin of the southern Bug
river, the Dnestr, and the northern Donets (GRITSAY
& YAKUBOY,1970); a total of 96 village foci of human infection were detected in 1984-88 in a vigorous
opisthorchiasis programme carried out in the Chernigov region, at the Desna river, by NESTERENKOet at.
(1990); prevalences of 0-61 % were recorded in the
Sumy, Chernigov and Poltava regions (ZAYOIKINet
al., 1989b). A review of the geographical distribution
of opisthorchiasis in Ukraine has been made by PADCHE KO& LOKTEYA(1990);
9) Bielorussia: foci of opisthorchiasis have been found
in the Brest, Gornel, and Grodno provinces (WHO,
1995); the highest prevalence of infection was recorded in villages in the Dnepr basin and the lowest in
168
the Pripyat and Neman river basins (SKRIPOVAet al.,
1991).
Forty-six per cent of the territory of the Russian Federation is endemic for opisthorchiasis and nearly 84% of
the population of the country reside in these areas. In
1992, opisthorchiasis was endemic in 24 out of 77 administrative territories; imported cases were registered in
38 others, and in 15 territories no infected people were
found. The only places where there is a risk of acquiring
infection are the river basins where 10% of the total population (approximately] 2 million people) reside. The
health services examine about 200000 people each year;
40000-95000 cases of opisthorchiasis were registered
annually between 1986 and 1992 in the river basin areas
(WHO, 1995).
This species infects several species of fish-eating
mammals in southern, central, and eastern Europe, i.e.
Italy, Albania, Greece, Switzerland, Holland, Germany,
Poland, and the European part of the former USSR
(Ukraine and Bielorussia), and in Asia it is present in
Turkey, in areas east of the Urals up to eastern Siberia
(ERHARDT, GERMER & HORNING, 1962; ZAVOIKl ,
1991; WHO, 1995). The distribution of O. felineus in
freshwater fish and human opisthorchiasis do not coincide; human infection occurs at some distance from the
main endemic areas because of the natural fish migration
patterns and transport of fish for sale (WHO, 1995).
Life cycle
O. felineus follows a fresh-water three-host life cycle,
whose development pattern is the same as in C. sinensis
and O. viverrini. Embryonated eggs are excreted with the
faeces of the definitive host. Once in water, hatching does
not occur until after ingestion by a snail belonging to a
specific species. The miracidium hatches and penetrates
the wall of the snail digestive tract to metamorphose to
the following larval stage of sporocyst. Sporocysts develop near the lower intestine and in about 1 month give
rise to rediae, which migrate to the region of the digestive
gland. The rediae produce cercariae which are shed while
still immature (VOGEL, 1934). The prepatent period in
the snail is from 2 months (VOGEL, 1934) to 4-4,5
months (BLYUZNYUK,1963). The liberated cercaria is
characterized by pigmented eye spots, ten pairs of penetration glands with ducts opening dorsal to the mouth and
a flame-cell formula of 2[(5 + 5) + (5 + 5 + 5)] (WYKOFF
et al., 1965). Its body measures ] 32-172/41-48 urn and
the tail is 400-500 um long. The unforked tail has a transparent, integumentary, rudder-like sheath. The cercariae
are phototactic and geotactic, tending to settle and live at
the bottom with intermittent periods of swimming. The
positive phototaxis stimulate cercariae emergence from
the snail in daylight hours, during the period of maximum
activity of fish, their second intermediate host. Simulta-
neously, positive geotaxis directs them into the deeper
water where these benthophagous fish also usually live
(VOGEL, 1934). When the mature cercariae come in contact with a suitable species of fish, they attach themselves
to the scales, lose their tails, and penetrate the tissues,
where they encyst. These cysts measure 213-2301147197 urn and the metacercariae when removed from the
cyst have a length of 340-590 urn. In fish, the metacercariae mature in approximately 6 weeks at 18-20° C and,
after ingestion by the suitable host, they excyst in the
duodenum. When ingested by humans or other fish-eating mammals, the metacercariae excyst in the small intestine and migrate to the distal bile ducts, where they
mature and produce eggs (HARINASUTA,PUNGPAK&
KEYSTONE,1993). Adults require no less than a month to
reach sexual maturity (VOGEL, 1934) and are able to live
in the host for 10 years or more.
Only three fresh-water hydrobiid snail species pertaining to the genus Codiella have been reported as intermediate hosts of O. felineus: C. inflata (synonym: Bithynia inflatai, C. troscheli and C. leachi. C. tentaculata
(considered a synonym of C. leachi by several authors)
has also demonstrated its capacity to transmit at least experimentally.
Among them, C. inflata appears to be the most important in the transmission. Interestingly, however, cross-infection experiments carried out by BEER & GERMAN
(1987) demonstrated that there are geographic strain differences in the compatibility between O. felineus and C.
inflata.
A recent taxonomic review of the Hydrobiidae Bithyniinae considers the group at family level (Bithyniidae)
and redistributes the species in different genera: Bithynia
tentaculata, Codiella leachi, Opisthorchophorus troscheli, and Opisthorchophorus hispanicus (syn.: Bithynia
inflata, Codiella inflata) (BERIOZKINA,LEVINA & STAROBOGATOV,1995).
The following species of fresh-water cyprinoid fish
have been recorded as second intermediate hosts of 0.
felineus: Abramis balerus, A. bramae, A. sapa, Alburnus
alburnus, Aspius aspius, Barbus barbus borysthenicus,
Blicca bjoerkna, Carassius carassius, Chondrostoma
nasus, Cobitis taenia, Cyprinus carpio, Gobio gobio,
Leucaspius cephalus, L. delineatus, Leuciscus idus, L.
leuciscus, Phoxinus chekanowskii, P. phoxinus, Polecus
cultratus, Rutilus rutilus, Scardinius erythrophthalmus
and Tinea tinea (WHO, 1995).
Epidemiology
The habits of the definitive hosts, mainly man but also
other fish-eating mammals, of defaecating in or near
fresh-water
collections
where the appropriate
snail and
fish species are present, allow the infection of the aquatic snails by eating the eggs. The snail hosts are infected
by faeces containing the eggs deposited on sandy shores
and washed into streams. Studies by DROZOOY (1962)
demonstrated
that about 50% of the eggs remain viable
for a period of 160 days in river water at 0-5° C, and
thus, many can overwinter
in rivers and streams, whereas in dried faeces they remain viable for only up to 3
days at a temperature
of -24°C, and for up to 12 days at
_3° C. According to BEER (1975), the snail infection rate
in water bodies depends upon the population density of
molluscs and the degree of remoteness
of the water bodies from the sources of the invasion. The seasonal dynamics of the extensiveness
of snail invasion is characterized by a one-peak curve. The peak is observed in late
July, the spring period presenting the greatest epidemiological danger.
Studies by BEER, ZELYA & ZAYOIKIN (1987) on the
distribution
and ecology of the most important intermediate snail host species, Bithynia inflata, in the Poltava
region, Ukraine, showed that this snail species is not regularly
distributed,
but has a mean density
of 26
snails/m", which ranges from 0,1 to 600 snails/m". Its population density in small rivers was dependent
on the
amount of vegetation
and on the relationships
between
floating and submerged
plants. B. inflata was absent or
very rare in sites devoid of vegetation
or where large
above-water
macrophytes
predominated.
Snails infected
with O.felineus were found only in waters close to villages where infection was present in man or cats.
According to KRIYE KO et al. (1981), O. felineus eggs
obtained from man, cat, dog, pig, and golden hamster
had similar biological properties (size, original viability
and survival
periods in soil and water). The largest
amount of infective material was passed by man (82,5
and 96,5% of the total number of eggs shed into the environment of 2 villages), with cats in second place (3,36
and 15,8%); dogs and pigs shed relatively small numbers
of ova.
The effects of hydrobiological,
physical-geographical
and anthropogenic
factors on O. felineus infection in the
population were analysed by PL YUSCHEYA et al. (1990).
Changes in the water regime of a river affect the moll uscan hosts and this results in changed prevalence rates in
the human population within the distribution
area of the
intermediate
hosts, but not new foci outside it. The creation of reservoirs in river basins, which are unfavourable
for opisthorchiasis,
results in the desinfection
of the reservoirs in the first 5 to 7 years. Later, during the formation of the reservoirs, as a result of the restoration of the
biotopes in which gastropods
develop, an opportunity
for the restoration of opisthorchiasis
foci arises (lZYOUMOYA, 1977).
Man and other animals acquire the infection by ingestion of fish containing
metacercariae.
O. [elineus infection is contracted
by the consumption
of raw or insufficiently cooked fish (fresh-salted
fish, most frequently of
169
the first day of salting, dried in the sun, pickled in garlic
juice, etc.) is the main factor of opisthorchiasis
transmission
(TIMOCHfNE, 1967; GRITSA Y & Y AKUBOY,
1970). The greater or lesser importance
of given fish
species in the transmission
varies according to the endemic zones (different prevalences
and infection intensities in fish, even up to 100% infected - NIKITIN & KUIMOYA, 1992) and human habits. This is reflected in
human infection. In general, human infection levels declined from a downstream
to upstream direction, and towards the periphery of the basin, where man is least involved in the maintenance
of the parasite's
life cycle
(ZAYOIKIN, DARCHE KOYA & ZEL YA, 1991). Opisthorchiasis appears to be anthropogenic
inasmuch as man is
the main host responsible
for the transmission
of the disease (ZAYOIKIN et al., 1973). At any rate, in given
areas, such as in Kazakhstan,
foci of opisthorchiasis
differ from those in other areas of the former USSR in that
there are more natural than anthropogenic
foci (SIOOROY & RYBALOYA, 1983).
Carnivores,
mainly cats but also dogs, play an important role in maintaining
the parasite life cycle, showing
very high prevalences
in given opisthorchiasis
foci: 76%
of the cats and 70% of the dogs infected in the Altai Territory (NIKITIN & KUIMOYA, 1992); 61,5% of the local
cats, with an intensity of 75-560 adults per host, on the
river Kama (UCHUATKIN et al., 1988); 29-51 % of the
cats, with a burden of 1-519 adults per host, in the Kirov
region (MALKOY, 1991); 68,7-92,8%
of the cats in Bielorussia (SKRIPOYA et al., 1991).
In the Khanty-Mansiisk
region, Siberia, human post
mortem
studies showed
that the worm burden was
<1000 (in 12 individuals),
1000-5000 worms (in 23),
5001-15000
(in 22) and >15000 (in 5). Examination
of
faeces showed an irregular distribution
of eggs in the
large intestine and a correlation was not established between the number of adults in the liver and the number of
egg (BYCHKOY et al., 1990). Also in the Khanty-Mansiisk, the prevalence
rate was 57,6% in children aged 2
to 15 and 70,8% for adults. There was a direct correlation between age-related prevalence levels and the numbers of eggs in faeces which rose sharply at the age of 10
and reached
a maximum
level in the 40-year-old
(BRONSHTEI , 1985).
A direct relationship
has been noted between infection
incidence and age. In the Sumy, Chernigov and Poltava
regions of Ukraine, human prevalence ranged from 0 to
61, I %, so that in children below 14 years old it was 4,221 % and the highest prevalence was recorded in the 3050 year old group (ZAYOfKIN et al., 1989b). In Bielorussia, human prevalence ranged from 0 to 12%, prevalence
rising gradually from the age of 14 to a peak in the 25- to
40-year-old
age group (SKRIPOYA et al., 1991).
Several studies have demonstrated
the interest of human population
migration phenomena
on opisthorchiasis infection. Concerning
immigrants
from non-endemic
areas, the prevalence
of infection rises with the length
of stay in the endemic area, which is particularly
mar-
170
ked in the first 10 years after arrival and is related to the
rapid acceptance of the local custom of eating raw fish
(BRONSHTEIN,1987). Concerning the consequences of
emigration from endemic areas, the risk of disseminating the disease is related to the long life span of the parasite adult stage and the presence of appropriate snail
and fish hosts as well as with the human diet habits in
the immigration zones (UCHUATK1Net al., 1988; PUSTOVALOVA,1991).
The endemicity of opisthorchiasis in the territories of
the former USSR is classified according to the prevalence, the intensity of infection, and the degree of clinical manifestations as follows: A) not endemic: imported
cases of disease only; B) hypoendemic: sporadic cases
or a prevalence of < I0%; the mean number of eggs per
gram of faeces is <100; clinical manifestations are severe in <10% of infected persons; C) mesoendemic: prevalence is 10-40%; 100-300 eggs are found per gram of
faeces; clinical manifestations are moderate or severe in
10-50% of infected persons; D) hyperendemic: prevalence rate is >40%; >300 eggs are found per gram of faeces; clinical manifestations are moderate or severe in
>50% of infected persons (WHO, 1995).
Morbidity and mortality due to O. felineus is very different from that of its close relative, O. viverrini, although signs and symptoms are similar. Authors characterize O. felineus infection as having a number of clinical
stages, from acute to late chronic, with accompanying
symptoms and pathological consequences which can be
determined by physical examination (BRONSHTEIN,
1986; SITH1THAWORN
et al., 1994). As in other liver fluke
diseases, the degree of its pathogenicity and clinical involvement depends largely on parasite number and the
duration of the infection.
The incubation period between ingestion of metacercariae and the appearence of the first symptoms usually varies from 2 to 4 weeks, and rarely is as short as J week.
Maturation of the larval worms in the distal bile ducts initiates inflammatory and proliferative changes of the biliary epithelium. These changes are accompanied by fibrosis of the distal biliary branches. In heavy infections,
the pathological changes may extend to the proximal bile
ducts and gall-bladder or be associated with mild periportal fibrosis (WHO, 1995). Adults cause iritation and
trauma to biliary epithelial cells that desquamate and proliferate, causing glandular or adenomatous formations to
project into the biliary lumen. Periductal infiltration with
eosinophils and round cells and fibrosis in the portal areas
are commonly found. At this stage, obstruction of biliary
tracts occurs with dilatation of intrahepatic ducts and the
development of subsequent cystic and saccular formations
(HARINASUTA,PUNGPAK& KEYSTONE,1993).
The acute clinical manifestations are fever, abdominal
pain, dizziness, and urticaria. Acute infections have ra-
rely been observed among aboriginal ethnic groups and
indigenous Russians in areas where the prevalence of
chronic infection is high. Acute opisthorchiasis has, however, been reported among new arrivals from other territories and occasionally among indigenous Russians
who have probably been reinfected after treatment. In
areas of low prevalence, acute infections are rarely diagnosed. No relationship has been found between the presence of acute clinical manifestations and the number of
O. felineus eggs in faeces (BRoNSHTEIN, 1985). Few O.
felineus eggs are found in the faeces of patients with
acute clinical manifestations. In individuals with low
and moderate liver infection intensity, a positive correlation was established between number of faecal eggs and
long-term health deterioration; no such correlation existed for individuals with heavy infections (BYCHKOVet
al., 1990). Individuals presenting symptoms of early
opisthorchiasis but not excreting ova have also been detected (ZHURAVLEV& PUZYREV,1987).
The signs and symptoms of chronic opisthorchiasis include diarrhoea, flatulence, fatty-fodd intolerance, epigastric and right upper quadrant pain, jaundice, fever,
hepatomegaly, lassitude, anorexia, and, in some cases,
emaciation and oedema (MARKELL & GOLDSMITH,
1984). Although local damage may be considerable in
the distal biliary tree where the worms are lodged, there
is usually no measurable effect on liver function. In severe cases, hepatitis has been observed (HARINASUTA,
PUNGPAK& KEYSTONE,1993).
Most individuals with light to moderate infection
show no significant signs or symptoms of disease when
compared with uninfected matched control groups. Pathological studies have revealed no gross changes in the
liver in light or early infections. Epidemiological studies
have consistently shown that liver enlargement, whether
assessed by physical or ultrasound examination, is not
directly related to intensity of infection. An enlarged
non-functional gall-bladder correlates closely with heavy infections. In highly endemic areas, manifestations
of chronic infection include cholecystitis, cholangitis, liver abcess, chronic portal hepatitis, hepatic cysts and
gallstones (BRAZHN1KOVA& RODlCHEVA,1989; AL' PEROVICH,BRAZHNIKOVA& YAROSHKINA,1990; AL'PEROVICH,RODlCHEVA& MITASAOV ,1991; RODICHEVA
& MITASOV, 1991; TUN et al., 1991). In the pancreas a
marked disturbance of external secretion is detected
(lMAMKULIEV,1971). Contrarily to what succeeds in the
case of O. viverrini infection, cholangiocarcinoma does
not appear to be associated with O. felineus (PONOMAREVet al., 1987; BYCHKOV& YAROTSKll,1990).
Diagnosis
Diagnosis is based on the recovery of the typical eggs
in the faeces or duodenal drainage. Differential diagnosis regarding O. viverrini and Clonorchis sin ens is is
made using morphological and morphometrical aspects
(see chapters on these species) but mainly for geographi-
171
cal reasons, the distribution
of O. felineus not overlapping that of the other two flukes.
In cases of light infection or biliary obstruction or during the prepatent period, eggs may not be present in the
stool (SADUN, 1955; HARINASUTA, PUNGPAK & KEYSTONE, 1993).
The Kato-Katz technique (URBAZAEYA & URBAZAEY,
1990) and sedimentation
techniques
with various modifications
(ZAYOIKIN, PL YUSHCHEYA & NIKIFOROYA,
1985; PAYLYUKOY, BEREZANTSEY & MEZHAZAKIS,
1990; KOTEL'NIKOY & VARENICHEY, 1991) have been
used for clinical diagnosis of opisthorchiasis
in the field
and hospitals
in the former USSR. Serological
tests,
mainly ELISA, have been used in clinical diagnosis and
for epidemiological
surveys (GlTSU, BALLARD & ZAYOIKIN, 1987; GORBUNOYA et al., 1988; ZAYOIKIN et al.,
1989a; VERBOY et al., 1990).
The reaction double diffusion in agar gel after Ouchterlony is suggested as a diagnostic test in early stages of
human opisthochiasis
(RIM, 1982).
Transhepatic
cholangiography
may show dilations of
the biliary tract, classified as mulberry, saccular, or cystic, which are considered
pathognomonic
if found in
combination.
Occasionally,
cholangiography
also shows
slender filling defects. Leukocytosis
varies according to
the intensity of infection. Eosinophilia
may be present
(MARKELL & GOLDSMITH, 1984).
Treatment
Chlorinated
derivatives
of xylol, such as Chloxyl@
(hexachloroparaxylol)
and hexachlorophene,
are very effective and were extensively
used in the past (at a dose
of 0.15-0.3 g/kg body weight daily, for 2 days) (DROZDOY, 1965; PANTYUKHOY, 1966; YALDYGINA TISHCHENKO & MUROMTSEYA, 1971; PLOTNIKOY et al.,
1969; SKAREDNOY, 1969, etc.), However, because of its
toxicity close medical supervision
or even hospitalization was required, and large-scale chemotherapy
was not
possible (SKAREDNOY & STEPANOYA, 1986).
The use of these xylol derivates changed with the introduction of praziquantel,
which proveed to be very effective. A 100% cure rate was obtained with a dosage of
25 mg/kg three times in 1 day. A single dose of 40 to 50
mg/kg is more convenient for mass therapy and yields a
91 % to 95% cure rate. Side effects with praziquantel
are
mild and transient;
they include insomnia,
headache,
dizzness, nausea, vomiting and diarrhea. Although eggs
disappear
in a week, symptoms
and signs may take a
few months
to subside
(HARINASUTA, PUNGPAK &
KEYSTONE, 1993). Praziquantel
at 75 mg/kg in 3 doses
at 4 intervals was well-tolerated
and 90,5% effective
(BELOBORODOYA, KALYUZHINA & BUZHAK, 1990).
The clinical condition of the patients improved 2 weeks
after treatment
and 94,3% were free of infection
6
months after treatment. Symptoms of digestive dysfunction continued in a number of patients following parasitological cure (NIKITIN & KUIMOYA, 1992). Nowadays,
Russians produce a drug called Azinoks, which is an
analogue of Biltricide (praziquantel)
and similar to it in
parasitological
efficacy and side-effects
(STEPANOYA et
al., 1991).
Other drugs such as albendazole
and mebendazole
are
also effective. Albendazole
at a dosage of 400 mg twice
daily for 3 and 7 days cures only 40% and 63%, respectively (PUNGPAK, BUNNAG & HARINASUTA, 1984).
A method for treating 0. felineus infection complicated by cholangitis is described by AL'PEROYICH, BRAZHNIKOYA & SOKOLOYICH (1989). This technique involves
the removal of the gall bladder and redirection of the bile
into the intestine, with a mandatory external drain of the
bile ducts for the purpose of their desinfection,
using iodionol or 1% aqueous lugol solution. Daily washing
ducts should be continued for 10-20 days until no more
worms or their eggs are present in the bile. Clearing of
infection in the post-operative
period was achieved in
50% of 160 patients where traditional disinfectants
and
antibiotics were used, and 90% of 70 patients where ioidine-containing
rinsing agents were used.
The prevention
and control measures are similar to
those for C. sinensis and O. viverrini. The infection may
be prevented by cooking fish and by sanitary excreta disposal. The most practical method of preventing human
infection is to avoid eating raw, freshly pickled or imperfectly cooked freshwater fish. At the same time, the control of O. felineus infection consists of preventing mainly
cats, but also dogs and other domestic and free-living potential definitive mammal hosts from eating raw fish. The
choice of methods must be directed by the nature of the
environment,
the habits and customs of the people, the
pattern of transmission,
and the resources of the country
(RIM, 1982).
The strategy of control of opisthorchiasis
is based on
integration of control activities into primary health care
systems, with the main goal of reducing the prevalence
of disease, but in some districts of the former USSR it
has never been fully operational.
In highly endemic
areas the achievements
of pilot control projects have
been difficult to sustain and the prevalence has usually
returned to the original levels over a five-year period because people have continued
to eat fish that is raw,
slightly salted, frozen or poorly cooked. The migration
of infected fish and consumption
by the local people
even in non-endemic
areas contribute
to the relative
ineffectiveness
of control measures (WHO, 1995).
FASCIOLA HEPATICA
Morphology
The adult stage
usually 20-50/6-13
has a broad flat, leaf-shaped
body,
mm in size. The suckers are relati-
172
vely small, the ventral being slightly larger than the oral.
They are close to each other in a conelike anterior extension of the body. The posterior end of the body is broadly pointed. The pharynx is prominent
and the caeca
are long, reaching the posterior end of the body and presenting a large number of lateral branched diverticula.
The testes are also branched, filling the second and third
fourth of the body. The cirrus pouch, containing
a protrusible spined cirrus, is well visible, preacetabular,
and
opening in a postbifurcal
genital pore. The ovary is also
dendritic,
dextral and pretesticular.
The vitellaria
are
dorsal and ventral to the caeca and extend in the whole
lateral field of the hindbody.
The uterus is relatively
short, with several coils situated between the ovary and
the intestinal
bifurcation.
The eggs are operculated,
ovoid, yellow, non-embryonated
when laid, and measure
about 130-150/63-90 I1m. They are not readily differenmodel
tiated from those of F. gigantica. A mathematical
for the ontogeny of the F. hepatica adult stage in the definitive host has recently
been developed
(V ALERO,
MARCOS & MAS-COMA, 1996).
The adult stage is a parasite of the large biliary passages and the gallbladder.
This species is a common parasite of ruminants, especially sheep, goats and cattle, causing important economic losses in the animal husbrandy
industry (FROYD, 1975; BORAY, 1981; DARGIE, 1986).
A large variety of other domestic and wild animals may
also be infected. The most important
alternate
hosts
which play a significant role in the epidemiology
of the
disease are horses, donkeys, mules, and also camelids.
Wild herbivorous
mammals
such as as buffalo, deer,
wild sheep, wild pig, various marsupials,
rabbit, hare,
and nutria are also susceptible
hosts, as well as various
wild species in Africa including monkeys. Grazing domestic pigs may also be infected, but this host has a higher natural resistance
against
the parasite
(BORA Y,
1982). Many rodent species have been found naturally
infected by F. hepatica and others are usually used for
experimental
purposes (MAS-COMA et al., 1987, 1988).
Reports in humans
Human cases have been reported
from numerous
countries in Europe, the Americas, Asia, Africa and the
western Pacific (CHE & MOTT, 1990). Several epidemics have been recorded in the literature. As the infection may be asymptomatic,
and the symptoms and signs
are not pathognomonic,
the actual number of human cases is undoubtedly
much greater than the reported. The
estimated number of people with fascioliasis
is 2,4 million (RIM et al. 1994). Numbers of clinical cases of F.
hepatica reported, as well as of infected persons identified during epidemiological
surveys, have been increasing since 1970. These increases may be due to a better
understanding
of the disease and the improvement
of
S.
MAs-CoMA
&
M.D.
BARGUES
diagnostic
methods, especially
in areas where serological tests have been used. The major sources of the infection, domestic herbivorous
animals, are widely distributed in the world and human infection is not rare in these
areas. The disease is mainly endemic in the temperate
and subtropical
zones. A moderate temperature
and a
high humidity are necessary
for the development
and
multiplication
of the intermediate
snail hosts and the flukes in various development
stages. A prolonged,
wet
summer in Europe has often been followed by an outbreak of the disease (CHEN & MOTT, 1990).
FACEY & MARSDE (1960) reviewed human infection
by F. hepatica some time ago, and recently. CHEN &
MOTT (1990) reviewed cases in publications
since 1970.
According to CHEN & MOTT (1990), the following 2594
cases have been reported during the past two decades:
- Africa: Algeria (6 cases), Egypt (125 cases), Morocco
(I case), Zimbabwe (1 case);
- America:
Argentina
(13 cases), Brazil (14 cases),
Chile (4 cases), Cuba (216 cases), Mexico (5 cases),
Peru (163 cases), Puerto Rico (18 cases), Uruguay (16
cases), USA (I case);
- Asia: China (41 cases), India (I case), Iran (16 cases),
Israel (2 cases), Japan (5 cases), Saudi Arabia (2 cases), South Korea (3 cases), Thailand (I case), Turkey
(8 cases), Yemen (3 cases);
- Europe: Austria (4 cases), Belgium (3 cases), Bulgaria
I case), Czechoslovakia
(2 cases), France (963 cases),
the French island of Corsica (2 cases), Greece (I case),
Ireland (I case), Italy (1 case), Poland (16 cases), Portugal (1099 cases), Spain (142 cases), Sweden (2 cases), Switzerland
(13 cases), UK (93 cases), former
USSR (131 cases), West Germany (3 cases), former
Yugoslavia (I case);
- Australia: 8 cases.
According to CHEN & MOTT (1990), of these 2594 cases, a total of I 103 of the cases have been detected by
parasitological
methods (either by finding the eggs in the
stool or bile, or adult worms at surgical operation or at
autopsy), 778 persons have been diagnosed by serological tests, 624 persons by parasitological
and/or serological methods, 28 patients have been diagnosed after pathohistological
examinations
of liver sections, or with
ultrasound showing the adult worms, or from their clinical persentation,
and finally in several cases (61 from
Cuba) the diagnostic
technique
was not mentioned.
Worth mentioning
is that most papers described
small
series of hospital inpatients, and only a few communitybased or epidemiological
surveys have detected larger
numbers of infected persons, as in Peru (STORK et al.,
1973), Egypt (FARAG et al., 1979), France (LA BORDE,
1985; RIPERT et al., 1988), Portugal (SAMPAIO SILVA,
CAPRO & CAPRON, 1980; SAMPAIO SILVA, SA TORO
& CAPRO , 1981) and Puerto Rico (BENDEZU, FRAME &
HILL YER, 1982).
According to the review of CHEN & MOTT (1990), more
than half of the human infections were described in Europe, mainly in France, Portugal, Spain, the UK and the
Human
liver flukes:
former
USSR. France is an important
173
a review
endemic
area for F.
hepatica (ANO YMOUS, 1988). The first large modern
epidemic of human fascioliasis in France occurred in 1956
(COUDERT & TRIOZON, 1958). Between 1950 and 1983,
GAILLET et al. (1983) catalogued 3297 cases from published reports. Most cases were reported from the areas of
Lyon, Bretagne NordlPas de Calais and Sud-Ouest. Wild
watercress is the main source of human infection in these
areas, where fascioliasis
in domestic
animals is also
highly endemic. Other recent reports contain detailed reviews on the situation in South-west France, referring to
274 cases (LA BORDE, 1985) and 37 cases (GIAP, 1987)
respectively. Most cases have been reported from France,
in part because serological tests have been widely used
there, whereas in other countries the diagnosis of the infections is mainly based on parasitological
examinations.
The disease is also important in Portugal, with northern
Portugal as a marked endemic area. Cases reported in this
country included those in residents from 2 islands, Madeira and Cape Verde (ROMBERT & GRACIO, 1984). Concerning the former Soviet Union, almost all reported cases
were from its southern, Asian republic, Tadzhik, near the
Afghanistan border (KAMARDI OV, 1985; KHASHIMOV &
KAMARDI OV, 1975; RAKHAMA OV, 1987). The situation in Hungary is also worth mentioning, whereas no recent report on fascioliasisis
is available from that country
despite the several severe outbreaks of human infection
recorded between
1959 and 1970, usually after heavy
summer rainfall (KOBULEJ, 1981/1982). There are countries such as Switzerland,
in which fascioliasis
is quite
common in animals, especially in the northern part of that
country (ECKERT, SAUERLA DER & WOLFF, 1975), but
reports on human infection are only occasional.
In the Americas,
Cuba (ESPINO et a/., 1987; FABREGAS RODRIGUEZ et al., 1976; Go ZALEZ et al., 1985;
GUERRA PEREDA et al., 1980; MILLA MARCELO et al.,
1985; PEREZ RODRIGUEZ et al., 1986; RODRIGUEZ BARRERAS et al., 1986) and Peru (KNOBLOCH. 1985; KNOBLOCH et al., 1985; STORK et al., 1973) have each reported more than 100 cases.
In Africa, most cases have been reported from Egypt
(probably due to F. gigantica, since it appears to be the
only species in domestic animals in this country) (FARAG
et al., 1979, 1986, 1988; FARID et al., 1986; MA SO R et
al., 1983; RAGAB & FARAG, 1978; SALEM, ABOU BASHA
& FARAG, 1987).
In Asia, fewer cases have been described,
including
China and Iran (CHEN & MOTT, 1990). In most case reports from Korea and Japan the parasite was determined
as Fasciola sp. (AKAHANE et al., 1975; CHO et al., 1976;
KANEDA et al., 1974; LEE et al., 1982; RIM, 1981; YosHIDA et al., 1974), the question being related to the overlapping distribution
of both F. hepatica and F. gigantica
in these 2 countries (CHU & KIM, 1967; RIM, 1981).
Concerning
Australia and
ew Zealand, there are only
a few reports from the former (CROESE, CHAPMA &
GALLAGHER, 1982; GOODMAN, HE DERSON & CULLlTY, 1973; MANGOS & MENZIES, 1973; WOOD, POTER
& STEPHE s, 1975; WOOD, STEPHENS & POTER, 1975),
despite the important livestock production
of both and
the high prevalences
in sheep and cattle in Australia
(BORA Y, 1969).
An important
paper not included
in the review of
CHEN & MOTT (1990) is that of PICOAGA, LOPERA &
MONTES (1980), who found 220 human cases in Arequipa, Peru, from 1950 to 1977. In Iran, recent estimates
suggest more than 30000 human cases (see BAHAR et al.,
1990; MASSOUD, 1990; POURTAGHVA et al., 1990). In
Spain, a more recent review increases the estimated
number of cases between the years 1970 and 1989 to 244
(SORRIBES et al., 1990). On Corsica island, a total of 18
cases were detected between
1984 and 1989 (GIL-BEITOetal.,1991).
Among studies carried out after the review made by
CHEN & MOTT (1990), the epidemiological
surveys
made in the Bolivian Altiplano are worth mentioning.
Although Bolivia is not even mentioned within the review by CHEN & MOTT (1990), the Northern Bolivian
Altiplano has proved to be the area in which the highest
human prevalences
and intensities are known. Different
studies have reported human prevalences
of up to 70%
in coprological
surveys (M AS-COMA et al., 1995; ESTEBA et al., I997a, b; ANGLES et al., 1997) and even higher in immunological
surveys (HILLYER et al., 1992;
MAS-COMA et al., 1995; BJORLA D et al., 1995;
STRAUSS et al., 1997). Intensities
in Bolivian children,
measured
as egg output in stools, ranged from 24 to
5064 eggs per gram (epg), with arithmetic and geometric
means of 474-1001 and 201-309 epg, respectively
(EsTEBAN et al., 1997b). Moreover, the human fascioliasis
problem in the Altiplano is increased by the presence of
many other pathogenic
protozoan and helminth species
concomitantly
parasitizing
F. hepatica-infected human
subjects (ESTEBA et al., 1997a, 1998a, b).
Geographical
distribution
The distribution
of the parasite is mainly in temperate
and subtropical
zones, and thus the disease is prevalent
in Europe, North, Central and South America, northern
Asia, Oceania, and northern Africa and South Africa.
The disease also occurs in some large islands, including
ew Zealand, Tasmania, the UK, Iceland, Cyprus, Corsica, Sardinia, Sicily, Japan, Papua New Guinea, the Philippines, and several islands of the Caribbean.
In Europe, the disease is prevalent in almost every
county and on adjacent islands, prevalences
in animals
varying markedly depending
on given regions (PANTELOURIS, 1965). In the USA, the parasite is widely distributed but spotty in distribution.
F. hepatica occurs most
abundantly,
with considerable
losses among livestock
(MALO E, 1986), in Florida, Louisiana, Texas, California, Oregon, Washington,
evada, Idaho, Utah, Montana, but also in Arizona, New Mexico, Colorado, Arkansas, Wyoming,
Michigan,
Wisconsin,
Alabama
and
Missouri (BORA Y, 1982). The potential for the spread in
174
Oklahoma has recently been reported (CHERLUYOT&
JORDA , 1990). The parasite has not established itself in
the eastern states, other than Florida (BORAY, 1982). Outside the continental U.S., the parasite is very common in
Puerto Rico and Hawaii. It is also endemic in the eastern
provinces of Canada and British Columbia. In addition to
Puerto Rico, it is prevalent on several other Caribbean islands, such as Cuba, Hispaniola, Guadeloupe, Martinique, St. Lucia, and others. In Central and South America
it is well known in Mexico, Costa Rica, Venezuela, Peru,
Bolivia, Brasil, Uruguay, Argentina and Chile (REY,
1991), as well as in Colombia (MALEK, 1985).
In Africa, it appears in the northern Mediterranean
countries such as Morocco and Algeria, where it uses the
same intermediate snail host as in Europe, Lymnaea
truncatula (KHALLAAYOUNE et al., 1991; CHEN &
MOTT, 1990), as well as in southern Rhodesia and South
Africa (PANTELOURIS,1965). However, in Egypt fascioliasis seems to be due to F. gigantica (HAIBA & SELlM,
1960; CHEN & MOTT, 1990). F. hepatica is the species
present at high altitude in Kenya and Ethiopia (BERGEON
& LAURENT,1970).
In Oceania, besides New Zealand and Tasmania, it is
common and widespread in temperate, wet, agricultural
areas in the southestern part of the country (BORAY,
1969; SPRATT& PRESlDENTE,1981).
In Asia, it is well known from Turkey, Israel, Saudi
Arabia, Yemen, the former USSR (to Vladivostok), Iran,
Pakistan, India, Nepal, Burma, China, Taiwan, Thailand,
Vietnam, Korea, Japan, and the Philippines (TERASAKI,
AKAHANE& HABE, 1982; CHE & MOTT, 1990). In the
Asian continent, the distribution of F. hepatica overlaps
that of F. gigantica in various regions, such as in Iran
and Pakistan, F. hepatica being apparently confined to
high altitude there (KENDALL, 1954; KENDALL& PARFITT, 1959). This overlapping distribution of both species has become the basis of an already long controversy
on the taxonomic identity of the Fasciola species occurring in Asian countries, especially Japan, Taiwan, the
Philippines and Korea, in which a wide range of morphological types is detected. At the extremes of this morphological range, some resemble F. hepatica, whereas others resemble F. gigantica, with an intermediate form
also occurring.
Studies have shown that the three morphological types
(hepatica, gigantica, intermediate) exist in Japan, two chromosome types having been found: diploid (2n = 20) and
triploid (2n = 30). Another type which had both 20 and 30
chromosomes within a single fluke was also found. In
both diploid and triploid types spermatogenesis is abnormal and no fertilization occurs. Flukes with a few or no
spermatozoa in the seminal vesicle perform abnormal
spermatogenesis
(called «abnormal spermatogenetic
type» - AST), while those with many perform normal
spermatogenesis (called «normal spermatogenetic type» NST). All specimens examined from Europe, South and
North Americas, and Oceania, where mainly F. hepatica
is considered to be distributed, and from Africa, where F.
gigantica is dominant, belong to NST. At any rate, AST is
known in Hawaii. NST was also found in Pakistan,
Burma, and the former USSR (Vadivostok). Both AST
and NST are however present in several Asian countries:
India, Nepal, Thailand, Vietnam, the Philippines, and Taiwan. And finally, in Japan and Korea especially the AST
is known to be distributed. In the southeastern part of
Asia, AST flukes are sympatric with ST F. hepatica and
NST F. gigantica, but AST flukes are considered reproductively isolated from NST F. hepatica and NST F. gigantica because they perform parthenogenesis. It is clear
that the AST flukes belong to a different strain from those
to which NST F. hepatica and NST F. gigantica belong
(TERASAKI,AKAHANE& HABE, 1982).
This situation has encouraged numerous molecular studies with interesting results in recent years. Lack of variation in enzymatic studies has been thought to be due to
the parthenogenetic mode of reproduction of these
worms, the examined populations consisting of descendants of a single individual. True host-induced molecular
variation seems rare. A number of authors have commented on the lack of such variation. In F. hepatica, the same
isozymes were detected regardless of the host species
(cattle, sheep, goats), although densities of some isozyme
bands did differ according to host (BLAIR, 1993). On the
island of Corsica, an electrophoretic study on 23 enzymatic systems allowed the detection of small differences in 6
systems (AK, CK, EST, HK, MPI, and 6-PGD) between
F. hepatica from cattle in the southern part of the island
and from rats in the northern part of the island (PASCUAL
et al., 1990). Concerning nucleic acid sequences, studies
on ribosomal genes have shown F. hepatica and F. stgantica to be distinct, with Japanese Fasciola sp. being
close to F. gigantica (BLAIR, 1993).
A recent study carried out by AGATSUMAet al. (1994)
has confirmed that Japanese flukes reproduce by parthenogenesis, regardless of their diploidy, triploidy and rnixoploidy, because of their abnormal gametogenesis.
AGATSUMAet al. (1994) distinguished three different
genotypes among six laboratory-raised, uniparental triploid Japanese isolates with no normal sperm formation,
indicating that these parthenogenetic lines have arisen
independently of each other: genotype I = F. hepaticalike worms; genotype 2 = F. gigantica-like worms; and
genotype 3 = intermediate form worms. Genetically, F.
hepafica-like worms were clearly distinct from the other
two genotypes. Other F. gigantica-like worms from Kochi belonged to genotypes 2 and 3. Korean worms resembled genotypes 2 and 3 more than genotype 1, and
differed from American and Australian diploid strains
with sperm. American and Australian strains had similar
patterns and proved to be mendelian populations. The independent origins of parthenogenetic strains in Japan
might have occurred through independent hybridization
events between strains. The existence of such hybrids
would explain the continuing confusion among scientists
with respect to the taxonomic status of the Japanese liver
flukes.
Human
liver flukes:
175
a review
Life cycle
The general pattern of the diheteroxenous life cycle of
F. hepatica was the first to be elucidated among trematodes and has already been the subject of several extensive
reviews (TAYLOR, 1964; DAWES & HUGHES, 1964,
1970; PANTELOUR1S,1965; KENDALL, 1965, 1970; no.
RAY, 1969; OOEN1NG,1971).
Eggs are produced by parasite adults and are excreted
with faeces. Daily egg output per adult fluke is generally
inversely proportional to the intensity of the fluke burden. In moderate infections the daily egg output is
usually constant, but in heavy infections egg output varies considerably (CHEN & MOTT, 1990). The parasite
follows an aquatic life cycle. Eggs mature in water. If
the climatic conditions are suitable (15-25° C), the miracidia develop and hatch in about 9 days (LAPAGE, 1968)
to 21 days (BORAY, 1969). If conditions are unfavourable, they may not mature but may remain viable for several months (LAPAGE, 1968). The miracidium, about
130128 urn, hatchs under light stimulation and swims rapidly by means of its cilia until it contacts an appropriate
aquatic or amphibious snail host. The miracidium is positively phototropic and negatively geotropic. Miracidia
failing to penetrate an appropiate snail die within 24
hours (OLSEN, 1974).
The miracidium penetrates the snail and changes into
an elliptical saccular sporocyst, 150-500 urn in length,
in the mantle, mantle collar and perioesophageal area.
This sporocyst produces mother rediae which in turn
produce cercariogenous daughter rediae. Mature rediae,
presenting a rudimentary digestive system (pharynx and
a short caecum), are cylindrical, about 250-750 urn in
length, with a raised collar near the anterior end and two
bulging projections in the posterior third of the body.
They come out of the sporocyst and migrate mainly to
the digestive gland. Up to four redial generations have
been found, although 3 generations are usually produced after a monomiracidial infection (RONDELAUO&
BARTHE, 1986). The redial generations follow the same
developmental pattern in different Iymnaeid species
(RONOELAUD& BARTHE, 1987). Cercariae develop within 6-7 weeks at 20-25° C. At lower temperatures the
development is delayed.
The cercaria has a large, almost round, spinose body
(28-3201250 um) and a long, simple, motile tail (about
700 um long). Cercariae escape from the redia through a
birth pore located just posterior to the collar at the anterior end, and are shed by the snail into water. The prepatent period is dependent on temperature, higher temperatures reducing the period (15° C: 56-86 days; 20° C:
48-51 days; 25° C: 38 days). The shedding process takes
place between 9° and 26° C, independently of light or
darkness, and it seems to follow an infradaily shedding
pattern of 7 days in the daily production during the
whole emergence and a circadial rhythm with maximum
production between midnight and I am. (AUDOUSSETet
al., 1989). Cercariae swim for a short time (1 hour) until
contacting a solid support, mostly leaves of water plants
above or below the water line. They then lose their tails
and quickly encyst, changing into metacercariae. Metacercarial cysts are round and about 200 urn in diameter,
and become infective within 24 hours after encystment.
Floating infective metacercarial cysts are also originated
at the level of the water surface line (VARE1LLE-MoREL,
DREYFUSS & RONDELAUD, 1993). Metacercarial cysts
are resistant and remain viable for a long period, but are
killed by excesive heat and dryness.
Metacercariae infect the definitive host after ingestion. A proportion of metacercariae die in the gastrointestinal tract and a relatively few eventually develop
into adults. Metacercariae excyst in the small intestine
within an hour after ingestion, penetrate the host's intestine wall, and appear in the abdominal cavity by about 2
hours after ingestion. Most reach the liver within 6 days
after excystment. In the liver they migrate for 5 to 6 weeks, preferentially feeding directly on liver tissue. They
eventually penetrate into the bile ducts where they become sexually mature. The prepatent period is about 2
months (6-13 weeks) in sheep and cattle (CHEN &
MOTT, 1990). Thus, the whole cycle takes about 14-23
weeks (LAPAGE, 1968; BORAY, 1969). It has also been
speculated that the immature flukes may enter the blood
stream and be carried to various parts of the body, or
may reach the liver by travelling up the bile duct (CHEN
& MOTT, 1990).
The prepatent period (from the ingestion of metacercariae to the first appearance of eggs in the faeces) varies
according to the host, and also depends on the number of
the adult flukes in the liver, so that the greater the fluke
number, the longer the time to mature and to initiate egg
laying: 35-42 days in mice; SS days in guinea pigs; 63
days in sheep infected with 200 metacercariae, 13-15
weeks in sheep infected with 2000 metacercariae; 56-61
days in cattle, depending on host age (BORAY, 1969; DE
LEON,QUINONES& HILLYER, 1981). In man, a period of
at least 3-4 months is necessary for the flukes to attain
sexual maturity (FACEY & MARSDEN, 1960; WASOWA,
AUDRZEJAK& JANICKI, 1979).
Several studies (DAWES & HUGHES, 1964; LAPAGE,
1968; SMITHERS,1982) show that the life-span of the parasite in sheep can be as long as II years and 9-12
months in cattle. Concerning man, DAN et al. (1981)
suggested that F. hepatica may survive for at least 9 years based on imported cases from Afghanistan, and up to
13,5 years according to another report. CHATTERJEE
(1975) estimated that the life span of the adult fluke in
man is between 9 and 13 years.
The intermediate snail hosts are amphibious and
aquatic species of the family Lymnaeidae. Principal or
obligatory intermediate snail hosts mentioned for F. hepatica are: Lymnaea truncatula in Europe including
most of the former USSR; L. truncatula and L. colume-
176
lIa in Africa; L. humilis, L. bulimoides and L. cubensis
in North America; L. viatrix (= L. viator) and L. diaphana in South America; L. truncatula and L. viridis in
Asia; L. tomentosa in Australia; L. tomentosa, L. columella and L. truncatula in New Zealand; L. viridis and
L. ollula in Hawaii, Papua New Guinea, Philippines and
Japan. Alternate or facultative host species are: L. palustris and L. glabra in Europe and former USSR; L. columella in North and South America; and L. columella
and L. viridis in Australia (BORAY, 1982). Later studies
have also shown the role of L. cubensis in Central America and northern South America, and L. gedrosiana in
Iran (CRuz-REYES & MALEK, 1987). Research studies
on snail anatomy and shell morphology (OVIEDO et al.,
1995; SAMADI et al., 1997), DNA sequencing (BARGUES& MAS-COMA, 1997; BARGUESet al., 1997) and
isoenzymatic studies (JABBOUR-ZAHAB et al., 1997)
proved that L. truncatula is the only intermediate host
species in the Northern Bolivian Altiplano. Several of
these snail species are included in other Iymneid genera
by MALEK(1985).
Interestingly, recent molecular biology studies have
confirmed the applied parasitological importance of the
18S rRNA gene, both in the distinction between fascioliasis transmitter and non-transmitter lyrnnaeid snail species and in the distinction between Iymnaeid species
which transmit F. hepatica and those which transmit F.
gigantica, as well as in the development of specific probes for the distinction of infected from non-infected
snail individuals in epidemiological surveys and control
studies of human and animal fascioliasis (BARGUES &
MAS-COMA, 1997; BARGUESet aI., 1997).
Epidemiology
Human infection is determined by the presence of the
intermediate snail hosts and herbivorous animals, and related to climatic conditions and dietary habits of man.
Both appropriate snail host species populations and
parasite larval stages are dependent on the presence of
the necessary water and of the local climatic conditions.
Concerning the ecological characteristics of the snail
species, two recent studies have shown that under special circumstances given Iymneids are really able to
adapt to extreme conditions, thus contributing to the
spread of the disease. In Corsica, L. truncatula has preferentially adapted to being in reservoir habitats (permanent presence and renewal of water) instead of in invasion habitats (only seasonal presence of water) as is
usual in the European continent, and several atypical
habitats even suggest an ecological niche-widening, as a
consequence of the influences of the insularity phenomenon (OVIEDO et al., 1992). In Bolivia, the Iymneid
intermediate host is perfectly adapted to the extreme climatic conditions of 4000 m altitude of the human fascioliasis high endemic zone in the Northern Altiplano
(MAS-COMA et al., unpublished data). In southern Europe, it is even adapted to places where human activities
S. MAs-CoMA
& M.D. BARGUES
include frequent drastic environment changes and insecticide treatments, such as rice fields (V ALERO et al.,
1998b).
It has recently been shown that computer-based Geographic Information System (GIS) may be used to characterize the epidemiology of the disease, soil-hydrology
based GIS models being proposed for analysis and predictions (MALONE, 1994). However, such methods do
not appear today to be sensitive enough to detect the local patchy distribution of snail populations according to
environmental elements such as small salt concentration
differences in water collections. Also recently, a fasciolid-specific molecular assay has been developed to permit the study of seasonal transmission patterns and parasite-snail interactions. This assay detects individual
infected snails immediately after miracidial exposure
and throughout the parasite's development
period
(ROGNLlE, DIMKE & KNAPP, 1994), but possible crossreactions with other digenean parasites using the same
snail species have not yet been evaluated.
The development of the parasite larval stages in the
snails is inversely proportional to the ambient temperature (BORAY, 1969). Although studies have demonstrated that parasite development is arrested below 10° C or
over 30° C (BORAY, 1969; OLSEN, 1974), recent experimental research by MAS-COMA et al. (unpublished data)
carried out with an F. hepatica strain from the Northern
Bolivian Altiplano (4000 m altitude) has shown that this
parasite is sometimes able to adapt to more extreme conditions and continue its development even when the local daily ambient temperature falls below 0° C and the
water temperature decreases to 5° C during the night.
Lymneid snails appear to be more resistant to low than
to high temperature. They can survive through the winter
although there is little or no development and multiplication (BORAY, 1969). Contrarily, persistent high temperatures and dry conditions adversely influence both snail
populations and parasite larval stages. The metacercariae
may survive for long periods at low temperatures if the
level of moisture is sufficient, but they are susceptible to
desiccation and to temperatures over 25° C (BORAY,
1969). In contrast, high humidity associated with heavy
rainfall and moderate temperatures may herald hyperendemicity in herbivorous animals. Thus, human infection
has been more frequently observed in the years with heavy rainfall in France (RIPERT et al., 1988).
Mainly sheep, goats and cattle act as animal reservoir
hosts in relation to man. There is no evidence that sheep
or goats acquire immunity against F. hepatica, whereas
cattle are resistant to challenge after initial infections.
According to BORAY (1969), in sheep the egg output of
the adult flukes is relatively high (daily output of 400050000 eggs per fluke and 8800-25100 eggs per host in
weeks 13-19 after infection), whereas in cattle the duration of egg production is short and high egg output lasts
for only a few weeks. Most of the flukes in cattle are eliminated within 9-12 months (BORAY, 1969; DAWES &
HUGHES, 1964; SMITHERS, 1982). Thus, sheep play a
Human
liver flukes:
177
a review
more important role in contamination of the pastures and
in human transmission.
A large variety of other domestic and wild animals as
well as laboratory animals can be infected with F. hepatica, but they are usually not very important for transmission of the human disease (CHEN & MOlT, 1990). However, MAS-COMAet al. (1987, 1988, 1990) and VALEROet
al. (1992, 1998a) have demonstrated, both experimentally and in the nature, that the rat Rattus rattus may play
an important role in the epidemiology of the disease, in
the spread as well as in the transmission of the parasite, at
least in the Mediterranean island of Corsica. Moreover,
MAS-COMA et al. (1997) have recently concluded that
pigs and donkeys also represent important reservoir hosts
participating in the transmission of the parasite in human
endemic areas, such as the Northern Bolivian Altiplano,
and have consequently emphasized the need to take pigs
and donkeys into account within preventive and control
measures against human fascioliasis. Among wild animals, lagornorphs have also shown to be able to develop
a role in the epidemiology of the disease in different areas
(BAILENGERet al., 1965).
Worth mentioning at this point are the results of experimental research carried out by BARGUESet al. (1996b)
which demonstrate the viability of humans as definitive
host, eggs excreted by infected persons of the Bolivian
Altiplano being able to experimentally start the life cycle
of the parasite for several generations in the laboratory.
According to the investigations made by MAS-COMA et
al. (unpublished data) in the endemic zone of the orthern Altiplano of Bolivia, infected Aymara children undoubtedly participate in the transmission of the disease
in given localities owing to their defaecating habits.
Dietary habits of the human populations are very important in fascioliasis. Watercress and other aquatic vegetables able to carry attached metacercariae and included in the human diet in different countries serve as
vehicles of the infection. The habits of eating raw watercress and other vegetables cause the metacercariae to enter the human alimentary tract, but the possibility of
being infected by means of drinking water carrying floating metacercariae cannot be neglected (BARGUESet al.,
1996a). In some countries, such as in China, where vegetables are always cooked for eating, infection may rarely
occur by ingestion of unboiled drinking water, or from
the metacercariae on cutting boards and other kitchen
utensils (CHEN & MOlT, 1990).
The epidemiological analysis made by CHE & MOlT
(1990) on the existing data shows that there is no marked
seasonal incidence, human infections occurring nearly
throughout the year, that distribution by sex is very similar, although in Egypt a higher prevalence was observed
in women (10,3%) than in men (4,4%) (FARAG et al.,
1979), and that all age groups can be affected. However,
studies carried out on the Bolivian Northern Altiplano
endemic zone have demonstrated that children between
5 and 15 constitute the most infected age group (ESTEBANet al., 1997a, b). Fascioliasis is predominantly a ru-
ral disease and sheep- or cattle-herders are more frequently infected than those in other professions (STORK
et aI., 1973).
Further analysis of the literature allows us to distinguish three types of reports (CHE & MOlT, 1990): A)
the majority of papers concern only individual case reports; B) the incidence of infection is significantly aggregated within family groups because the family shares
the same contaminated food (FARAG et al., ·1979; GALLARDO,SAFZ & E RIQUEZ, 1976); C) the existence of
only a few reports on community-based surveys having
shown a large numbers of infected persons identified by
stool examinations combined with serological tests (FARAGet al., 1979 in Egypt; STORK et al., 1973 in Peru;
SAMPAIOSILVAin CHEN & MOlT, 1990 in Portugal) and
indicating that symptoms were not pathognomonic nor
were they severe enough for most persons to seek medical attention. Familial clustering and high prevalences
have been also found in community-based surveys in
Corsica and Bolivia, respectively (M AS-COMAet al., unpublished data).
Little information is available on the pathology offatal
fascioliasis (ACOSTA-FERREIRA, VERCELLI-RElTA &
FALCO I, 1979; DUAN et al., 1986) since death rarely
occurs. However, the histopathology of surgical specimens, or laparoscopic biopsies, has been reported by
many investigators from different countries. In contrast,
the literature on the experimental pathology of fascioliasis is extensive. A large review on pathology, symptomatology and clinical manifestations has been made by
CHE & MOlT (1990).
Pathogenesis depends on the number of flukes that penetrate the intestine wall and invade the liver. In animals
the mortality rate is inversely proportional to the number
of flukes in the liver. The penetration of the intestinal
wall may cause focal haemorrhage and inflammation.
The major pathological effects correspond to parasite
migration through the liver parenchyma for 4-6 weeks or
longer, flukes digesting hepatic tissue and causing extensive parenchymal destruction with intensive haemorrhages and inflammation. Migration tracks may be observed
in histological sections. Migratory flukes sometimes die,
leaving cavities filled with necrotic debris, and when
these heal, considerable areas of the liver may be replaced by scar tissue (SMITHERS, 1982). In man, the presence of the parasites in the bile ducts causes fewer pathogenic effects, although inflammation resulting in
fibrosis, thickness and expansion is common (CHE &
MOlT, 1990). ISSEROFF,SAWMA & REI 0 (1977) suggested that the extensive hyperplasia resulting in enlargement of the bile ducts is mediated by proline synthesized and released by the parasites. Both in animal and
human infections, anaemia is one of the most characteristic symptoms, especially in heavier infections (Bo-
178
RAY, 1969; DAWES & HUGHES, 1970). Blood loss into
the bile seems most probably to be an important, if not
the only, factor contributing to severe anaemia.
Immunologically, cell- and/or antibody-mediated response varies from host to host, and in the same host, according to the phase of the infection (OLDHAM, 1985).
Immunity to reinfection differs greatly from host to host.
Disease is self-limiting in cattle, as well as in rats, guinea pigs and rabbits, resistance being acquired during
the primary infections, but severe hepatic lesions and
high mortality may occur, particularly in young or debilitated animals. In sheep, as in goats, hamsters and mice,
low or no resistance is seen and the infection is highly
pathogenic in both the acute and chronic phases, death
being a usual sequela in heavy infections (BORAY, 1969;
SMITHERS,1982). In man, studies on immunity are limited, although it is generally believed that man is not a
suitable host, most migrating flukes becoming trapped in
the liver parenchyma and dying without reaching the
bile ducts (ACOSTA-FERREIRA, VERCELLl-RETTA &
FALCONI,1979). Considerable tissue reaction and calcification of the bile passages due to the flukes have been
recorded (ACOSTA-FERREIRA,VERCELLl-RETTA& FALCONI, 1979) and a spontaneous cure of the infection is
not uncommon (BORAY, 1969).
Disease is chiefly confined to the liver, so that the
most important pathogenic sequelae are hepatic lesions
and fibrosis, and chronic inflammation of the bile ducts.
Worth mentioning is that, unlike clonorchiasis or opisthorchiasis. there have been no reported associations with
biliary carcinoma.
According to CHEN & MOTT (1990), human liver is
usually enlarged with a smooth or uneven surface. The
most common macroscopic lesions are multiple soft, yellowish or grey white nodules ranging 2-30 mm in diameter, which microscopically appear to be eosinophilic
abscesses. Haemorrhagic stippling appears at the margin
of the nodules. White or yellow striae are observed on
the liver capsule. Close to the nodules. ribbed or vermiform formations with similar colour and consistency as
nodules are also observed. Hepatic capsular thickening
of varying degree appears, and in a few cases the entire
hepatic capsule is thickened. Subcapsular lymphatic vessels are dilated. The lymph-nodes near the porta hepatis
may be markedly enlarged. In cases with marked involvement of the peritoneal wall and the liver surfaces, yeHow and opalescent ascites was present. Apart from mild
splenomegaly in 2 patients, no significant portal hypertension was found in 18 cases by Japaroscopic examinations (MORETO& BARRON, 1980).
The common bile ducts are usually large and dilated
and the wall is thickened on palpation. The gall bladder
wall is greatly thickened and oedematous. Multiple, greyish-white subserous nodules are present and adhesions
of the gall bladder to adjacent structures are common.
The mucosal folds of the gall bladder are prominent. The
wall of the gall bladder appears thickened owing to muscular hypertrophy and perimuscular fibrosis. There is
glandular epithelial hyperplasia. All layers of the wall
contain patchy infiltrates with Iymphocytes, plasma cells
and eosinophils. Lithiasis, often multiple, in the common
bile ducts and gall bladders is very common (CHEN &
MOTT, 1990).
The microscopic changes may be specific or non-specific. Generally, the migration tracks can be found in the
liver and other organs. The walls of the tracks in the liver
often contain Charcot-Leyden crystals and eosinophils.
The cavities of the tracks are filled with necrotic cellular
debris, including hepatocytes, fibrin and red cells. A
considerable eosinophilic infiltrate surrounds the tracks.
Longer tracks can cross several hepatic lobules. In older
lesions macrophages, Iymphocytes, eosinophils and fibrous tissue are observed. Focal calcification is sometimes seen in the margin of the necrotic debris. Calcifications may form the outline of a dead fluke (CHEN &
MOTT,1990).
Egg granulomas have been described (ACOSTA-FERREIRA, VERCELLI-RETTA& FALCON], 1979; GOODMAN, HENDERSON & CULLlTY, 1973; IONES et al.,
1977). The portal triads were dilated and oedematous
with infiltrates of lymphocytes and eosinophils. Bile
duct proliferation, periductal fibrosis, necrotizing arterial
vasculitis and portal venous thrombosis were frequent.
Immature flukes may deviate during migration, enter
other organs and cause ectopic fascioliasis. In cattle, F.
hepatica is frequently observed in the lungs (SOULSBY,
1965). In man, the most frequent ectopic lesions are
those of the gastrointestinal tract (ACOSTA-FERREIRA,
VERCELLl-RETTA & FALCONI, 1979; PARCK et al.,
1984). Other ectopic lesions are in: abdominal wall (ToTEV & GEORGIEV, 1979), pancreas (CHITCHANG,MITAR UM & RATANANIKOM,1982), spleen (WEI, 1984),
subcutaneous tissue (AGUIRRE ERRASTIet al., 1981b;
GARCIA-RODRIGUEZet al., 1985; PARCK et al., 1984),
heart (CHO et al., 1994), blood vessels, the lung and
pleural cavity (GARCIA-RODRIGUEZet al., 1985; PARCK
et al., 1984), brain (RUGGIERI, CORREA & MARINEZ,
1967), orbit (GARCIA-RODRIGUEZet al., 1985; CHO et
al., 1994), skeletal muscle, appendix (PARCK et al.,
1984) and epididymis (AGUIRREERRASTIet al., 1981 b).
Such ectopic flukes never achieve maturity. The usual
pathological effects of ectopic lesions are due to the migratory tracks causing tissue damage with inflammation
and fibrosis. Parasites may be calcified or become incorporated in a granuloma (FACEY& MARSDEN,1960).
From the clinical point of view, the following periods
can be distinguished (FACEY& MARSDEN, 1960; MANGOS & MENZIES, 1973): the incubation period (from the
ingestion of metacercariae to the appearance of the first
symptoms), the invasive or acute phase (corresponding
to fluke migration up to the bile ducts), the latent phase
(beginning with the maturation of the parasites and starting of oviposition), and finally the obstructive or chronic phase.
The incubation period varies considerably depending
on the number of metacercariae ingested and the host's
response. The period of incubation in man has not yet
been accurately determined: only «a few» days (RAGAB
& FARAG, 1978), 6 weeks (RIMBAULT, 1981), or 2-3
months (HARDMA , laNES & DAVIES, 1970).
In the acute phase, the symptomatology is due mainly
to the mechanical destruction of the liver tissue and of
the abdominal peritoneum by the migrating larvae causing localized or generalized toxic and allergic reactions
lasting 2-4 months. However, in endemic areas, the infection with F. hepatica is usually repetitive and the
acute lesions are superimposed on chronic disease. Thus,
the acute phase may be prolonged and overlap on to a latent or an obstructive phase. The major symptoms of this
phase are fever, abdominal pain, gastrointestinal disturbances and urticaria. Fever is usually the first symptom,
usually low or moderate but sometimes reaching 40° C,
and in heavily infected cases as high as 42° C; it may be
remittent, intermittent or irregular with higher temperature in the evening. In some cases, a low, recurrent fever
lasted for a long time (4 to 18 months). Abdominal pain,
from mild to excruciating, was generalized at the outset
but usually localized in the right hypochondrium or below the xyphoid, sometimes vague. Among gastrointestinal disturbances, loss of appetite, abdominal flatulence,
nausea and diarrhoea are common, whereas vomiting
and constipation are infrequent. Urticaria, with derrnatographia, is a distinctive feature in the early stage of the
fluke invasion and may be accompanied with bouts of
bronchial asthma. Among respiratory symptoms, nonproductive cough is common, whereas chest pain occurs
occasionally. In the acute phase, the following signs may
appear on physical examination: hepatomegaly and splenomegaly, ascites, anaemia, chest signs and jaundice
(CHE & MaTT, 1990).
The latent phase can last for months or years. The proportion of asymptomatic persons in this phase is unknown. Diagnosis of infection may be confirmed after clinical suspicion or in epidemiological surveys by finding
the eggs in the duodenal fluid and/or in the stool. An
unexplained, prominent eosinophilia may suggest a helminthic infection. These persons may have gastrointestinal complaints or one or more relapses of the acute
symptoms during this phase (FACEY& MARSDEN,1960;
MANGOS& ME ZIES, 1973).
A chronic or obstructive phase may develop after
months to years of infection. Adult flukes in the bile
ducts cause inflammation and hyperplasia of the epithelium. Thickening and dilatation of the ducts and the gall
bladder walls ensue. The resulting cholangitis and cholecystitis, combined with the large body of the flukes,
are sufficient to cause mechanical obstruction of the biliary duct, which is comparatively small in diameter.
The proportion of those whose infection develops into
the obstructive phase or their prognosis has not been defined. The clinical manifestations in this phase, such as
biliary colic, epigastric pain, fatty food intolerance, nausea, jaundice, pruritus, right upper-quadrant abdominal
tenderness, etc., are indistinguishable from cholangitis,
179
cholecystitis and cholelithiasis of origins other than F.
hepatica infection. Hepatic enlargement may be associated with an enlarged spleen or ascites. If obstruction is
present, the gall bladder is usually enlarged and oedematous with thickening of the wall. Lithiasis of the bile duct
or the gall bladder is frequent. Stones are usually small
and multiple. The bile duct and the gall bladder may
contain blood mixed with bile (haemobilia), blood clots
and fibrinous plugs. The diagnosis has usually been confirmed at laparotomy by the finding of flukes in the common bile duct or in the gall bladder, commonly associated with cholangitis and cholelithiasis. With proper
clinical management - removal of the obstruction and
temporary biliary drainage - the prognosis is good
(CHEN & MaTT, 1990).
The outstanding abnormal laboratory finding in all
phases of F. hepatica infection is eosinophilia (always
greater than 5%, the highest detected being 83%), accompanied by leucocytosis (over 10000/mm3 up to
43000/mm3), especially in the acute phase. Anaemia is
common, but usually not very severe (mostly between
7,0 and 11,0 g/dl haemoglobin; levels as low as 2.8 and
4.0 g/dl have been reported). The erythrocyte edimentation rate (ESR) may be high in the acute phase (possibly
reaching 165 mm in an hour). Abnormal liver function
tests may be seen both in the acute and in the obstructive
phases, but high serum bilirubin levels are associated
with the obstructive phase (CHEN& MaTT, 1990).
Serum immunoglobulin studies (laNES et al., 1977;
SALEM, ABOU BASHA & FARAG, 1987; SAMPAIOSILVA
et al., 1985) have shown that levels for IgG, IgM and
IgE are usually elevated. Specific IgE antibodies were
detected in 48% of the patients. Total and specific IgE
levels have been shown to be positively correlated with
the egg burden, age, clinical features and degree of eosinophilia. Ig A levels are usually normal.
In man, complications may comprise bleeding and biliary cirrhosis, which may be the major causes of death.
Death is rare as the infection is usually sporadic and the
overall prevalence is low. Only 8 deaths related to fascioliasis have been reported in the recent literature
(CHEN & MaTT, 1990).
Diagnosis
Coprological examination is still the main method for
diagnosis. However, serological methods have been developed and have confirmed the diagnosis in the acute
phase of the disease, in which no eggs can be found in
stools owing to the absence of sexually mature adults in
this initial phase. They are also useful for monitoring
post-treatment evolution.
Parasitological diagnosis is based on egg identification
in the stool or in duodenal or biliary drainage. The possibility of a spurious infection must always be taken into
account, the presence of eggs in faeces being only the
consequence of the consumption of infected liver from
ruminants. To avoid false fascioliasis, stool examination
180
should be repeated after a few days of a liver-free diet.
Methods for the detection of the presence of parasite
adults can also be applied. Adult flukes and/or eggs may
be found in the biliary tract or in the bile at exploratory
laparotomy. Histological examination of liver biopsy
material may occasionally reveal an egg granuloma or
sections of the fluke. It must also be taken into consideration that the prepatent period is about 3-4 months, so
that coprological techniques become useful only after
that moment.
According to CHEN & MOTT (1990), coprological
techniques, ranging from a simple direct smear to different concentration methods, have been used. Egg concentration has been achieved by flotation, sedimentation
(ASHTON et al., 1970; BENDEZU, FRAME & HILLYER,
1982; BOLBOL, 1985; BORAY, 1969; DE LEON, QUINONES & HILLYER, 1981; FARAGet al., 1979; KNOBLOCH
et al., 1985; STORKet al., 1973) and the cellophane faecal thick-smear techniques (Kato, Kato-Katz) (KREMER
& MOLET, 1975). The sedimentation technique is more
accurate and sensitive than flotation techniques as most
of the hyperosmotic solutions distort the eggs (BORAY,
1969). The Kato cellophane faecal thick-smear technique has the advantages of being rapid, having low cost,
being reproducible and quantitative. The Kato technique
has been used in the diagnosis of experimental F. hepatica infection (LEVlNE, HILLYER & FLORES, 1980) but,
although it may be useful in epidemiological studies, its
relatively low sensitivity limits its clinical application.
According to KNOBLOCHet al. (1985), rapid sedimentation (using 20 g faeces on each of 3 consecutive days),
although inconvenient, seemed to be largely more sensitive than the merthiolate-iodine-formaldehyde
concentration method (MIFC) (using 1 g of faeces in a single
examination) or the Enterotest (single examination of
duodenal fluid). Among five concentration techniques
compared by AKAHANEet al. (1975), the recovery rates
were: formalin-ether method, 5,3%; HCl- ether method,
7,8%; Weller-Damrnins
modification method, 37,7%;
citrate buffer-Tween 80-ether method, 25,3%; and
AMS III (Tween 80) method, 30,5%.
The early diagnosis of the acute phase may be achieved by immunological techniques.
Skin tests employing an antigen prepared from the
adult flukes (SMITHERS,1982) or purified fraction of F.
hepatica (STORK et al., 1973) have been used occasionally since the early 1960s. The tests were simple and
sufficiently sensitive to propose a diagnosis of the infection (CAPRONet al., 1973) but not very specific (STORK
et al., 1973). The technique is rarely used nowadays.
During the past 2 decades, with the development of
new technology, different serological tests have been
used both in experimental infections and in humans (see
review by CHEN & MOTT, 1990). These include: complement fixation (CF), immunofluorescence assay (IFA),
counter-electrophoresis (CEP), enzyme-linked imrnunosorbent assay (ELISA), kinetic-dependent ELISA, double diffusion,
indirect
haemagglutination
(IHA),
enzyme-linked immuno-electrotransfer blot (EITB), Falcon" assay screening test-enzyme linked irnrnunosorbent assay (FAST-ELISA), automated assay of anti-PI
antibodies, circulating antigen, and circulating immune
complex (CIC). Almost all the serological tests are
highly sensitive. With partially purified somatic or excretory-secretory products of adult F. hepatica as antigen, ELISA (ESPINOet al., 1987; HlLLYER, 1981; HILLYER & SANTIAGODE WElL, 1979; LEVlNE, HILLYER&
FLORES, 1980), IFA (BULAJICEet al., 1977; CAPRONet
al., 1973) and CEP (HILLYER, 1981; HILLYER & SA TIAGODE WElL, 1981) have been reported to have the
highest sensitivity and specificity. IFA was reported to
have 92-96% sensitivity in the acute phase of the infection by CAPRONet al. (1973). In chronic infection with
F. hepatica, IFA and CEP may not be positive (CAPRON
et al., 1973). However, cross-reactions in other helminthic infections such as schistosomiasis, ascariasis and filariasis have been reported. Crude F. hepatica antigen
may have cross-reactivity with other trematodes (HILLYER, 1981). The specificity of the serological tests may
be improved by elimination of cross-reactivity with antibodies to Schistosoma and other trematodes through partial purification of the antigen (HILLYER & SANTIAGO
DE WElL, 1979). Summing up, no consensus as to the
optimal antigen or test system has been reached so far
(STORKet al., 1973; CHEN& MOTT, 1990).
Worth mentioning are several experimental studies having shown that after effective chemotherapy, anti-F. hepatica antibodies became undetectable: ELISA titres
dropped rapidly and the test was useful for the evaluation of chemotherapeutic
success (HILLYER & SANTIAGODE WElL, 1979), precipitins in CEP test disappeared by 4 weeks (HlLLYER & SANTIAGODE WElL, 1981),
and CEP and ELISA became negative 3-4 weeks later
(LEVlNE, HILLYER & FLORES, 1980). However, double
diffusion and IHA became negative after a longer period
(1-2 years after treatment) according to GARCIA-RoDRIGUEZ,MARTINSANCHEZ& GARCIALUlS (1985).
The clinical presentation may be helpful for the diagnosis (CHEN & MOTT, 1990). Fascioliasis is frequently
considered among the differential diagnoses in a wellknown endemic area. However, in areas where the disease is rarely reported or absent, physicians may not consider this diagnostic possibility. History of ingestion of
raw wild or cultivated watercress or other vegetables, or
other contaminated food or water may be suggestive of
the infection.
According to ARJONAet al. (1995), the clinical situations in which the diagnosis of F. hepatica infection
should be considered are: history of watercress ingestion, eosinophilia, fever of unknown origin, atypical abdominal pain, focal intrahepatic lesions, granulomatous
hepatitis, serositis and meningitis with peripheral or
fluid eosinophilia, family history of fasciolosis, biliary
colic or cholangitis, and normal ultrasonography. Eosinophilia has also been successfully used for a first selection in general surveys (GlL-BENlTO et al., 1991).
In the acute phase the clinical presentation includes fever, pain in the right hypochondrium, prominent eosinophilia with leucocytosis, anaemia and a moderately to
significantly high ESR.
In the chronic (latent and obstructive) phase the clinical
picture is attenuated and easily confused with other diseases. The classic pattern includes: vague gastrointestinal
complaints, pain in the right hypochondrium or epigastrium, cholecystitis, cholangitis and bile duct or gall bladder stones. The liver is usually enlarged with or without
pain on palpation. Ascites may appear in advanced cases.
Non-invasive diagnostic techniques which can be used
for the diagnosis in this chronic phase are radiology, radioisotope scanning, ultrasound and computed tomography (CT). Fascioliasis has been diagnosed by: abdominal and chest X-ray examination; oral, percutaneous
and intravenous cholangiography; and endoscopic retrograde cholangio-panchreatography
(ERCP). However,
the findings are not pathognomonic of F. hepatica infection. Radioisotope liver scan may be useful in the diagnosis of fascioliasis, patterns observed being however
not specific. Ultrasound has proved useful in the diagnosis of the pathological lesions secondary to F. hepatica
infection in the liver and the biliary tract (BASSILY et al.,
1989). In fascioliasis, the ultrasound image is usually
normal and the individual adult flukes are not visualized
by the current ultrasound technology. CT has a high level of resolution for auxiliary and pathological diagnosis
of F. hepatica infection. Several months after treatment
for F. hepatica infection, a marked improvement in the
CT images has been shown by different investigators.
The multiple hypodense areas in the liver were reduced
significantly in number and size (DE MIGUEL et al.,
1984; GOEBEL,MARKWALDER& SIEGENTHALER,1984;
PAGOLASERRANOet al., 1987; TAKEYAMAet al., 1986).
CT scan can be a useful tool for the diagnosis of the disease and its possible complications as well as followup
of the patient's response to the treatment.
In both the acute and chronic infections, ectopic localization of the parasite may cause a confusing clinical presentation.
An acute dysphagia and laryngeal obstruction after ingestion of raw liver of sheep or goats, was formerly considered to be due to invasion of immature F. hepatica
and was known as «Halzoun» or pharyngeal fascioliasis
(FACEY & MARSDE , 1960). Now it is attributed to the
ingestion of nymphs of Linguatula serrata, a pentastomid parasite (CHATTERJEE,1975).
Treatment
Emetine and dehydroemetine are the classic drugs and
have been used widely, at a usual dose of 1 mg/kg daily
for 10 days given intramusculary or subcutaneously
(CHEN & MOTT, 1990). They are effective and are still
being used. However, owing to their side effects, several
other types of drugs have been developed during the past
decade.
181
Hexachloro-para-xylol
has been effectively used at a
dose of 50-80 mg/kg body weight daily divided into 3
doses given orally for 7 consecutive days in China (SUN,
CHAI & CHENG, 1984; WANG et al., 1981) and at a dose
of 60 mg/kg daily for 5 days in the former USSR (KHASHIMOV & KAMARDINOV, 1975; RAKHMANOV, 1987),
side effects including gastrointestinal complaints and
dizziness.
Bithionol (Bitin) is used at a dose of 50 mg/kg daily,
divided into 3 oral doses on alternate days for 15 days. In
cases of fascioliasis resistant to emetine and praziquantel
treatment, bithionol achieved cure in dosages of 50
mg/kg daily for 10 alternate days (GRADOS& BERROCAL, 1977) or 40 mg/kg daily for 15 alternate days
(BHATTACHARYYA,1985). The side effects are mild and
are related to the gastrointestinal tract including anorexia, nausea, vomiting and abdominal pain.
Daily oral doses of 1,5 g of metronidazole for 13, 14,
21 and 28 days were effective in 4 patients (NIK-AKHTAR & TABIBI, 1977), but a smaller total dose of 4 g was
reported to have failed to cure a chronic infection (ECKHARDT& HECKERS,1981).
Albendazole is a broad-spectrum anthelmintic which
has been demonstrated to be effective in cattle at a single
oral dose of 15 mg/kg body weight (MI et al., 1983)
and sheep at a single dose ranging from 3.8 to 7.5 mg/kg
body weight, but the efficacy of the drug against the immature flukes was lower (JOHNS& DICKESON,1979).
Mebendazole, in a daily dose of 4 g for 3 weeks, was
reported to have cured a F. hepatica infection diagnosed
clinically and serologically in the invasive phase (DUGERNIERet al., 1986). Diamphenetide was effective both
in vitro (FAIRWEATHER,A DERSO & THREADGOLD,
1988) and in experimentally infected sheep at 120 mg/kg
body weight (JIN et al., 1984). Rafoxanide was reported
to be effective in sheep and cattle (CAI, 1988) and was
used in the treatment of a child with fascioliasis (YURDAKOK,1985).
Niclofolan, widely and successfully used for veterinary
purposes in China (CHEN & MOTT, 1990), has been applied twice for human treatment showing such a toxicity
that clinical use cannot be recommended (ECKHARDT&
HECKERS,1981; RESHEF,LOK & SHERLOCK,1982).
Worth mentioning is that Fasciola may be the only genus of trematode that has practically no response to praziquantel, most clinical reports having shown that praziquantel failed to cure F. hepatica infections, even at high
doses (CHEN & MOTT, 1990). In vitro and in mice, rats
and sheep, F. hepatica is refractory to praziquantel (ANDREWSet al., 1983; PEARSON& GUERRANT,1983).
Triclabendazole is effectively used in veterinary medicine against both adult and immature F. hepatica. In experimental studies in sheep, BORAY et al. (1983) and
TURNER et al. (TURNER, ARMOUR& RICHARDS,1984)
showed that doses of 2,5-5,0 mg/kg body weight eliminate almost all the flukes (98,1-100% reductions) 12 weeks after infection. A higher dose of 10 mg/kg body
weight achieved reductions of 93-98% of the flukes, one
182
week after infection (BORAY et al., 1983). Concerning
humans, there are some preliminary clinical data already
published, although this drug is not yet registered for human use (CHEN& MOTT, 1990). Three patients were effectively treated (12 mg/kg single dose for the first patient; 5 mg/kg first dose, followed by 10 mg/kg second
dose on the next day for the second patient; 10 mg/kg
single dose for the third patient). Clinical tolerability
was excellent in 1 of these patients while in the other 2
patients after a single dose a transient febrile episode
with reversible liver function alteration was observed
(MARKWALDERet al., 1988; WESSELY, REISCHlNG &
HEINERMANN,1987; WESSELY et al., 1988). Four patients, whose diagnosis was confirmed by specific immunoelectrophoresis
and indirect haemagglutination,
were also successfully treated with a single dose of 10
mg/kg (LE BRASet al., 1989). Three other patients have
been treated with a single oral dose of 10 mg/kg body
weight; two of them recovered steadily over 3 weeks,
but the third again felt ill after a month of slight improvement, very few eggs being found in subsequent stool
examinations, so that a second treatment of triclabendazole in 2 successive postprandial doses (10 mg/kg) 12
hours apart were given (LOUiAN et al., 1989).
No new drugs have been developed during the last 15
years for the treatment of fascioliasis and drug resistance in F. hepatica has already been reported to affect
the efficacy of the drugs against immature stages. Drug
combinations have been recently tested and it was
shown that their synergistic action increased efficacy
against immature flukes, removed resistant flukes and
would also reduce the development of resistance (BoRAY, 1994).
Among the current drugs, until triclabendazole is registered for human use, bithionol seem to be the drug of
choice, although its treatment course is comparatively
long. Emetine and dehydroemetine are still effective
drugs. Triclabendazole, albendazole and niclofolan are
quite effective in veterinary infections, but the absence
of toxicological information required for registration or
clinical trials in man, their use cannot yet be recommended (CHEN & MOTT, 1990).
the livestock farming community. Forecasts of outbreaks
may be made based on climatological data and epidemiological models. Recommendations for control measures should be made on a preventive rather than a curative basis, and all measures have to be considered from
the point of view of the economy and assessment of local topographical and meteorological conditions. The efficiency of fascioliasis control depends on the correct
and integrated application of: A) reduction of the parasite load of the animal hosts and pasture contamination
by regular strategic use of drugs (preventive treatment in
appropriate year periods according to different regions);
B) reduction of the number of snails by physical, chemical and biological means; C) reduction of the risks of infection through correct farm management practices (rotational system through fluke-infected and fluke-free
paddocks, combined with effective treatment) (BORAY,
1982). A wide variety of candidates for vaccination has
been proposed and studied at veterinary level, and the
possibility of disposing of an effective vaccine for ruminants seems feasible even for the near future, but further
work is needed.
Contrarily to the veterinary aspect, owing to the well
known important impact of fascioliasis on production
(DARGlE, 1986), intermediate snail host control has unfortunately not received the attention from public health
officials required to definitively eliminate transmission
(CHEN & MOTT, 1990). Intensive agricultural methods
must be applied to reduce suitable snall habitats. Besides
physical methods, there are available control strategies
which consist of the use of chemical molluscicides, natural molluscicides of plant origin, biological control (including predators, competitors, the decoy effect and related phenomena,
parasitic
castration,
interspecific
trematode antagonism, and pathogens), genetic manipulation, and engineering control (MALEK, 1985; COMBES
& CHENG, 1986). The practical application of chemical
methods in the control of snails is of doubtful value, requires labor and equipment, and regular yearly strategic
moIluscicide applications (BORAY, 1982).
FASCIOLA
GIGANTICA
The prevention of human fascioliasis may be achieved
simply by strict control of watercress and other metacercariae-carrying aquatic plants for human consumption,
especially in endemic zones. Commercial growing of
watercress should be carried out under completely controlled conditions, without access for snails and ruminants. Worth mentioning in endemic areas is that the
community should be appropriately informed about the
disease, its transmission and its danger.
As for control measures, previous epidemiological studies may provide for general recommendations on the
appropriate time for treatment with effective drugs to
achieve economic control, and better information from
Morphology
First described from a giraffe (COBBOLD, 1855), the
giant liver fluke has a morphology similar to that of F.
hepatica, but is much larger and slightly narrower, measuring 24-76/5-13 mm. The average length/width ratio is
4,39-5,20 in F. gigantica, while it is 1,88-2,32 in F. hepatica (SAHBA et al., 1972). Other differental characteristics are the following: in F. gigantica, the shoulders
are less developed, the cephalic cone is shorter, and the
caeca are more branched than in F. hepatica, especially
those toward the midline of the body (the centipedal
branches). The branches of the ovary are longer and
more numerous in F. gigantica and are smaller and club-
183
shaped in F. hepatica. The average distance between the
posterior border of the body and the posterior testis is
longer in F. glgantica (14,9 mm; range: 6-19 mm) than
in F. hepatica (7,78 mm; range: 3-13 mm) (SAHBAet aI.,
1972). The eggs are morphologically similar to those of
F. hepatica but larger, measuring 150-196/90-100 urn.
VARMA(1953) erected F. indica for the liver flukes of
India, thus differentiating it from F. gigantica. However, SARWAR (1957) and KENDALL& PARFITT (1959)
considered both identical. As already stressed by KENDALL (1965), morphological differences detected seem
to be attributable to differences in fixation and mounting of materials, normal biological variation within a
species or even to the use of material from different
hosts. At any rate, evidence from experimental infections suggests that various strains of the parasites have
developed because of geographic isolation (MANGO,
MANGO & ESAMOL, 1972; SRIVASTAVA & SINGH,
1974; KHAJURIA& BAll, 1987).
Mapping of rDNA genes did not allow BLAIR & Mc
MANUS (1989) to detect intraspecific variation in F. gigantica from Indonesia and Malaysia. Worth mentioning
is that one specimen of Fasciola sp. from Japan (where
both F. hepatica and F. gigantica overlap, causing identification problems because of the detection of intermediate
forms) yielded a restriction map identical to that of F. gigantica. Studies by ADLARDet at. (1993) on the nucleotide sequence of the 3' end of the second internal transcribed spacer region (lTS-2) of the ribosomal DNA showed
sequence divergence between F. hepatica and F. gigantica (2,8%) and the sequence of Fasciola sp. from Japan
closely matched that of F. gigantica. More recently, HASHIMOTOet al. (1997) concluded that Japanese Fasciola sp.
must be considered a strain of F. gigantica, taking into account the absence of differences in the sequences of the
ITS-2 and the similarity of the sequences of the mitochondrial cytochrome c oxidase subunit I (COl).
It is a common parasite of the bile ducts and gall bladder of domestic and wild herbivorous animals, especially
ruminants, in Africa and Asia. Reported definitive host
species are sheep, goat, cattle, and buffalo, camel, pig,
horse, donkey, larger antelope, deer, giraffe, and zebra.
Occasionally F. gigantica has also been reported in nutria and in monkeys. Several species of laboratory rodents can also be infected experimentally (BORAY,
1982). Many other African wild animals have been also
found naturally infected (Losos, 1986).
Reports in humans
There are relatively few records
with F. gigantica, and furthermore,
fer to single cases or to very small
although this parasite is widespread
tropics and subtropics.
of human infection
nearly all of these renumbers of patients,
in many areas of the
In Africa, human infection with F. gigantica has been
recorded in many countries. Human cases have been
diagnosed in Rwanda and Burundi (JANSSENSet al.,
1968; HAMMOND, 1974), Malawi (SPECKHART,1969;
HAMMOND, 1974), Rhodesia (PERRY, GOLDSMID &
GELFAND, 1972; HAMMOND, 1974), Uganda (HAMMOND,1974), southern Africa (GELFAND, 1971; GOLDSMID, 1975), Zaire (FAIN, DELVILLE & JACQUERYE,
1973), Cameroon and Gabon (GRANGE et al., 1974;
HAMMOND,1974), Madagascar (MOREAU et al., 1975),
Zambia (HIRA, 1976), Egypt (MANSOUR et aI., 1983),
Mali (MAIGA et al., 1991), and Cabo Verde archipelago
(CRUZ E SrLvA et aI., 1972).
In Asia, reports of human fascioliasis sometimes do
not refer to the species of Fasciola because both F. hepatica and F. gigantica occur in the country in question
or because the specific identity is not agreed upon;
among these countries are Iran, China, Korea, and Japan.
In Iran, FARID(1971) identified three cases by stool examination and cited 11 other cases previously reported in
that country. In Korea, a case was described by CHO et
al. (1976) in which a complete worm, identified as Fasciola sp., was removed during bile duct exploration; the
morphology of this worm was considered intermediate
between F. hepatica and F. gigantica. This is also the
view of Japanese investigators concerning the Japanese
Fasciola (WATANABE(1965). In Japan, only 19 cases
were reported up to 1974, the last of which was a 49year-old woman from Kyoto City; the parasite was identified as Fasciola sp. on the basis of eggs in the faeces
and bile (YOSHLDAet al., 1974). Sometimes, however,
human infection was diagnosed as concretely caused by
F. gigantica (ISHIGAMIet al., 1973). Human parasitation
by F. gigantica has also been recorded in former USSR
(Tashkent and Uzbekistan), Vietnam, and Iraq (HAMMOND, 1974). Recently, SADYKOV(1988), in post-mortem examinations, detected fascioliasis in 81 inhabitants
of the Samarkand region, USSR, in 1968-1986; F. hepatica was in 45, F. glgantica in 25, and both species in 11;
deaths were not due to fascioliasis, which was detected
incidentally, suggesting that it is much more frequent
than reported. More recently, TESANA, PAMARAPA&
SIO (1989) reported human fascioliasis by F. gigantica
from Northeast Thailand.
Cases have also been reported from humans in Hawaii
(ALlCATA, 1938, 1953). ALlCATA& BONNET(1956) stated that at least 19 outbreaks occurred on the island up to
1956.
As already stated by HAMMOND(1974), human infection with F. gigantica may be more common than is
thought, but has not been reported more frequently because it has not been looked for adequately. A further
possible reason for the apparently low human infection
rate is that the disease may be mild and cause few symptoms in persons of given ethnic groups. Thus, the symptomatology observed in indigenous persons in Malawi
were mild as compared with those in three Europeans in
central Africa and in some cases reported in Hawaii. At
184
any rate, it is impossible to compare these reports in detail without information on the level of infection.
GOLDSMID(1975) believes that the overall paucity of
human records of fascioliasis in the wetter areas of southern Africa, even where fascioliasis in domestic stock is
common, may be due to the fact that fascioliasis, being a
rural infection, is often not diagnosed in such country
clinics which have no laboratory facilities. Probably this
is also the case in other parts of Africa and other parts of
the world. Even where laboratory facilities are available,
infected patients do not always pass eggs, as in the case
recorded by PERRY,GOLDSMID& GELFAND(1972).
According to BORAY(1982), F. gigantica is present in
large areas of the African continent, from the Nile Delta
in the north to the Cape Provinces of South Africa in the
south, including Sudan (MALEK, 1959), Senegal (VASSTLIADES,1974), Chad (GRABER& OUMATIE, 1964), Guinea-Bissau (MANDINGA, 1986), Ghana (ODEI, 1966),
Togo (GNINOFOU,1988), Niger (TAGAR-KAGAN, 1977,
1979), Central African Republic (GRABER & THALL,
1979), Tanzania (MEGARD, 1975) and Kenya (WAMAE
& CHERUIYOT,1990), as well as Mocambique, Ethiopia,
Ivory Coast, Liberia, Sierra Leone, Nigeria, Zimbabwe
and Angola (SCHILLHORNVAN VEEN, 1980; Losos,
1986), besides the already mentioned Rwanda and Burundi, Malawi, Rhodesia, Uganda, southern Africa,
Zaire, Cameroon, Gabon, Zambia, Egypt and Mali. It is
also present in the islands of Cabo Verde (CRUZ E SILVA
et al., 1972), Zanzibar and Madagascar (BORAY, 1982).
The major endemic areas of F. gigantica are tropical
Asia, Southeast Asia, and the Pacific regions, including
countries such as old USSR (Tashkent, Uzbekistan,
Turkmenia, Samarkand region), Iran, Iraq, China, Korea,
Japan, India, Pakistan, Vietnam, Thailand, Laos, and finally, in the Pacific, Malaysia, Philippines and Hawaii.
F. gigantica infection is one of the most important diseases threatening the livestock populations of India, Pakistan, Indonesia, Indochina, and the Philippines. Less important endemic areas of F. gigantica are the southern
parts of Europe, Turkey, the Near East, and some southern states of the old USSR, particularly Armenia (BoRAY, 1982).
In North America, according to PRICE (1953), there
seem to be 3 Fasciola types in animals in the USA: those
from various parts of the U.S. which are identical to F.
hepatica of the Old World, those from Texas and Florida, approaching F. gigantica, and those from the Gulf
coast area which appear to be intermediate between F.
gigantica and F. hepatica. This author stated two possibilities: whether they are a consequence of importations
into the Gulf coast area from India carried out in the years 1875 and 1906, or simply the consequence of intraspecific variability of a same species.
Overlapping infections may occur with both F. hepatica and F. gigantica in some parts of Africa, Asia and
North America, where the snail intermediate hosts are
suitable for both species. Generally, in tropical countries
where both species exist together, F. gigantica is usually
endemic in the lower regions while F. hepatica is endemic in the highlands (BORAY, 1982).
Life cycle
The life cycle is essentially similar to that of F. hepatica and includes Iymnaeid snails, especially those species associated with standing or slow-flowing water containing abundant vegetation, in which sporocyst and
rediae develop (ALICATA, 1938, 1953; THAPAR& TANDON, 1952; DINNIK & DINNIK, 1956, 1963; KE DALL,
1965). The miracidium of F. gigantica shows a different
behaviour from that of F. hepatica. The miracidium of
F. hepatica is positively phototropic and negatively geotropic, as an adaptation to the amphibious or water surface snails. In F. gigantica, it moves into deeper waters
which harbour Lymnaea natalensis in Africa and varieties of L. auricularia in Asia. AUCATA (1938) observed
2 redial generations, only the second being cercariogenous. DLNNIK& DINNTK(1963, 1964) observed 3 redial
generations, cercariae alternating with rediae in all 3 generations depending
on environmental
conditions.
OGAMBO-ONGOMA& GOODMAN(1976) found 4 generations of rediae, the third and fourth being cercariogenous. Shedding of cercariae by the snail shows a nocturnal periodicity, emergence taking place in the dark phase
(PRASAD, 1992). Shed cercariae attach to water plants
and become encysted metacercariae, which infect the definitive host by ingestion. The intraorganic migration of
the fluke up to the final location of the adult stage is similar to that of F. hepatica.
Principal or obligatory intermediate snail hosts mentioned for F. gigantica are: Lymnaea natalensis in Africa, L.
auricularia sspp. in the Near East, Middle East, Far East
and southern states of the old USSR, L. cubensis in North
America on the gulf coast, L. rufescens in Asia and the
Indian subcontinent, L. rubiginosa in the Far East and
Malaysia, L. swinhoei in South Eastern Asia, and the Philippines, and L. ollula in Hawaii and Japan. Alternate or
facultative host species are: L. truncatula in Africa, L. peregra in the Near East, Middle East, and southern states
of the old USSR, L. columella on the North American
gulf coast, and L. viridis in the Far East (BORAY, 1982).
L. caillaudi in Egypt (FARAGet al., 1979), L. gedrosiana
in Iran, L. euphratica in Iraq and L. luteola in Nepal (MoREL& MAHATO, 1987), as well as L. bactriana, L. tenera
and L. subdisjuncta in Turkmenia (CHARVEY,1989) must
be added.
These Iymnaeid intermediate hosts of F. gigantica are
distinguishable from those of F. hepatica, both morphologically and as to habitat requirements. Their habitats
are permanent water bodies rich in aquatic vegetation.
Human
liver flukes:
185
a review
Interestingly,
a planorbid species, Biomphalaria alexandrina, has recently been found naturally infected by
F. gigantica larval stages in Egypt (FARAG & EL SA YAD,
1995). The epidemiological
tions of this finding remain
and transmission
unknown.
implica-
Epidemiology
Mode of spread, epidemiology
and factors influencing
the life cycle are similar for both F. hepatica and F. gigantica. There are, however, several differences:
intermediate host snails are not drought-resistant
as are molluscan hosts of F. hepatica; the rate of development
of
the various stages of F. gigantica is slower; F. gigantica
metacercariae
survived longer at high temperatures
and
are more susceptible to desiccation
than F. hepatica metacercariae (BORA Y & ENIGK, 1964); Iymnaeid intermediate hosts need higher temperatures
(>20° C) for their
development
(MEGARD, 1975). All this suggests that F.
gigantica is a parasite which is adapted to tropical areas
and to aquatic snails and to an aquatic environment
for
its transmission.
This is related to the fact that F. hepatica prevails in temperate zones while F. glgantica is
predominant
in tropical regions (OVER, 1982).
Prevalences
of F. gigantica infection differ according
to different regions and zones, as well as to definitive
host species and races. The following prevalences
have
been recorded: 3% in Chad, 30% in the Central African
Republic, 45% in Cameroon,
37% in Sudan, 30-90% in
Ethiopia, 16% in Uganda, 4-8% in Tanzania, 60-70% in
Zimbabwe,
50% in Ruanda and 33% in Kenya (MEGARD, 1975).
Human infection takes place by the accidental
ingestion of raw vegetation, including watercress (ALlCATA &
Bo
ET, 1956) containing
encysyted
metacercariae,
particularly
in areas where infected cattle are permitted
to roam (STEMMERMAN , 1953a, b). In Africa, human
infections with F. gigantica are believed to be caused by
ingestion of watercress
in Rwanda and Burundi (JANSSENS et al., 1968), and infection could also occur after
chewing infested grass or green rice. Cercariae can also
encyst on very small floating particles or on water surface, in which case they may be swallowed
in contaminated drinking
water. In Samarkand
region, the old
USSR, the relatively high human prevalence was related
to the important percentage (10,5%) of green vegetables
sold in the Samarkand
market, which presented encysted
metacercariae
(SADYKOV, 1988). GOLDSMID (1975) and
GELFAND (1971) believe that one of the reasons human
fascioliasis
is rare in southern Africa may be the dietary
habits of the Africans in this area, where water plants do
not seem to be an important source of food or relish and,
in any case, are mostly eaten cooked. However, SPECKHART (1969), in Malawi, has pointed out that some vegetable plants are eaten uncooked,
listing cabbage, tanaposi, and mnadzi, and these may serve as sources of
infection in swampy areas. This author also suggests that
sugar cane grown in swampy
areas may serve as a
source of metacercarial
ingestion, the cane commonly
being stripped by Africans with their teeth.
In man, the disease is similar to that observed in F. heAccording
to HAMMOND (1974), the
pathogenicity
varies and only mild and subclinical disease with few symptoms sometimes occur in authochthonous persons. Signs and symptoms include severe epigastric pain, fever and hypereosinophilia.
Acute cholecystitis
was found by TESANA, PAMARAPA & SIO (1989). Worth
mentioning is the recovery of a worm from a painful subcutaneous swelling that moved from the right to the left
side of the chest (FAIN, DELVILLE & JACQUERYE, 1973).
Information on the pathology of the human liver infected with F. gigantica was given by STEMMERMANN
(1953a, b) from human cases in Hawaii. There were
many soft, yellow elevations measuring 2-3 mm in diameter over the surface of both lobes. On sectioning the
liver, many pus-filled cavities from 3 to 2,5 mm in diameter were noted in both lobes. The smaller cavities had
soft, poorly defined, gray walls. The larger cavities had
ragged lining and brownish-red
walls which varied from
I to 3 mm in thickness. The intervening parenchyma had
a flabby consistency.
The intrahepatic biliary ducts containing the flukes were dilated. Microscopic
examination
revealed both the smaller and the larger bile ducts to be
filled with neutrophils,
fibrin, and nuclear debris. The
periportal
connective
tissue was extremely
edematous
and contained
plasma cells, neutrophils,
Iymphocytes,
and histiocytes. The ductal walls were greatly thickened.
Large areas of the liver had undergone necrosis. Present
within the necrotic areas were numerous Charcot-Leyden crystals. The necrotic tissue was surrounded by vascular granulation tissue containing many neutrophils and
eosinophilic
granulocytes,
plasma cells, plump fibroblasts, histiocyts, and giant cells. Some of these necrotic
granulomatas
spanned several hepatic lobules, but the
hepatic architecture
of the uninvolved portions was well
maintained. GRA GE et al . (1974) described hepatic calcification found surgically.
In animals, the disease also resembles that due to F.
hepatica. Because of the larger size of this species and
the slightly longer period of migration in the liver tissues, the acute disease may be more severe in F. gigantica infection. The chronic disease is similar to that caused by F. hepatica and deaths are caused by severe
anemia (BORA Y, 1982). Pathogenicity
in cattle is similar
to that of F. hepatica (SINCLAIR, 1967). SEWELL (1966)
found bilirubinemia
and jaundice to be a marked feature
of the terminal stages of subacute fascioliasis
in cattle
produced by F. gigantica.
The normal definitive host of F. gigantica is cattle. F.
gigantica appears to be a parasite not well adapted to
sheep, in which it is more pathogenic than F. hepatica
(OGU RINADE, 1979), inducing a higher mortality and
patica infections.
186
hence a greater
economic
problem
(OGU RINADE,
1984a; AlA USSI et aI., 1988). The greater pathogenicity
has been related to the longer migration period through
the liver parenchyma
(EL HARITH, 1980; OGU RI ADE,
1984b).
Similarly as with F. hepatica, the association of F. stgantica with Clostridium infection (Clostridium novyi
type B) also leads to infectious necrotic hepatitis (Black
disease) among African sheep (ABU-SAMRA et al., 1984).
S.
The etiologic diagnostic methods and aspects to be taken into account are similar to F. hepatica. The possibility of spurious fascioliasis
due to passing of transient
eggs after eating infected cattle or sheep liver must be
verified. In the not uncommon
case of failure to find
eggs in faeces, egg search can be made in liver aspirate
(PERRY, GOLDSMID & GELFAND, 1972).
Among immunological
tests, immunoelectrophoresis
was used by MOREAU et al. (1975), counterirnmunoelectrophoresis by MA SOUR et al. (1983), and passive haemagglutination
and electrosyneresis
(counterimmunoelectrophoresis)
by MAIGA et al. (1991). HILL YER (1988)
emphasized
ELlSA as an extremely
sensitive method,
becoming seropositive
by 2 weeks postinfection
and seronegative
after therapy,
in which cross-reactivity
of
crude extracts with other parasitic infections have been
resolved by gel filtration
in the case of F. gigantica
(MANSOUR et al., 1983). YOUSSEF & MA SOUR (1991)
evaluated partially purified F. gigantica antigens in an
ELlSA for the specific serological diagnosis of fascioliasis. The diagnostic potential of 10 antigen fractions derived from gel-filtration
peaks (II and Ill) were evaluated
in patients with Fasciola, Schistosoma, Entamoeba and
Echinococcus. Fractions 2 and 10 were highly specific
for Fasciola infection and failed to react with other parasites. It is considered that the ELlSA should be considered as a rapid and specific technique for the diagnosis of
fascioliasis and also as an epidemiological
surveillance
technique in areas endemic for F. gigantica infection.
Treatment
In animals, the same compounds as for F. hepatica are
used (rafoxanide,
oxiclozanide,
brotianide,
niclopholan,
niclosamide,
hexachlorophene,
etc.). The same can be
said for man. In man, treatment with metronidazol
and
emetine
hydrochloride
was
apparently
successful
(PERRY, GOLDSMID & GELFA D, 1972). Recently,
SUHARDONO et al. (1991) applied triclabendazole
in Indonesian cattle for the control of F. gigantica at a dose of
12 mg/kg orally every 8 weeks for I year; egg count in
treated animals was significantly
reduced to almost zero.
Concerning
a future possible
vaccine,
HAROUN &
HILLYER (1986) reviewed attempts to actively stimulate
or passively transfer resistance to Fasciola, including F.
gigantica, in various laboratory and farm animals, inclu-
& M.D.
BARGUES
ding mice, rats, rabbits, sheep, goes and cattle. These attempts comprised
sensitization
by primary homologous
or heterologous
normal or irradiated infections per os,
sensitization
by subcutaneous,
intramuscular
or intraperitoneal implantation
with the various fluke stages, sensitization by somatic extracts or metabolic products of
mature or immature flukes and passive transfer of resistance by immune serum or sensitized Iymphocytes.
Prevention
Diagnosis
MAS-COMA
and control
Owing to the similarity of the life cycles, prevention
and control measures follow the same patterns as for F.
hepatica. The peculiarities of F. gigantica must, however, be taken into consideration.
Thus, in enzootic areas
of the infection by the aniof F. gigantica, contraction
mals and their contamination
of the area with eggs of the
parasite in the faeces take place when the animals go to
drink, rather than when they are grazing in the pasture.
Accordingly,
avoiding the watering of the animals from
swampy banks of rivers and from bodies of water rich in
vegetation would considerably
reduce the chances of infection.
A molluscicide
such as N-trytylmorphine
at a concentration of 0,09-0,1 parts per million allowed the eradication of the snail host for II months (PRESTO & CASTELINO, 1977).
Worth mentioning
are the studies by GUPTA, PRASAD
& CHA DRA (1986) on the possibilities
of biological
control of the snail host of F. gigantica. These authors
observed that Channa punctatus, a freshwater fish which
may be cultured in derelict, weed-infected
waters, feed
on L. auricularia. Laboratory studies showed the rates of
predation to vary with the size of the fish and of the molluscs.
DICROCOELIUM
DENDRITlCUM
Morphology
This species is popularly known as the lancet fluke, the
lanceolate fluke, the little liver fluke or the small liver
fluke. The adult stage has an elongate body, which is narrow anteriorly,
and the widest portion is behind the
middle, 8-1412-2,5 mm in size. Host-related size differences have been observed (FETISOV, 1978). The tegument
is mooth, without spines. The oral sucker is smaller than
the acetabulum,
which lies in the first third of the body
length. The pharynx is small and the caeca do not reach
the posterior body end. The testes are postacetabular,
juxtapose or tandem in position, sometimes
asymmetrical,
frequently lobed. The ovary is postesticular.
The two lateral fields of minute vitelline follicles are situated extracaecally in the mid-body. The uterus starts at the ootype
about the middle of the body, and its ramified transverse
coils occupy the central field from the middle of the body
to the posterior end, ascending and descending
uterine
branches traversing one another. An ascending branch
proceeds to the postbifurcal,
median genital pore, in
which a prominent cirrus pouch also opens. The embryonated eggs are dark brown, thick-shelled, operculated at
one pole, and measure 35-45/22-30 um.
The adult of this species is a parasite of the bile ducts
and gall bladder. It shows a scarce host specificity, according to the more than 60 mammal species of the orders
Rodentia,
Lagomorpha,
Artiodactyla,
Perissodactyla,
Carnivora and Primates in which it has been reported so
far. Additional new host records have appeared in recent
years (i.e. GVOZDEV & ORLOV, 1985). However, only
members of the suborder Ruminantia, notably sheep and
cattle, may be considered as true definitive hosts, remaining definitive host species, including humans, being
mere alternate hosts according to the relatively low incidence and intensity of infection in them.
Numerous species have been used as definitive hosts
for experimental purposes: the Syrian hamster proves to
be the better host, and the golden hamster and rabbit are
good hosts; other species used are cotton rats, white rats.
guinea pigs, rabbits, sheep, cows, dogs, cats, monkeys,
and white mice (HOHORST & LAMMLER, 1962). Experimental infections proved the wide range of hosts which
become infected with this fluke (SALlMOV, 1973).
Reports in humans
Human infections have been recorded in D. dendriticum enzootic areas. Although the majority of these infections are of rare and sporadic occurrence, they are undoubtedly
underestimated.
Most infections
are only
spurious (STAHEL, 1981; BERNHARD, 1985; KHA et al.,
1988; MOHAMED & MUMMERY, 1990; etc.), the appearance of eggs in stools being due to the ingestion of infected livers of sheep, goat and cattle, eggs being detected in
faeces for only a few days. The reasons for the availability of infected animal livers on the market is that not all
infected livers show signs of the infection. Genuine human infection can be verified through parasite finding in
surgical operations, evidence of permanent egg shedding
through time, egg recovering in duodenal aspirates, or the
existence of related symptomatology.
Human cases were reported long ago from: A) Asia:
USSR (ASSATOUROW, 1931; GIGITASHVILI, 1962; JAGUBOFP, 1929; KALANTARIAN, 1926; MTSCHEDLlDZE,
1931; PIGOULEWSKY, 1927a, b; V ASILlEVA, 1927), Iran
(FARID, 1971), Java (mentioned in ROSICKY & GROSCHAFf, 1982), and China (SCHEID, MENDHEIM &
AME DA, 1950); B) northern Africa: Lebanon (COMBESCOT, MAMO & AKATCHARIAN, 1973 in TOHME &
TOHME, 1977), Syria (YENIKOMSHIAN & BERBERIA ,
1934), Egypt (SCHEID, ME DHEIM & AME DA, 1950).
Tunisia (BOURGEO et al., 1974); C) Europe: France (SIGUIER et al., 1952; LAVIER & DESCHIE S, 1956; CA VIER
187
& LEGER, 1967; MA DOUL et al., 1966; VERMEIL et al.,
1964), Italy (V A UCCHI & RICCARDI, 1962), Sweden
(BE GTSSON et al., 1968), Germany (SCHEID, MENDHElM & AMENDA, 1950), Switzerland (GALLI- VALERIO
& BORNAND, 1931; STAHEL, 1981), Spain (VASALLO
MATILLA, 1971a, b), Hungary (LORINZ, 1933), and Rumania (SCHEID, MENDHEIM & AMENDA, 1950); and D)
South America: Brazil (TRAVASSOS, TEIXEIRA DE FREITAS & KOHN, 1969). In the past, several post-mortem
examinations disclosed the presence of D. dendriticum in
the liver of man in Germany, Rumania, Armenia, Egypt
and China (SCHEID, ME DHEIM & AMENDA, 1950).
Reports on true human infections published in recent
years concern different countries, such as Czechoslovakia, Turkey, Uzbekhistan (old USSR), Iran, Saudi Arabia, and the USA. In Czechoslovakia
dicrocoeliasis
in
man is reported for the first time by LOFAYOVA, CATAR
& HOLKOVA (1987). In Turkey, KILI<;:TURGAY et al
(1982) reported D. dendriticurn at 0,96% among 6311
patients, and COSKU ER et al. (1979) found seven mature D. dendriticum in a 26-year-old woman after a gall
bladder operation. In Uzbekhistan, old USSR, D. dendritiCU111 adults were found in the livers (up to 4 flukes/liver) of 37 of the 13287 corpses autopsied from 1968 to
1986; in no case was death caused by the infection, nor
was the infection ever diagnosed intra vitam (AZIZOVA
er al., 1988). In Iran, two cases were reported by SOHRABI (1982/1983).
In Saudi Arabia, D. dendriticum was found in the stools of seven Saudis, of which six patients complained of
abdominal pain and other gastrointestinal
problems; D.
dendriticum was consistently found in the faeces of a 30year-old male patient with hepatomegaly
(BOLBOL,
1985). Also in Saudi Arabia, 208 patients were found
excreting D. dendriticum eggs. in 1984-1986. Peak incidence occurred between October and ovember in each
year. At least 7 had true infections, 134 patients were
symptomatic
(mainly eosinophilia,
right hypochondrial
pain, flatulence and diarrhoea), 16 patients had disturbed
liver function, 13 had gall bladder or biliary tree disease,
and this was clinically considered to be caused by D.
dendriticum in at least 2 patients (MOHAMED & MUMMERV, 1990). In the same country, findings of eggs in feaces have been also recently described by KHAN et al.
(1988) and OMAR, ABU-ZEID & MAHFO Z (1991).
In the USA, DRABIK et al. (1988) reported a case of D.
dendriticum infection considered to be genuine in a 23year-old homosexual
man from northern New Jersey,
USA, who was found to be HIV seropositive in September 1986. Faecal examination revealed 5 ova of D. dendriticum. Before the possibility of a spurious infection,
false infection was excluded only through information
provided by the patient about his diet. Authors were unable to obtain further stool specimens since the ova were
only directed after the patient had been discharged from
hospital; authors stress that the patient had vehemently
denied ever consuming liver. They considered that the
small number of ova observed is more consistent with
188
S.
true infection and conclude that it is a genuine case. The
infection is thought to have been acquired through ants
found floating in bottled drinking water supplied at the
patient's work place in ew Jersey.
Geographical
distribution
This parasite species has a more or less cosmopolitan
distribution in herbivorous mammals, mainly in ruminants of the Holarctic region. Thus, sheep and cattle-raising countries are menaced by dicrocoeliasis due to D.
dendriticum. This species is common in almost every
country and adjacent islands of the European continent
and is also found along the northern coast of Africa. It
has been said to occur in South Africa, but such reports
have not been corroborated. In Asia it is found in the old
USSR, especially in Siberia and Turkestan, as well as in
Turkey, Syria, Iran, India, China, the Philippines, and
Japan. In the Americas, the fluke is found in the USA
and Canada in North America and in Cuba, Colombia
and Brazil in Central and South America.
In the USA, animal dicrocoeliasis was detected during
meat inspection at Newark, New Jersey, in cattle coming
from New York state (PRICE & KI CHELOW, 1941).
Subsequent reports showed that the infection occurred in
cattle and sheep in several countries of the state of New
York and that the infections could sometimes be extensive. In the same enzootic area, infections were reported
from goats, horses, the white-tailed deer Odocoi/eus virginianus, the wood-chuck Marmota mona, and rabbits.
The parasite is believed to have been introduced with the
extensive importations of dairy cattle into New York
state from European countries.
In Canada, the first report of D. dendriticum was in
1930, in sheep from Nova Scotia and Quebec. Subsequent reports were again from eastern Canada until 1974
when it was found in cattle in British Columbia, western
Canada (LEWIS, 1974).
Life cycle
The life cycle of D. dendriticum follows a triheteroxenous pattern. Embryonated eggs expelled by adult
worms pass through bile ducts and intestine and are excreted with the faeces, to follow a completely terrestrial
life cycle. Hatching of the eggs deposited on the soil
does not occur until ingested by appropriate land snails,
which act as the first intermediate host. A total of20% of
hatched eggs are found in the snail's intestine 20 minutes after initial infection (RATCLIFFE,1968). There appears to be no relationship between egg dose used and percentage of eggs hatching in molluscs (ALU DA &
ROJO-YAZQUEZ,1982), and some molluscs which eliminate hatched eggs with the faeces are afterwards not
found to be infected (MAPES, 1951; TARRY, 1969; KALKAN, 1971). SIDDlKOV(1986) has demonstrated the role
of beetles and grasshoppers as disseminators of D. dendriticum eggs, a small proportion of which remain unda-
MAS-COMA
&
M.D.
BARGUES
maged after complete digestive crossing, so that when
gi ven to appropriate snailsthey continued development.
Miracidia hatched inside the snail intestine migrate
through the gut wall to the adjacent connective tissues
where they metamorphose to mother sporocysts. These
migrate to the digestive gland or hepatopancreas where
they develop. Each mother sporocyst gives rise to several cercariogenous daughter sporocysts. Mature daughter sporocysts, sac-shaped, 1,2-3,5 mm in length (MATTES, 1936; KRULL& MAPES, 1952c), can be numerous
in a host individual depending of its size: 396 in a 4,5
mm long snail, 587 in a 6,5 mm snail (MATTES, 1936).
The time necessary for sporocyst development differs
according to the molluscan species and environmental
conditions. Sporocysts are first observed from 50 days
postinfection (d.p.i.) in Zebrina detrita (N6LLER, 1932),
70-80 d.p.i. in Cionella (= Cochlicopa) lubrica (MAPES,
1951; BADIE& RONDELAUD,1990), or 123 d.p.i. in Helicella (Helicopsis) arenosa (TIMON-DAVID, 1965).
Stylet-bearing, long-tailed, xiphidiocercous cercariae,
360-760/51-164 urn in size (tail 0,20-1,0 mm long), originally described as Cercaria vitrina by YOGEL(1929), are
produced inside these second generation sporocysts and
exit through a birth pore. The production of the cercariae
is slow, and it requires about 3 months. The number of
cercariae simutaneously present in one sporocyst ranges
from 10 to 40 (MATTES, 1936; NEUHAUS, 1936). They
are expelled by the snail in some mucus when there is a
drop in the temperature. A mass of these cercariae in mucus is known as a «slime ball» (matrix surrounded by a
layer of clear, gelatinous material, all forming a spherical
structure). The number of cercariae contained (280-460)
and size of the slime balls (1-3 mm in diameter) differ according to the snail hosts (NEUHAUS, 1938; KRULL &
MAPES, 1952a; GROSCHAFT,1959). Slime balls offer cercariae an appropriate aquatic environment for the transit
between the terrestrial snail host and the second insect intermediate host. The slime balls are released from the
snails individually or in clusters of 4 to 16. A production
of up to 5 slime balls per snail in 23 days was observed
by KRULL& MAPES (1952a).
Ants, foraging over leaves and sticks where the snails
live, find the slime balls and carry them to their nests.
Whether the adult ants eat the slime balls or feed them to
larval ants is not known. Inside the ants, the cercariae
migrate through the gut wall and encyst in the abdominal
cavity and infrequently the other parts of the body of the
ant to form encysted metacercariae (SCHNEIDER& HoHORST,1971). Fully formed metacercarial cysts are oval
(228-440/192-328 urn), relatively firm, thick-walled (1040 urn), resilient, and only slightly sticky, resembling
thick gelatin (KRULL & MAPES, 1953a). The development within the ant up to the ripe metacercarial stage requires at least 38-56 days at 26° C (YOGEL & FALCAo,
1954). Reports on metacercaria number per ant varies
considerably. As many as 580 cysts have been found,
but the average is usually lower than that: 1-5,1-120,680,17-74, up to 370, 7-107, 2-304, etc. (KRULL& MA-
Human
liver flukes:
PES, 1953b; KLESOV & POPOVA, 1956; GROSCHAFf,
1961; HOHORST, 1962; etc.).
When infected ants are swallowed with the food by the
mammalian
host, the metacercariae
ex cyst in the duodenum (the protective envelope is softened by the digestive
juices, mainly trypsin and bile, of the host). As verified
in experimental
infections,
the parasite (540-635
urn
long) enters the common bile duct and reaches the biliary tree in about an hour after ingestion (KRULL & MAPES, 1952b; KRULL, 1958). Although rejected by several
authors
(KRULL, 1958; SOGOY A , 1960; LAMMLER,
1962), the other suggested alternative
way, entering the
intestine wall and being carried passively to the liver by
means of the portal blood system, cannot be excluded, so
that both modes may exist simultaneously
(ALlEV, 1966;
ROSICKY & GROSCHAFf,
1982). Sexual
maturity
is
achieved in about 6-8 weeks (TARRY, 1969; CHANDRA,
1972; FETISOV, 1978). The prepatent period slightly differs according to the host species: 47 days in lambs, 4450 days in rabbits, 50 days in calves, 52 days in kids, and
54 days in donkeys. The infection capacity of metacercariae pronouncedly
differ according
to host species:
32,4% in donkeys, 50% in kids, 60,6% in lambs, 56,7%
in calves, and 21,3% in rabbits.
D. dendriticum may survive in the definitive host for
greatly
prolonged
periods.
According
to Ko 0 ov
(1963), it may survive for as long as 8 years in a ram
kept in isolation.
First intermediate
189
a review
hosts
According to ROSICKY & GROSCHAFf (1982), up to 54
land snail species have been identified so far to serve as
first intermediate
host: Cochlicopidae:
Cochlicopa lubrica; Pupillidae: Abida frumentum; Enidae: Chondrula
tridens, Jaminia potaniniana (= Subzebrinus p.), Ena
obscura, Jaminia sieversi, Zebrina hohenackeri, Z. de-
trita, Subzebrinus sogdianus, Pseudonapaeus miser, Ch.
microtraga ("), Pseudochondrula brevior, P. schelkovnikovi; Claisilidae: Armenica brunae, Laciniaria varnensis;
Zonitidae:
Zonitoides nitidus, Oxychilus derbentinus;
Ariophantidae:
Macrochlamys cassida ("), M. monticola;
Eulotidae:
Eulota lanizi, E. macci, E. duplocincta, E.
phaeozona, E. fruticum, E. paricincta, E. almaatini, E.
rubens, E. semenovi, E. skwortzowi, E. plectotropis t=
Cathaica plectotropis); Helicidae: He/icella candicans,
H. candaharica, H. itala, H. candidula, H. crenimargo,
H. derbentina, H. unifasciata, H. virgata, H. krynickii, H.
protea (?), H. schelkonickovi, Theba carthusiana, Zenobiella rubiginosa, Fruticocampylaea narzanensis, Trichia eichwaodi, E. selecta, Metafruticicola pratensis, Cepaea nemoralis, Helix vulgaris, H. lucorum, Trochoidea
pyramidata, Cochlicella acuta.
In another review made by ALU DA (1984), several
other species are added. And there are even snail species
not mentioned
in the list of ROSICKY & GROSCHAFf
(1982), nor in that of ALUNDA (1984), such as Theba syriaca and Xerophila vestalis detected by TOHME &
TOHME (1977) and Cochlicella ventricosa (BADIE &
Ro DELAUD, 1987). It is evident that D. dendriticum is
able to adapt to different land snail species depending on
the geographical
area, a capacity which is not usually
found among Digenea in general and which has allowed
this parasite to spread up to its actual very wide geographical distribution.
It must be taken into account, however, that reports of several species considered to be the
snail hosts of D. dendriticum were based only on circumstantial
evidence,
because they were the only species encountered
in the area surveyed.
Second intermediate
hosts
The various ant hosts have been tabulated in a recent
report, together with their geographical
distribution and
the number of metacercarial
cysts encountered
(SRIVASTAVA, 1975; ROSICKY & GROSCHAFf, 1982). Of the 17
species of ants reported infected with the rnetacercariae
of D. dendriticum, 14 species are members of the genus
Formica, including Ffusca, F cinerea, F clam, F cuni-
cularia, F gagates, F lugubris, F meroasiatica, F nigricans, F picea, F polyctena, F pratensis, F rufibarbis, F. sanguinea and F subpilosa. The remaing three
intermediate
host species are Proformica nasuta, Catagliphis bicolor and C. aenescens.
Interesting
behavioural
changes are produced in ants
as a result of their infection with D. dendriticum metacercariae.
Some cercariae
invariably
become encysted
in the brain of the ant and cause abnormal
behaviour
which enhances the chances of ingestion of the ant by
the grazing mammalian
host. The metacercariae
in the
brain, mainly in the suboesophageal
ganglion, causes
paralysis of the mandibles, and thus, the ant remains fixed to pieces of vegetation
at various times of the day
(HOHORST& GRAEFE, 1961; HOHORST, 1962; BADIEet
al., 1973). Apparently, there is a diurnal rhythm exhibited by the paralyzed ant (called periodic catalepsis): the
number of cataleptic
ants is high in the morning and
evening and low during midday. Temperature,
and not
light, seems to be the environmental
factor regulating
this rhythm. The daily rhythm followed by the cataleptic state of the ants seems to coincide with daily activities of grazing animals. The latter are active in the morning and evening but are inactive and seek shady areas
at midday
(ANOKHI , 1966; SPINDLER, ZAHLER &
Loos-FRA
K, 1986).
Epidemiology
In some enzootic areas, infection rates with D. dendriticum in the snail hosts may be high. From 10% to 20%
of the snails H. candidula and Zebrina detrita were infected in Germany (VOGEL, 1929). More than 24% of Cionella lubrica were infected in ew York, infection rates
varying according to the month (17, 18,24, and 18% for
the months of June, July, August, and September, respectively) (KRULL & MAPES, 1952c). In sheep pastures in
190
Germany, it was found that the majority of specimens of
Helicella obvia, become infected in the autumn of their
second year of life, when their shell diameter was of medium size. The percentage of snails containing daughter
sporocysts was highest in spring. Slimeball output could
be provoked only in May and June (SCHUSTER, 1993).
The formation of the slime balls is associated with a drop
in the temperature in the snail environment (KRULL &
MAPES, 1952a; VOGEL& FALCAO, 1954).
High prevalence rates of infection among ants are also
on record: 31 % in New York (KRULL & MAPES, 1953b);
33% in Bulgaria (DENEV et al., 1970); 83,4% also in
Bulgaria (SRIVASTAVA, 1975). Moreover, rates vary
both seasonally and from year to year: in France 100%
and 35% in June and July 1973, respectively, and 100%,
13% and 30% in April, August and September 1974, respectively (BADIE, 1976). There are considerable variations in the incidence of metacercarial infection in the
ant intermediate host depending on the site where ants
are collected and the labour organization in the ant colony. The incidence of infection was reported to be only
2% among ants that were collected directly in the nest,
while 43,3% of the ants that were collected outside the
nest, in the pasture, were infected (SVADZHYAN,1956),
SPINDLER,ZAHLER& Loos-FRANK (1986) studied the
behaviour of naturally-infected Formica spp. on a steep.
On a given day, 36% of the infected ants in the meadow
were attached to grasses, 9% to bushes and 55% to flowering plants. On the slope the corresponding percentages were 9, 13 and 77. A total of 74% preferred the blossom of flowering plants, 24% the leaves and 2%
preferred the stalks. The lowest number of metacercariae
found in the ants was one; 32% contained less than 20
metacercariae. The study showed that most attached ants
leave the plants during the day, that ants do not readily
die from starvation, and that in conditions of high temperatures and low humidity ants die regardless of whether
or not they are infected.
Infections in ants are apparently of long duration, ants
probably harbouring mature and viable cysts throughout
their life span, although the infection is believed to shorten the life span of the ant. It has also been noted that the
metacercariae evidently overwinter in the ant (BADIE,
1976). The overwintering of the infection in the ant, as
well as the diurnal rhythm of the cataleptic state of the
infected ants, are factors of significance in the epizootiology of the disease, because they enhance the chances of
the mammalian hosts becoming infected.
Despite the very limited capacity of metacercariae for
successful mammal infection (approximately 30% of ingested rnetacercariae continue their development in the
definitive host, after VOGEL & FALCAO, 1954), adult
burdens are usually large because of the cumulative nature of infections, which increases the number of eggs
being discharged in the faeces and thus ensures the
maintenance of the life cycle. Infected sheep in some
areas might harbour up to 7000 worms in the gall bladder and 50000 in the liver.
S. MAs-CoMA
& M.D. BARGUES
Examples of prevalence rates of the infection of cattle
in different countries are: 46-65% in Switzerland (EcKERT, SAUERLANDER& WOLFF, 1975), 0,7-100% in
Spain, 5-60,6% in Italy, 0,8-26% in Sweden, 0,5-21 % in
Bulgaria, 2,7% in Russia, 30% in Azerbaidzhan, 1,51 %
in Pakistan, and 27-35% in Lybia (see review in GONZALEZ-LANZA, MANGA-GONZALEZ & DEL-POZO-CARNERO, 1993). In sheep, up to 100% has been recorded in
Bosnia and Herzegovina, with fluke burdens averaging
1650-2837 (even more than 14000 worms) per animal
(RUKAVINA,1977). In cattle, infection prevalence usually
increases with age. Monthly average numbers of eggs per
gram of faeces in Spanish cattle ranged from 26 to LOO in
cattle. Seasonal differences in egg elimination appear according to different regions (GONZALEZ-LANZA,MANGA-GONZALEZ& DEL-POZO-CARNERO,1993).
That dicrocoeliasis occurs in a number of reservoir
hosts is an important aspect in the epizootiology of the
disease. In addition to sheep and cattle, it has been naturally found in goats, deer, elk, rabbits, and pigs. Rabbits
seem to intensify the infection in local areas (BAILENGERet al., 1965), and deer in their wider movements disseminate it. Moreover, the practice of shipping heep
and cattle from one area to the other for new pasture also
helps in the spread of the infection, especially because of
the wide distribution of the snail and ant intermediate
hosts (ROSICKY& GROSCHAFT,1982).
Humans acquire the infection accidentally (by swallowing an infected ant together with the food, such as vegetables, fruit, etc.) while staying in the endemic area.
Thus, the principal human source of dicrocoeliosis becomes infested sheep with extremely high worm loads (up
to 108000 worms), and a very high level of incidence of
infection (often 100%). The consequence is a high rate
of pasture infestation resulting from faecal contamination, which is in turn potentiated by large-scale, intensive breeding of these animals. The great quantity of
eggs laid by a single fluke during its several-year lifespan is multiplied many times by the larval stage multiplication at snail host level. This is responsible for the
heavy infestation of the pasture environment, especially
under favourable conditions. Another important epidemiological feature is the fact that the cercariae are intermittently shed by the snail intermediate host at short intervals dictated by sudden cJimatological changes, such
as decrease in atmospheric pressure and temperature,
and increase in relative humidity notably during thunderstorms (ROSICKY& GROSCHAFT,1982).
D. dendriticum infection is an important parasitic disease in animals from an economic and health viewpoint
(LUKIN, 1980; WOLFF, HAUSER& WILD, 1984). As with
other liver fluke infections, the pathology depends on the
number of flukes present and the duration of the infection. Because of the small size of the fluke and its smo-
Human
liver flukes:
191
a review
oth and spineless surface, mechanical and toxic damage
are much less than in fascioliasis and opisthorchiasis.
Also worth mentioning here is that the main route of migration of D. dendriticum via the bile ducts differs from
that of F. hepatica, which reaches the liver via the abdominal cavity route.
The incidence of infection and intensity of the clinical
manifestations are dependent on the frequency of exposure and the length of time that the population has been
exposed to the infected environment. These are likewise
dependent on the degree of infestation in the environment and the prevailing conditions and practice of hygiene by the population living in the vicinity of potential
dicrocoeliasis foci.
Approximately 300 cases of human dicrocoeliosis,
identified at least on the basis of finding of eggs in the
stool, were reported in the literature up to 1982 (Ro
SICKY & GROSCHAFT, 1982). However, this number
may not be accurate since: A) dicrocoeliasis may be
confused with infections of different etiology; B) for the
most part of reported cases, absence of false infection is
not demonstrated (eggs merely passed through the intestinal tract following the consumption of infected livers);
C) true dicrocoeliasis usually appears to be symptomless, so that cases are simply not diagnosed because affected persons do not go to the specialist (when apparent, clinical symptoms may suggest a hepatitis-like
infection).
In man, clinical symptoms of true dicrocoeliosis are
neither uniform nor specific. Generally, the infection is
accompanied by either a prolonged period of constipation or diarrhea, nausea, and vomiting. Some patients
may complain of abdominal discomfort and pain in the
right half of the abdomen and in the epigastrium radiating to the right shoulder. Sometimes, the disease is accompanied by lassitude, headache, and giddiness. Pain
in the liver is continuous, independent of the uptake of
food, and intensifies mainly at night. Objective signs include subicteric colouration of the cornea and the skin
and enlargement of the liver and the spleen. In the initial
stages, there is leukocytosis, eosinophilia (8-25%), and
occasionally, traces of bile acids in the urine. Later on,
slight anemia may ensue; the leukocytosis drops to normal level and eosinophilia diminishes to 5 to 7% (PRICE
& CHILD, 1971; ROSICKY& GROSCHAFf, 1982).
Cerebral involvement in dicrocoeliasis is rare, but a
French shepherd aged 17 years, infected with D. dendriticum, showed a brain condition apparently due to dicrocoeliasis. The body developed convulsive crises and
Jacksonian gait, affecting the left-hand side, with slight
symptoms of deficiency in that side. Several days later
he had a hemiplegia on the right-hand side, and finally a
meningeal syndrome was imposed on these symptoms.
Evidently, D. dendriticum or its eggs had been carried to
the brain via the blood and caused these neurological
symptoms. In addition to eggs of the parasite constantly
in the boy's faeces, he was positive for an intradermal
test using «distome» antigen. There was an eosinophilia
of 48%, which was maintained at levels of 58 and 50%
(SIGUIERet al., 1952).
It is assumed that the same pathological changes occur
in humans as in animals. The extent of liver changes
conform to that described for infected animals (see a detailed description in ROSICKY & GROSCHAFf, 1982).
Worth mentioning in animals is that a relationship with
bile duct carcinoma has never been reported.
Diagnosis
Coprological methods, for egg finding in faeces, provide sufficient diagnostic evidence and are technically
undemanding. Satisfactory diagnostic results have been
reported with the use of modified flotation and sedimentation methods. In heavy infections, examination of a direct faecal smear is adequate to demonstrate the presence
of characteristic eggs. The «cellophane faecal thicksmear technique» or simply «Kato-Katz method» according to KATO & MIURA(1954) modified by KATZ, CHAVES& PELLEGRINO(1972) is recommended because it is
rapid, inexpensive, reproducible and allows quantitative
as well as qualitative detection of eggs.
The finding of D. dendriticum eggs in the faeces of humans and carnivores does not necessarily indicate a true
infection with this parasite. The presence of eggs in the
faeces of these hosts could follow the consumption of infected livers resulting in spurious infection. To establish
diagnosis of a true infection, the stool should be examined at intervals and shown to be repeatedly positive. It
should also be complemented with a serological test or
an adequate clinical examination. In some instances, true
dicrocoeliosis can also be distinguished from spurious
infection in that, in the former, the eggs in the faeces are
all embryonated and of a dark brown colour (ROSICKY&
GROSCHAFf, 1982). For the recovering of eggs, duodenal aspirates have also been used in genuine human cases (ASSATOUROW,1931).
Sero-diagnostic methods, such as complement-fixation-test, precipitation test, and skin tests, have also been
used more or less successfully.
Treatment
Human dicrocoeliasis has received little attention on
account of the small (a few hundred) number of cases so
far encountered. Thymol was one of the first drugs to be
used against dicrocoeliasis in a few human cases. Hetol,
Hetolin® (Hetol-D), thiabendazole, and their analogs are
the commonly used anthelminthics for dicrocoeliosis
which cause no side effects on the host. Dicrocoeliosis in
humans, as well as in animals, has been more or less successfully treated with these drugs (GUILHON, 1956;
LAMMLER, 1964a, b, c). Human dicrocoeliosis has hitherto been treated mainly with emetin and Entobex (CAVIER & LEGER, 1967; VERMEILet al., 1964; CAVIER&
ERHARDT, 1973). More recently, BUNNAG & HARINASUTA(1989) recommended praziquantel, in doses of 25
192
mg/kg 3 times daily after meals for 1 or 2 days. This
drug has already been used in human dicrocoeliasis
(DRABTKet al., 1988; MOHAMED& MUMMERY, 1990),
as well as in animals (GURALP,OGUZ & ZEYBEK, 1977).
If praziquantel is not available, bithionol, 15 to 25 mg/kg
twice daily on alternate days for 10-15 days may be effective (MARKELL& GOLDSMITH,1984).
Thymol, Fouadin®, thiabendazole, hexachloroparaxy101,hetol (effective against the sexually mature flukes),
Hetolin® (effective against the young, sexually immature flukes), and diamphenetide are drugs having been
successfully used against animal dicrocoeliasis (ROSICKY& GROSCHAFf, 1982). Combinations of Hetol or
hexachloroparaxylol and Hetolin® (FETISOV, 1971a, b)
or thiabendazole and Hetolin® (DELIC, CANKOVIC&
ROZMAN,1971) proved to be even more effective than
the same drugs used separately.
Prevention
and control
The control of dicrocoeliasis is similar to that of several
fluke infections, although taking into account that the intermediate hosts are terrestrial snails and ants. Preventive
measures performed to control the intermediate host populations in the pasture should be extended to the entire
endemic area, because otherwise foci of dicrocoeliosis
would persist. Altering the character of the infested pastures must be the first step to reduce the intermediate host
populations. Periodic changes of the planted grasses lead
to unfavourable conditions for the survival and multiplication of the intermediate hosts and simultaneously improve
the quality and productivity of the pasture (KLESOV& PoPOVA,1956; GROSCHAFT,1959; HASSLER,1963).
Land snails can be controlled biologically, physically,
or chemically. For the biological control, chickens have
been successfully used in areas of the old USSR, as they
feed voraciously on land snails, thus considerably reducing their populations in a short time (PETROCHENKO&
TVERDOKHLEBOV,1971). Certain physical methods,
such as hand picking and crushing, have been employed
against terrestrial snails with great success in some places. Chemical measures, such as the use of repellents, attractants, or contact poisons, have also been applied with
some success. Of course, care must be taken in the use
and handling of certain types of chemicals because they
may be poisonous to man and animals and may be injurious to certain plants on the pasture.
Concerning ants, effective chemical preparations are
available for chemical control. Satisfactory results have
been obtained using a combined biological and chemical
methods. An aqueous emulsion 0,35% of dicresyl ester
at a dose of 200 to 250 ml/nr' was sprayed on sites colonized by the ants. The chemical paralyzes the ants and
they are in turn picked up by the flocks of free chickens
(SALTMOV,1970). However, in some areas, the use of insecticides to kill the ant hosts is objectionable or even
forbidden, because of the possible contamination of the
environment.
The administration of suitable anthelminthics to infected
animals has an adjuntive value in the prevention and control of dicrocoeliosis and enhances the efficacy of the preventive measures applied. A satisfactory measure to prevent debilitation or death of animals infected in the spring
and to limit the degree of infestation of the pastures is the
administration of anthelminthic drugs in between pasture
seasons (FETISOVet al., 1970; TvERDOCHLOBOV,1971).
DICROCOELIUM
HOSPES
Morphology
The adult stage of D. hospes is similar to that of D. dendriticum, but differs in presenting a more slender, slightly
smaller (4,5-12/0,5-1,4 mm in length/width, and thus a
different ratio of body length to width) body of an almost
uniform width except for the tapering anterior portion,
ventral sucker lying somewhat closer to the anterior end
of body, lobed, tandem or slightly oblique testes, vitellaria
in larger follicles occupying a compact and smaller area,
being intracaecal and always posterior to the ovary, uterus
less ramified with descending uterine branch on the ovarian side of the body and ascending branch on opposite
side, the two branches not crossing each other. The eggs
are embryonated, dark brown, with thick walls, operculated at one pole, and measure 35-45/20-30 um (GRABER&
OUMATTE,1964; BOURGAT, SEGUIN & BAYSSADE-DuFOUR,1975; KAJUBIRI& HOHORST,1977).
An interesting study on variability range and frequency of occurrence of morphological types, carried
out by MACKO& PACENOVSKY(1987) by comparing D.
dendriticum materials from Algerian and Czechoslovak
cattle, lead the authors to think that D. hospes could be
interpreted as an intrapopulation morph of D. dendriticum and its junior synonym.
This species is an African parasite of the biliary ducts
and gall bladder. Recorded definitive hosts are sheep,
cattle, zebus, goats, and monkeys from the Ethiopian region (ROSTCKY& GROSCHAFT,1982)
Reports in humans
D. hospes has several times been reported as a human
parasite. Several reports of spurious human infection
have appeared, such as in Ghana (ODEI, 1966; WOLFE,
1966) and Kenya (CHUNGE& DESAI, 1989). Such human infections appear to have resulted from consumption of infected sheep, goat and cattle livers containing
adult worms, with subsequent appearance of eggs in human stools but only for a few days. The reason for the
availability of infected animal livers on the market is
that not all infected livers show signs of the infection;
and in Ghana, for example, only about one third of these
193
are condemned
due to the presence of gross pathology
(WOLFE, 1966). In Senegal and Mali, MALEK (1980) encountered
D. hospes in livers which had already been
inspected and were on their way to the market.
Genuine human infections have been reported in Zaire
(former Belgian Congo) (VAN DEN BERGHE & DENECKE,
1938), Ghana (ODEI, 1966), Sierra Leone (KING, 1971)
and Nigeria (ROCHE, 1948; HARMON & OYERINDE, 1976;
REINTHALER et aI., ] 988). V AN DEN BERGHE & DE ECKE
(1938) reported one case and ODEI (1966) two cases.
KI G (1971) reported D. hospes infections in 15 persons,
including
10 Americans
and 5 who had never left the
country; all were residents in cattle-raising
areas and two
of them appeared to be heavily infected. ROCHE (1948) reported one human case due to D. hospes (identified in the
report as D. dendriticums. HARMON & OYERINDE (1976)
found eggs in the faeces of I I people; 2 of the cases were
established infections, 4 were spurious (eggs only found
once) and the other 5 people were examined only once.
REINTHALER et at. (1988) examined 479 stool specimens
and found Dicrocoelium eggs in 0,4%.
Other genuine human infections reported from Africa,
such as in northern Africa, Lebanon, Syria and Egypt do
not concern H. hospes but D. dendriticum.
Geographical
distribution
In the Ethiopian region, the species D. dendriticum seems to be replaced by D. hospes, the dicrocoeliid species
present in almost all west African countries. D. hospes has
been recorded so far from Angola (GRABER & PERROTIN,
1983), Cameroon (GRABER & OUMATIE, 1964), Central
African Republic (GRABER & OUMA TIE, 1964; GRABER
& PERROTIN, 1983), Chad (GRABER & OUMATLE, 1964),
Congo (GRABER & PERROTI , 1983), Etiopia (GRABER &
PERROTI , 1983), Ghana (ODEI, 1966; WOLFE, 1966),
Guinea Republic (GRABER & OUMATIE, 1964; KAJUBIRI
& HOHORST, 1977), Kenya (CHUNGE & DESAI, 1989),
Mali (MALEK, 1980; TEMBELY et aI., 1988), Niger (TAGER-KAGAN, 1979), Nigeria (ROCHE, 1948, identified in
the report as D. dendriticum; HARMON & OYERINDE,
1976; SCHILLHORN VAN VEEN et al., 1980; OGU RI ADE
& ADEGOKE, 1982; ADEOYE & FASHUYI, 1986; FASHUYI
& ADEOYE, 1986; REINTHALER, MASCHER, KLEM &
SIXL, 1988), Senegal (VASSILIADES, 1978; MALEK, 1980;
DIAW, 1982, 1988), Sierra Leone (KI G, 1971; WILLIAMS, 1969; ASANJI & WILLIAMS, 1984, 1987), Sudan
(Looss, 1907; although it was not found in extensive surveys made by MALEK, 1959), Tanzania (MAHLAU, 1970;
GRABER & PERROTIN, 1983), Togo (BOURGAT, SEGUIN &
BAYSSADE-DuFOUR, 1975; BOURGAT & KULO, 1979;
CHEVALLIER, 1979; GNINOFOU, 1988), Uganda (ODEI,
1966; KAJUBIRI & HOHORST, 1977; THURSTON, 1970,
1972), Zaire (VA DEN BERGHE & DENECKE, 1938), and
Zambia (GRABER & PERROTIN, 1983). The African distribution of this parasite between latitudes of 20° Nand 20°
S has been related to the distribution of its intermediate
snail hosts (KAJUBIRI & HOHORST, 1977).
Life cycle
The life cycle of D. hospes is similar to that of D. dendriticum. The miracidium of D. hospes is ovoid, measuring 30-35/23 urn, Terrestrial snails act as first intermediate host in which cercariogenous
sporocysts develop.
The body of the cercaria of D. hospes measures 470550/150-170
urn. The tail measures 600-700/150-170
urn
in length/maximum
width. The argentophilic
papillae of
the cercaria of D. hospes are very similar in number and
location to those of D. dendriticum. Metacercariae
develop in ants (BOURGAT, SEGUI & BAYSSADE-DuFOUR,
1975; LUCIUS, ROMIG & FRA K, 1980). Metacercariae
are ovoid, 174/120 urn in size, and are found at a rate of
up to 363 metacercariae
per ant (ROMIG, LUCIUS &
FRANK, 1980).
Studies made by ROMIG (1980) and ROMIG, LUCIUS &
FRANK (1980) on the «brain-worms»
of both D. hospes
and D. dendriticum showed
differences
in location,
are
number, size and behaviour. D. hospes metacercariae
preferentially
located dorsally on the antennary lobes of
the deutocerebrum,
their number is usually 2 with a maximum of 4, their size is 410-450 urn, and their effects in
modifying the behaviour of the ant is not related to temperature, whereas those of D. dendriticum are mainly located ventrally on suboesophagic
ganglia and sometimes
on the optic lobes, their number is usually I with a maximum of 3, their size is 320-410 urn, and their effects in
modifying the behaviour of the ant are related to low environmental temperature.
First intermediate
hosts
In the first report, BOURGAT, SEGUI & BA YSSADEDUFOUR (J 975) demonstrated
that the snail hosts of D.
hospes in Togo are species of the terrestrial genus LimiLate studies by BOURGAT &
colaria (Achatinidae).
KULO (1979) and CHEVALLIER (1979) identify the species as Limicolaria aurora (Jay, 1839) and L. bourgati
Chevallier,
1979. Limicolaria flammea, L. felina and
another species similar to L. kambeul were found to play
the role of first intermediate
host of D. hospes in the
Ivory Coast (LUCIUS, ROMIG & FRA K, 1980). More recently, FASHUYI & ADEOYE (1986) experimentally
exposed the snail species Limicolaria flammea, L. striatula, an unidentified
Limicolaria, and Achatina sp.
collected
in Nigeria, and laboratory-reared
Lamellaxis
gracilis, to fully embryonated
eggs of D. hospes for 48
h. Larval stages develop to maturity in Limicolariaflammea, L. striatula and Lamellaxis gracilis, rates of infection being 30, 20 and 8%, respectively.
None of the other
snails became infected.
Second intermediate
hosts
Formicidae
ants act as second intermediate
hosts. The
metacercariae
of D. hospes have been found in two ant
species in Togo: Dorylus sp. and Crematogaster sp.
194
(BOURGAT, SEGUIN & BA YSSADE-DuFOUR, 1975). Experimental infections gave positive results in several ant
species from the Ivory Coast, such as Camponotus compressiscapus, C. chrysurus, C. vividus and C. acvapimensis, although mature metacercariae
infective for definitive hosts were only obtained in C. compressiscapus
because of ant-rearing
difficulties
(LUCIUS, ROMIG &
FRANK, 1980).
Epidemiology
Studies carried out at slaughterhouses
in different endemic African countries demonstrate
that, when present,
this dicrocoeliid usually reaches high prevalences
in cattle: 58,5% in Ghana (ODEI, 1966), 80,6% in Uganda
(KAJUBIRI & HOHORST, 1977).
Prevalences in African domestic animals differ according to regions, season and definitive host species. In cattle the following high prevalences were found: 0,0-54,094,0% in different regions of Niger, 80,6% in Uganda,
71 ,0% in Tanzania,
61,8% in Sierra Leone, 58,8% in
Ghana, and 57,8% in Chad (TAGER-KAGAN, 1979; KAJUBIRI & HOHORST, 1977; ASA JI & WILLlAMS, 1984,
1987; ODEI, 1986; GRABER & OUMATIE, 1964; SCHILLHORN V A VEE et aI., 1980). Lower prevalences found
in cattle were 40,0% in Togo (BOURGAT, SEGUIN &
BA YSSADE-DuFOUR, 1975), 18,5% and 45,0% in Nigeria
(ADEOYE & FASHUYI, 1986; OBIAMIWE, 1986), 3,038,0% in Senegal (MALEK, 1980; DIAw, 1982, 1987), and
16,6% in Mali (MALEK, 1980). Zebus appear to be more
susceptible
to infection
(12,0%)
than N'dama
cattle
(6,7%) (DIAw, 1982), and bovine females more susceptible than males (ASANJI & WlLLlAMS, 1987).
Sheep and goats present lower prevalences:
2,0-14,027,% in sheep and 10,0-15,0-26,0%
in goats in different
regions of Niger (TAGER-KAGAN, 1979), 0,97% and
3,33% respectively
in Senegal (DIAw, 1987), 3,2% and
0,0% respectively
in Sierra Leone (ASANJI & WILLIAMS, 1987).
Different relationships
of prevalences
to the season
have been found. Lower prevalences in cattle were found
in the dry season in Togo (TAGER-KAGAN, 1979) and Nigeria (SCHlLLHORN V AN VEEN et aI., 1980; ADEOYE &
FASHUYI, 1986), whereas the opposite, that is, the higher
prevalence
in the dry season were detected in Sierra Leone, Ghana and Tanzania (ASANJI & WILLlAMS, 1984).
Concerning humans, ROCHE (1948) showed a median
longitudinal section through the worm in the section of
the human liver; the only pathological
change was a moderate degree of fibrous thickening
of the portal tract.
IQ G (1971) reported, in two heavily infected patients,
hepatitis-like
symptoms: one of them had jaundice, both
had raised bilirubin and transaminase
levels.
Concerning animals, D. hospes does not seem to cause
S. MAs-CoMA
& M.D. BARGUES
much damage, even in heavy infections (DIA W, 1982).
Up to 973 adults were found in a cattle liver (TAGER-KAGAN, 1979).
Diagnosis
Certain diagnosis is only made by detection of eggs in
faeces over a long period without having ingested infected animal liver. Serological
tests, such as immunodiffusion and ELlSA, present the problem of cross-reactions
(common antigens) with Fasciola gigantica and Schistosoma bovis, two digeneans existing in both domestic animals and man in the same African countries as D. hospes
(FAGBREMI & OBARISIAGBON, 1991).
Treatment
The several
drugs having shown to be effective against
be applied against D. hos-
D. dendriticum may similarly
pes infection.
Prevention
and control
Preventive and control measures already described to
be useful in dicrocoeliasis
by D. dendriticum can be applied in a similar way against D. hospes.
EURYTREMA PANCREATlCUM
Morphology
The adult stage is thick, 8-16/5-8 mm in size, with a
tegument provided of caducuous spines. The oral sucker
is subterminal
and is larger than the acetabulum.
The
pharynx is small, the oesophagus
short and the caeca do
not reach the posterior extremity of the body. The testes
are lobed, symmetrical,
intercaecal,
and immediately
postacetabular.
The long and slender cirrus pouch extends from the anterior margin of the acetabulum
to almost the intestinal bifurcation.
The ovary is relatively
small, lobed, postesticular,
submedian
and is located in
the middle third of the body. The vitelline follicles are
disposed in two postesticular
lateral fields mostly overlying the caeca. The uterus is markedly coiled, fills the
posterior part of the body, and goes up to finish in a directly postbifurcal,
median, ventral, genital pore. The
embryonated
eggs, 40-50/23-24
I1m in size, are indistinguishable from those of D. dendriticum.
This species is normally found within the pancreatic
ducts and less frequently in the bile ducts. Natural definitive hosts are cattle, sheep, goats, rabbits, hogs, water
buffaloes, camels (Came/us bactrianusi, monkeys (Mathis digecaca syrichta) and carabao. Experimentally,
nean can be developed in additional definitive hosts.
195
Reports in humans
According to TANG & TANG (1977), E. pancreaticum
has so far been reported in man once each in Hong Kong
and in Jiang-su Province, China and in at least six cases
in Japan. More recently, ISHll et al. (1983) reported a human infection
in a 70-year-old
Japanese
woman with
gastric cancer in Fukuola Prefecture, Japan, who harboured 15 adult E. pancreaticum in the dilated pancreatic
ducts at autopsy. The number of eosinophils
in the blood
was within normal limits. Thus, parasites could be microscopically
determined:
body 10-1 1/5-7 mm; oral sucker 2,0-2,111,9-2,0
mm; ventral sucker 1,4-1,6/1 ,5-1,6
mm; embryonated
eggs in the uterus 43,2-50,9/27,633,0 urn. The same year, TAKAOKA et al. (1983) reported another human case of a 57-year-old
female farmer
from Notsuharu,
Oita, Japan, who was admitted to hospital complaining
of hypochondralgia
which had lasted 3
months. She was given a pancreatectomy.
Histopathological examination
of the pancreas reavealed 3 E. pancreaticum in the dilated pancreatic duct.
According to MORIYAMA (1982 b), all human cases of
eurytremiasis
seem to be due to E. pancreaticum, at least
in Japan.
Geographical
distribution
This species is known to occur in many areas of eastern Asia, such as the old USSR (KSEMBAEVA, 1967: in
south-eastern
Kazakhstan;
LOGACHEVA, 1974: in Kirgizia; DVORYADKIN, 1969: Amur region of the Far Eastern
USSR; NADIKTO & ROMANENKO, 1969: Primorsk Territory of Far-Eastern
Russia), Korea (JANG, 1969), Japan
(CHINO E, MARUY AMA & ITAGAKI, 1976; CHINONE &
ITAGAKJ, 1976; TANG & TA G, 1977; ISH" et al., 1983;
TAKAOKA et al., 1983), Mongolia
(Gu et al., 1990),
southern
and northern
China (TANG, 1950; TANG &
TANG, 1977; TANG et al., 1979), Hong-Kong
(TANG &
TANG, 1977), Vietnam
(NGUEN TKI LE & MATEKIN,
1978), Malaysia (BASCH, 1965), Philippines (EDUARDO,
MANUEL & TONGSON, 1976), and also Mauritius Island
in the Indian Ocean, near Madagascar
(LE Roux
&
DAR E, 1955). Ascriptions to this species in South America do not seem in fact to be E. pancreaticum, but E. eoelomaticum (Giard et Billet, 1892) Looss, 1907 (TRAVASSOS, TEIXEIRA DE FREITAS & KOHN, 1969), a
proximal species also present in eastern Asia and which
has also been differentiated
karyologically
from E. pancreaticum in areas where both species overlap, such as in
Japan (MORIY AMA, I 982a).
Life cycle
The egg and the miracidium
are very similar to those
described for other dicrocoeliids.
The eggs hatch only after being eaten by the snails. The daughter sporocysts develop within the mother sporocyst into large complicated
sacs with a heavy outer wall, and they escape from the
snails. The cercaria contained in the daughter sporocysts
has a short stumpy tail, and the structure of its body is
very similar to that of other dicrocoeliid cercariae (TANG,
1950). In experimentally-infected
snails, a great number
of daughter sporocysts are found on the outer wall of the
posteriormost
part of the stomach. Soon after being shed,
daughter sporocysts are found near mother sporocysts in
the subrenal and visceral sinuses. Daughter sporocysts
migrate towards the mantle collar through the rectal sinus
(if originally parasitic in the visceral sinus) or the lateral
sinus (if parasitic in the subrenal sinus). Daughter sporocysts then penetrate the mantle to the exterior. Emergent sporocysts are spindle-shaped,
whereas those migrating through the sinuses are of elongate fusiform shape.
The process of emergence
takes 5-10 minutes (KOZUTSUMI & ITAGAKI, 1989).
When sporocysts
from the snails are fed to grasshoppers, the contained cercariae penetrate the gut and encyst
in the hemocoel. Metacercarial
cysts grow to maximum
size in about 9 days and mature in 2 additional weeks.
When grasshoppers
are fed to goats, they develop to
young worms in the pancreas (BASCH, 1965).
In experimentally-infected
rabbits,
the trematodes
were found mainly in the duodenum before migrating to
the pancreas through the pancreatic
duct. In the pancreas, the trematodes reached the adult stage in 45 days
and on day 75-80 they began to lay eggs (PANIN &
KSEMBAEVA, 1971). Infected grasshoppers,
when fed to
rabbits, lead to the development
of juvenile flukes in 30
days and fully mature flukes in 90 days, the prepatent
period being about 100 days. (CHINONE & ITAGAKI,
1976). In experimentally-infected
lambs, the development to adults takes 87-89 days (DVORYADKIN, 1969).
First intermediate
hosts
Different terrestrial snails, mainly of the family Bradybaenidae (Gastropoda),
are used as first intermediate host
by E. pancreaticum, depending of the geographical zone.
The following species have been reported with natural
and/or experimental
infection by the larval stages: in
south-eastern
Kazakhstan,
Bradybaena lantzi and Cathaica plectotropis (KSEMBAEVA, 1967); in the Amur region of the Far Eastern USSR, Bradybaena arcasiana
and B. dieckmanni (DVORY ADKI , 1969); in the Primorsk
Territory of Far-Eastern
Russia, Bradybaena fragilis, B.
selskii, B. middendorffi, B. maacki and B. arcasiana
(NADYKTO, 1973); in Kirgizia,
Jaminia albiplicata,
Bradybaena plectotropis, B. phaeozona and B. lantri
(LOGACHEVA, 1974); in Korea, Acusta despecta (JA G,
1969); in Mongolia, Ganesella virgo (Gu et al., 1990); in
China, Bradybaena similaris and Cathaica ravida sieboldtiana (TANG, 1950), Ganesella stearnsii, G. japonica and G. myomphala (TANG & TANG, 1977), and G.
virgo (TANG et al., 1979); in Japan, Fruticicola sieboldiana and B. similaris stimpsoni (MIYATA, 1965), and B.
similaris (CHLNONE, MARUYAMA & ITAGAKI, 1976; KoZUTSUMI & ITAGAKI, 1989); and in Malaysia B. similaris
196
S. MAs-CoMA & M.D. BARGUES
(BASCH, 1965). A land snail (Macrochlamys) has been
indicated as probable first intermediate
host in Mauritius
(LE Roux & DAR E, 1955).
Second intermediate
hosts
The second intermediate
hosts are mainly grasshoppers. Metacercariae
develop and encyst in the abdominal
cavity of the following species: Conocephalus maculaIus in Korea (lA G, 1969), Malaysia (BASCH, 1965), and
Japan (CHINONE & ITAGAKI, 1976); C. chinensis in
China (TANG et al., 1979), the Amur region (DVORY ADKIN, 1969), the Primorsk Territory
( ADYKTO, 1973),
and Mongolia (Gu et al., 1990); C. gladiatus in Korea
(lA G, 1969); C. dorsalis and C. discolor in Kirgizia
(LOGACHEVA, 1974); C. percaudatus in the Amur region
(DVORY ADKIN, 1969); C. fuscus and Platycleis intermedia in south-eastern
Kazakhstan
(KSEMBAEVA, 1967);
and Oecanthus longicaudus and Epocromia sp. in the
Primorsk Territory
(NADIKTO & ROM A E KO, 1969;
ADYKTO, 1973). The ant (Technomyrmax) has been indicated as probable second intermediate
host in Mauritius (LE Roux & DARNE, 1955).
Epidemiology
Temperature
has a noticeable
effect on the development of the parasite in the snail. In China, development
in snails stops under 10° C (TANG et al., 1979). In Japan,
at 26° C the development
of the larval stages is accelerated, cercariae developing
in 81 days. The length of the
development
depends on the year period (shortest
in
March). Mature daughter sporocysts
showed a 2-3 day
shedding rhythm from snails (CHINO E, MARUY AMA &
ITAGAKI,1976).
Under field conditions in the Amur region of the Far
Eastern USSR, eggs remained viable from April to November but could not survive the cold winter. In snails,
the development to cercariae took 12 to 13 months at temperatures varying from 8 to 25° C (DVORYADKIN, 1969).
In Korea, snails are infected with the eggs in autumn, and
the miracidia become mother sporocysts in the liver during the winter. Daughter sporocysts
originated
in the
spring penetrate the membrane
of the mantle cavity in
June to July. They are eaten by grasshoppers
in summer
and autumn and encyst in the abdominal cavity (lA G,
1969). In the Primorsk Territory, in snails the second sporocyst generation produces cercariae 10-11 months after
infection. In grosshoppers,
metacercariae
become infective in 23-40 days. In the final host (sheep and cattle) fully
embryonated eggs appear in faeces 80-100 days later. The
complete life cycle takes 500-560 days (NADYKTO, 1973).
In humans, complaints
of hypochondralgia
months and dilation of the pancreatic
ducts
lasting 3
have been
described, eosinophilia
being within normal limits (TAKAOKA et al., 1983; ISHII et al., 1983).
In animals, few changes are observed in the pancreas
in light infections. In moderate and heavy infections, catarrh, ectasis, hyperplasia
or fibrosis of the pancreatic
duct are found (SHIEN et al., 1979). Eggs may penetrate
into the walls of ducts causing inflammatory
foci and
granulomata
in which plasma cells and eosinophils
predominate (BASCH, 1966).
Diagnosis
Human cases have been diagnosed at a hispathological
examination
after pancreatectomy
(TAKAOKA et al.,
1983) or at autopsy (lSHII et al., 1983). Egg finding in
coprological
techniques
presents the problem of confusion with D. dendriticum eggs, from which they are indistinguishable.
Although they are also indistinguishable
from D. hospes eggs, in this case the different geographical distribution
(D. hospes is confined to the African
continent) becomes helpful.
Treatment
Numerous anthelmintics
have been unsuccessfully
assayed in animals. Finally, LI et al. (1983) demonstrated
that praziquantel
(oral doses of 50-70 rng/kg) was very
effective for the treatment of heavy infection in sheep
(more effective than hexachloroparaxylene).
Prevention
and control
The prevention
and control measures are similar to
those applied for dicrocoeliasis,
with the only difference
that in eurytrerniasis
the second intermediate
hosts are
grasshoppers
instead of ants.
AMPHIMERUS
PSEUDOFELlNEUS
The species Opisthorchis guayaquilensis Rodriguez,
G6mez et Montalvan,
1949 was originally described from
a human in rural Ecuador by RODRIGUEZ, GOMEZ &
MO TALVAN (1949). This species was later transferred to
the genus Amphimerus Barker, 1911 of the same family
Opisthorchiidae
(ARTIGAS & PEREZ, 1964; THATCHER,
1970) and synonyrnized
with the species Amphimerus
pseudofelineus (Ward, 190 I) Barker, 1911 (ARTIGAS &
PEREZ, 1964). THATCHER (1970) did not agree with this
synonymy and considered A. guayaquilensis distinct from
A peudofelineus because of the extent of the vitellaria: in
A. guayaquilensis the vitelline follicles extend to near the
posterior end of the body, well beyond the posterior testis,
whereas in A peudofelineus the vitellaria reach the posterior testis but do not extend beyond it. Later on, GOMES
(1977) had the opportunity to study the morphometries
of
various Amphimerus species in Brazil and again concluded on the validity of the above mentioned synonymy.
Human
liver flukes:
197
a review
A. pseudofelineus has apparently
a wide geographic
range and low specificity for its definitive host. It is a parasite of the bile-ducts of dogs, coyotes, domestic cats,
and marsupials (Didelphis marsupialis, Philander opossum) in the U.S.A., Panama, Colombia,
Venezuela,
Ecuador, and Brazil (CABALLERO, GROCOIT & ZERECERO, 1953; CALERO, ORTIZ & DE SOUZA, 1955; THATCHER, 1970; MAYAUDO , 196911970; TODD, BERGELAND & HICKMAN, 1975; GOMES, 1977). Its life cycle
does not seem to be elucidated so far, but it probably follows the same pattern as other Amphimerus species,
with aquatic snails shedding cercariae and fish harbouring encysted metacercariae
(FONT, 1991).
RODRIGUEZ, GOMEZ & Mo TALVAN (1949) made faecal examinations
of 245 persons in a lowland area of
Ecuador and found 18 of them passing opisthorchiid
eggs. They also found several dogs in the same area passing similar eggs, and upon sacrificing
the dogs they
found the worms which they describe as O. guayaquilensis. They believed it was the eggs of this species that had
been seen in human faeces. The eggs of this species obtained from humans
in Ecuador
measured
27-35/1117 urn (average 31,5/l3,5
urn), No additional human report of this species appears
in the literature.
Worth
mentioning
is, however,
that in Colombia,
RESTREPO
(1962) reported finding opisthorchiid-like
eggs in the faeces of 6 out of 176 persons residing on the Amazon river.
AMPHIMERUS
NOVERCA
the genus Opist1902; syn.:
1872 nee
Cobbold,
1859 - see NEVEU-LEMAIRE, 1936) and later
transferred to the genus Amphimerus Barker, 1911 (see
Y AMAGUTI, 1971), its adults do not appear to be location
specific, since they have been recovered from the lung
and pancreatic ducts of stray dogs (SAHAI, 1969), from
the bile ducts of pigs (BHALERAO, 1931) and also in pancreatic ducts of pigs in India (SI HA, 1968). Adults are
9,5-12,7/2,5
mm in size and the eggs measure 34/19 urn.
This species has been reported in the gall bladder at
autopsy of two Mohammedans
in India (MC Co
ELL,
1876, 1878). These reports offer considerable
doubt concerning the specific determination
of the human flukes
(LEIPER, 1913). Proliferative
changes in pancreatic duct
epithelium
and some epithelial desquamation
and periductal fibrosis have been observed in pigs, in cases of
heavy infections in the pancreas (SI HA, 1968).
Species
originally
described
within
horchis Blanchard, 1895 (0. noverca Braun,
Distoma conjunctum Lewis et Cunningham,
PSEUDAMPHISTOMUM
TRUNCATUM
P. truncatum parasitizes
the bile ducts of various
mammals including cat, dog, fox, seal, skunk, mink, otter, etc. (Y AMAGUTI, 1971). Adults are small digeneans
(1,64-2,5/0,6-1,0
mm) which have been reported from
numerous areas of Europe (Russia, Germany, Hungary,
France, Italy, etc.), as well as from North America (ULMER, 1975). Eggs measure 27-35/12-16
urn, Metacercariae develop in fish (Y AMAGUTI, 1971). The determination of the metacercariae
found encysted in cyprinoid
fishes by SCHUURMA S-STEKHOVE (1931) as belonging to P. truncatum is doubtful according
to Y AMAGUTI (1975).
Instances of human infection are relatively few (BITTNER 1928; PETROV, 1940; DELlANOVA, 1957). Apparently, however, human prevalences
may be relevant in
given zones, as in the Alekseev District of Tataria (old
USSR), a district situated near the River Kama, where P.
truncatum was found in the bile of up to 31 patients
(KHAMIDULLI et al., 1991). VI OGRADOV (1892) reported young stages of a fluke (later presumed to have been
P. truncatumy from a human source in Russia (ULMER,
1975). Both eggs and metacercariae
of P. truncatum can
be distinguished
from those of Opisthorchis felineus (ZABLOTSKll, 1973). There is no study on pathology at human level, but liver pathological effects are known in seals (Porov, KOROLEV & SKOROKHOD, 1985).
METORCHIS
CONJUNCTUS
First described from the bile duct of an American red
fox in the London zoological gardens, it was later observed that this species occurs in orth America, especially
in Canada, where it has a wide distribution.
It has been
also reported from several areas in the U.s.A. (Wisconsin, Minnesota, Maine, New York).
The first record of M. conjunctus in man was in the
stool from an Indian patient in Saskatchewan,
Canada
(CAMERO , 1945). Eggs of this species have also been
reported in stools of a human native of Greenland (BABBOIT, FRYE & GORDON, 1961).
It is a parasite of the bile ducts of the dog, wolf, cat,
fox, raccoon, mink, and fisher (Y AMAGUTI, 1971; DICK
& LEONARD, 1979; WOBESER, RUNGE & STEWART,
1983). Pancreatic involvement
has also been detected in
wolves (WOBESER, Ru GE & STEWART, 1983). The
worm measures
1,0-6,6/0,59-2,6
mm in length/width,
and its small eggs measure 22-32/11-18
urn. A detailed
morphometric
study of the adult stage was carried out by
WATSON (1981).
The life cycle is similar to that of species of Clonorreared
chis and Opisthorchis. It has been experimentally
in dogs, cats, red and silver foxes, minks, ferrets, raccoons, and cotton rats. The life span of the adult stage may
exceed 5 years (CAMERON, 1944). The aquatic hydrobiid
snail Amnicola limosa porata serves as the first intermediate host and the common sucker, Catostomus commersonii, as the fish second intermediate host, in which the
infective encysted metacercariae
are found in the muscles (CAMERO ,1944).
In Canada, sledge dogs appear to be commonly infected, and heavy infections may lead to death. At the level
198
of the bile ducts, adult worms may cause lesions similar
to those produced by Clonorchis sinensis and Opisthorchis felineus: proliferation of biliary epithelium, biliary
congestion and some degree of cirrhosis (MILLS &
HIRTH, 1968). Infection is acquired by eating raw fish. A
general prevention measure consists of eliminating raw
suckers from the diet of dogs.
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human liver flukes: a review - Biblioteca Virtual de la Real Academia

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