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Liver fluke infections 

Liver fluke infections
Chapter:
Liver fluke infections
Author(s):

David I. Grove

DOI:
10.1093/med/9780199204854.003.071102_update_001

Update:

Opisthorchiasis and clonorchiasis—tribendimidine is a potential new alternative anthelminthic.

Fascioliasis—artesunate for treatment.

Updated on 31 May 2012. The previous version of this content can be found here.
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Essentials

Clonorchiasis and related flukes

Clonorchis (syn. Opisthorchis) sinensis is a fluke (flatworm) acquired by ingestion of undercooked freshwater fish in eastern Asia. Larvae in the duodenum enter the biliary tree through the sphincter of Oddi and mature. Most patients are asymptomatic, but there may be right upper abdominal discomfort, and infection can be complicated by bacterial cholangitis and there is an increased risk of cholangiocarcinoma. Diagnosis is suggested by finding eggs in faeces or in duodenal aspirates, but can only be confirmed by examination of adult flukes. Treatment is with praziquantel.

Opisthorchis viverinni in South-East Asia and O. felineus in Eurasia, also acquired from undercooked fish, cause similar infections. Praziquantel is the treatment of choice.

Fascioliasis

Fasciola hepatica and its relative F. gigantica are acquired by eating watercress contaminated with cysts. These hatch in the duodenum, from which larvae pass through the peritoneum and track through the liver parenchyma, causing considerable damage before they mature in the bile ducts. This produces a hepatitis-like syndrome followed months or years later by features of biliary obstruction. Diagnosis is made by finding eggs in stool or duodenal fluid. Triclabendazole and artenusate are the treatments of choice.

Other liver flukes

Dicrocoelium dendriticum is a rare infection acquired by accidental ingestion of infected ants; Metorchis conjunctus infection follows consumption of infected freshwater fish. The clinical features of these infections and diagnostic approaches to them are similar to those of other liver fluke infections. Praziquantel is the treatment of choice.

Introduction

Liver flukes, otherwise known as trematodes, are leaf-like hermaphroditic flatworms. The hepatobiliary system of humans is commonly infected by flukes of the genera Clonorchis and Opisthorchis and occasionally by other species (Table 7.11.2.1). In addition, Eurytrema pancreaticum has been found rarely in the pancreatic duct. These infections are usually diagnosed by finding eggs in the faeces. Unfortunately, eggs of many of these species cannot be differentiated from each other, nor can they be distinguished reliably from the eggs of certain intestinal trematodes. In such cases, definitive diagnosis can only be made if adult worms are recovered from the stools after anthelmintic treatment, at surgery or at autopsy; parasitological texts should be sought for diagnostic details.

Table 7.11.2.1 Liver flukes infecting humans

Species

Geographical distribution

Source of infection

Size of eggs (µm)

Clonorchis sinensis

Eastern Asia

Freshwater fish

28–35 × 12–19a

Dicrocoelium dendriticum

Widespread

ants accidentally ingested with food

38–45 × 22–30b

Eurytrema pancreaticum

Eastern Asia

Grasshoppers

38–45 × 22–30b

Fasciola gigantica

Asia, Africa

Vegetation, e.g. watercress

130–150 × 60–90c

Fasciola hepatica

Widespread

Vegetation, e.g. watercress

130–150 × 60–90c

Metorchis conjunctus

Canada

Freshwater fish

28–35 × 12–19a

Opisthorchis felineus

Europe, Asia

Freshwater fish

28–35 × 12–19a

Opisthorchis guayaquilaris

Ecuador

Freshwater fish

28–35 × 12–19a

Opisthorchis viverrini

Indochina

Freshwater fish

28–35 × 12–19a

a, b, c. Superscripts indicate that eggs within each group are indistinguishable

Clonorchiasis

Life cycle

Clonorchis (syn. Opisthorchis) sinensis adult worms, 10 to 25 mm long by 3 to 5 mm wide, are found in the bile ducts or occasionally the gallbladder, attached to the mucosa. They may live for up to 40 years. They produce eggs which are passed in the faeces. The miracidium within the egg hatches after ingestion by a suitable species of aquatic snail; nine species belonging to the families Hydrobidae, Melanidae, Assimineidae, and Thiaridae are known to be susceptible. Parafossarulus manchouricus is perhaps the most common. The miracidia develop into sporocysts then in turn become rediae which produce larvae known as cercariae. After 6 to 8 weeks, the cercariae emerge from the snail, swim about in the water until they encounter certain freshwater fishes (>100 species, mostly of the family Cyprinidae, i.e. carp, are susceptible). They attach to the surface of the fish, lose their tails, penetrate under the scales, encyst in the skin or flesh, and develop into infective metacercariae over several weeks. When raw or undercooked infected fish is eaten by humans, the metacercariae excyst in the stomach, enter the common bile duct through the ampulla of Vater and ascend into the biliary passages where they mature in 1 month (Fig. 7.11.2.1).

Fig. 7.11.2.1 Life cycle of Clonorchis and Opisthorchis.

Fig. 7.11.2.1
Life cycle of Clonorchis and Opisthorchis.

Epidemiology and control

Fish-eating mammals including humans, dogs, cats, and rats may be infected with C. sinensis. Human clonorchiasis is endemic in Japan, Korea, China, and Vietnam where the first and second intermediate hosts are found and where the population is accustomed to consume raw fish. In endemic areas, fish are kept in ponds and fertilized with human and animal faeces. Over 20 million people are thought to be infected in China. Control programmes include proper waste disposal, measures to control snail numbers, and mass treatment with praziquantel, but the most important is health education to discourage the habit of eating raw or undercooked fish.

Pathology

Pathological changes are related to the intensity and duration of infection. They are produced by mechanical irritation, toxin production, immunological responses, and secondary bacterial infection. Inspection of the cut surface of the liver often reveals dilated, thick-walled bile ducts with adult worms visible within the lumen. Adult flukes may be found in the gallbladder but they are usually killed by bile. Histologically, there is desquamation and hyperplasia of epithelial cells, formation of adenomatous tissue and proliferation of periductal connective tissue, and infiltration with eosinophils and mononuclear cells. This may be complicated by epithelial metaplasia then mucinous cholangiocarcinoma. Recurrent pyogenic cholangitis is a common complication and the worms and eggs act as a nidus for gallstone formation (Fig. 7.11.2.2). Some patients have flukes in the pancreatic duct which may cause pancreatitis.

Fig. 7.11.2.2 Histological section of a gallstone showing masses of degenerate Clonorchis/Opisthorchis eggs.

Fig. 7.11.2.2
Histological section of a gallstone showing masses of degenerate Clonorchis/Opisthorchis eggs.

Clinical features

Most patients are asymptomatic and are diagnosed incidentally on stool examination. Symptoms are more common in older patients with heavy worm burdens. It is difficult to differentiate these symptoms from other conditions but they include right hypochondrial or epigastric pain or discomfort, lassitude, anorexia, and flatulence. Some patients complain of a peculiar, hot sensation on the skin of the abdomen or back. Cholangitis causes fever, right upper quadrant pain, and jaundice. Cholangiocarcinoma is associated with pain, jaundice, and weight loss.

Diagnosis

The diagnosis is suggested by finding eggs in faeces or in duodenal aspirates. They are yellow-brown, 25 to 35 µm long by 12 to 19 µm wide and have a seated operculum with a small knob at the other end (Fig. 7.11.2.3). They cannot be differentiated from ova of Opisthorchis species. Furthermore, they are extremely difficult to differentiate from eggs of flukes in the family Heterophyidae (see intestinal trematode infections) although the latter tend to have a smoother egg shell, a less prominent shoulder at the operculum and the knob may be absent. The diagnosis can only be confirmed by examination of adult flukes. Serological tests are not routinely used for diagnosis. Imaging techniques including ultrasonography, CT, and MRI may disclose adult worms or sludge in the gallbladder. The bile ducts are often dilated and contain sludge or calculi and there may be ‘too many ducts’ on MRI or increased periductal echogenicity on ultrasonography. Liver function tests may be abnormal, often with an obstructive picture.

Fig. 7.11.2.3 Egg of Clonorchis sinensis: this is identical with that of Opisthorchis viverrini.

Fig. 7.11.2.3
Egg of Clonorchis sinensis: this is identical with that of Opisthorchis viverrini.

(Courtesy of A R Butcher.)

Treatment

Praziquantel is the treatment of choice and in a dose of 25 mg/kg three times daily after meals for 2 days has a cure rate of close to 100%; eggs should disappear from the stool within 1 week. Biliary tract abnormalities sometimes reverse after treatment. Tribendimidine (see ‘Opisthorchiasis’) has recently been shown to be effective in experimental animals infected with C. sinensis and may eventually prove to be a useful alternative in human infections. Triclabendazole (see ‘Fascioliasis’) may prove to be useful, but there is insufficient documentation at present. Bacterial cholangitis is treated with antibiotic therapy such as a combination of amoxicillin, gentamicin, and metronidazole. Surgery or biliary extraction at enteric retrograde cholangiopancreatography may be required in some patients with obstructive jaundice.

Opisthorchiasis viverrini

This infection is very similar to clonorchiasis. The adult O. viverrini is smaller than C. sinensis, measuring 7 to 12 mm by 1.5 to 3 mm. It may live for over 10 years. The life cycle is similar to that of Clonorchis, with various species of snails of the genus Bithynia being the first intermediate host. Many species of carp serve as the second intermediate host. Humans, dogs, cats, and other fish-eating mammals are definitive hosts. This parasite is endemic in northern Thailand and adjacent Laos and Cambodia where 10 million people are estimated to be infected because of the popularity of chopped raw cyprinoid fish as a foodstuff.

The pathology and clinical features are similar to those induced by C. sinensis. The association with cholangiocarcinoma may be even more striking with this infection. The diagnosis is made as discussed under clonorchiasis. Praziquantel is the drug of choice; 25 mg/kg three times after meals for 1 day gives close to 100% cure rates. A recent preliminary study in Laos has compared the antimalarials mefloquine and artesunate (see ‘Fascioliasis’) with tribendimidine or praziquantel in patients infected with O. viverrini. Mefloquine and artenusate, alone or in combination, had only a modest effect on egg excretion and a negligible cure rate. On the other hand, the majority of patients were cured with either praziquantel or tribendimidine with near complete elimination of ova from the stools. Mebendazole (30 mg/kg daily) or albendazole (400 mg twice daily) may be effective if given for several weeks. Triclabendazole may prove to be useful but there is insufficient documentation at present. Control programmes depend heavily on intensive health education.

Opisthorchiasis felineus

This infection is very similar to clonorchiasis. The adult O. felineus is morphologically very similar if not identical to O. viverrini (the two species have been distinguished by the pattern of flame cells in the cercariae and more recently by molecular biological techniques). The life cycle is similar, with Bithynia leachi being the only known molluscan intermediate host. Many species of carp serve as the second intermediate host. Humans, dogs, cats, rats, foxes, seals, and other fish-eating mammals are definitive hosts. Infection is acquired by eating raw or undercooked fish; in Siberia, raw, slightly salted and frozen fish is often consumed. This parasite is endemic particularly in Russia and adjacent countries but also in parts of southern Europe and eastern Asia, with several million people probably being infected overall. Eggs are indistinguishable from those of O. viverrini and C. sinensis. The pathology, clinical features and diagnosis are similar to O. viverrini and C. sinensis infections. Praziquantel 25 mg/kg three times in one day or albendazole 5 mg/kg twice daily for 7 days are both effective.

Fascioliasis

Life cycle

Fascioliasis is due to infection with the sheep liver fluke Fasciola hepatica or with F. gigantica. Adult F. hepatica flukes 20 to 30 mm by 8 to 13 mm in size live in the large bile ducts and produce eggs which are passed in the stools. The eggs require a period of 9 to 15 days for the miracidia to develop and hatch in water at 22 to 25°C but remain viable for up to 9 months if kept moist and cool. The miracidia penetrate the tissues of various species of amphibious snails of the family Lymnaeidae and develop over the following 4 to 5 weeks through the stages of sporocyst, rediae, daughter rediae, and cercariae. The cercariae emerge from the snails and encyst on various kinds of aquatic vegetation to become metacercariae. A wide range of mammals is susceptible to infection but sheep and cattle are the most important. Human infections are usually acquired by eating watercress or by drinking water contaminated with metacercariae. Metacercariae excyst in the duodenum, penetrate the intestinal wall, and pass into the peritoneal cavity. They then invade the liver capsule and migrate through the hepatic parenchyma to the bile ducts where they mature in about 3 to 4 months. The life span of these flukes is several years.

F. gigantica is large, attaining a size of up to 7.5 cm. The eggs are difficult to distinguish from those of F. hepatica and the life cycles of the two parasites are similar.

Epidemiology and control

Because of the wide range of susceptible definitive and intermediate hosts, the infection is geographically widespread. Human infections with F. hepatica have been reported from all continents. Fascioliasis gigantica is less frequent and has been seen mostly in Africa and Asia. Infection is prevented by not eating fresh aquatic plants, particularly watercress (Nasturtium officinale) and by boiling drinking-water. Veterinary control measures include elimination of the snail intermediate hosts by drainage of pastures and treatment with molluscicides and by eradication of infection from infected herds.

Pathology

In the early stages of infection, larvae migrating through the liver parenchyma may cause considerable destruction with necrosis, abscess formation, and haemorrhage. The number of tunnels lined by ragged walls of necrotic, bleeding and inflamed liver tissue is proportional to the number of worms. In the chronic stages, the walls of the bile ducts become thickened by fibrous tissue and inflammatory infiltration, the epithelium becomes hyperplastic, and the bile ducts dilate. Occasionally the lumina of the bile ducts may become obliterated causing obstructive jaundice. These structural changes predispose to secondary bacterial infection which exacerbates the problem. Sclerosing cholangitis and biliary cirrhosis may follow prolonged heavy infection. There is no apparent association with cholangiocarcinoma.

Clinical features

Human fascioliasis is usually mild and related to the phase of infection. There are three phases.

  • Migratory phase—symptoms usually begin about 1 month after infection. Patients may develop abdominal discomfort or pain (especially in the epigastrium and right upper quadrant), anorexia, nausea, vomiting, fever, headache, tender hepatomegaly and urticaria. These initial symptoms may persist for several months.

  • Latent phase—this phase is asymptomatic and may last for months to years.

  • Obstructive phase—this phase is characterized by the recurrence or appearance for the first time of epigastric and right upper quadrant abdominal pain, biliary colic, anorexia, nausea, vomiting, tender hepatomegaly, fever, and jaundice. These features are frequently due to complicating bacterial cholangitis or cholecystitis and may be associated with bacteraemia.

Flukes occasionally migrate to other sites, especially the anterior abdominal wall, but have also been recovered from the breast, pleural cavity, lymph nodes, and subcutaneous tissue. Acute oedematous nasopharyngitis may be an allergic response to larval flukes which attach to the pharyngeal wall after ingestion of infected raw sheep or goat liver (see Chapter 7.13).

Diagnosis

In enzootic areas, early fascioliasis is suspected in patients with fever, tender hepatomegaly, and eosinophilia who give a history of consuming freshwater plants. If available, serological tests may be useful early in the illness before egg production begins. Liver biopsy may be helpful in some cases.

Chronic fascioliasis is diagnosed by finding the characteristic eggs in stools or fluid obtained by duodenal or biliary drainage but unfortunately egg excretion is often intermittent. The eggs of F. hepatica and F. gigantica cannot be distinguished reliably from each other or from those of the intestinal fluke, Fasciolopsis buski; differentiation of these two infections requires identification of adult flukes. Liver function tests are often abnormal and may show an obstructive picture. Radiolucent shadows of flukes may be seen by cholangiography. Ultrasonography and CT are useful in the demonstration of lesions in the liver and biliary tracts. If the patient has recently consumed infected liver, spurious infection (ingestion of eggs) should be ruled out by placing the patient on a liver-free diet for a few days and repeating the stool examination.

Treatment

Triclabendazole is the drug of choice but its safety in pregnant women has not been proven and resistance has developed in some veterinary populations that may be the source of infection. It is given in a single oral dose of 10 mg/kg although some patients require a second dose after a few weeks. This drug appears to have few side effects. It is available in some countries but not others; further information can be sought from the manufacturer (Novartis, Basle, Switzerland). Flukes are evacuated through the intestinal tract. If triclabendazole is unavailable or ineffective, the antimalarial artenusate may prove to be a useful alternative. A preliminary comparative trial found that artenusate 4 mg/kg once daily for 10 days produced a similar improvement in clinical symptoms to that seen with triclabendazole. Unfortunately, there have not yet been any studies reported in humans to correlate this observation with parasite eradication although studies in infected sheep and rats are encouraging. Nitazoxanide administered in a dose of 100 mg orally twice daily for 7 days cures approximately 50% of patients with fascioliasis; its safety in pregnancy has not yet been established. Good results have been claimed by some for oleo-resin of myrrh (mirazid) in a dose of 10 mg/kg per day for 6 consecutive days but others have reported that this drug is ineffective. Praziquantel, which is active against many trematodes, is usually ineffective in fascioliasis but may be tried if other agents are not available.

Dicrocoeliasis

Dicrocoelium dendriticum adult worms measuring 5 to 15 mm by 1.5 to 2.5 mm live in the biliary passages. Eggs passed in the stools are ingested by certain land snails (e.g. species of Zebrina and Helicella,) in which they develop through two stages of sporocysts with the eventual production of cercariae. The snail leaves slime balls of cercariae on the ground and these are ingested by ants (Formica species) in which they develop into metacercariae.

This organism is primarily an infection of sheep, goats, deer, and other herbivores which ingest ants on vegetation. Humans are rarely infected and are usually accidental. Cases have been reported from Europe, Asia, and Africa. Spurious infections result from the consumption of raw, infected liver, in which case ova disappear from the stools within several days. Patients may be asymptomatic but may complain of dyspepsia, flatulence, right upper quadrant pain and diarrhoea. The diagnosis is made by finding the eggs in faeces, bile, or duodenal fluid (Fig. 7.11.2.4); they cannot be differentiated from those of Eurytrema pancreaticum. Definitive diagnosis is made by identification of adult worms. Rare ectopic sites for adult worms include the peritoneal and pleural cavities and subcutaneous tissue. Treatment is with praziquantel 25 mg/kg three times after meals for 1 day. Triclabendazole (see ‘Fascioliasis’) has also been reported to be effective.

Fig. 7.11.2.4 Eggs of Dicrocoelium dendriticum.

Fig. 7.11.2.4
Eggs of Dicrocoelium dendriticum.

(Courtesy of A R Butcher.)

Metorchiasis

Many fish-eating mammals of North America serve as definitive hosts for Metorchis conjunctus. The aquatic snail Amnicola limosa is the first intermediate host; eggs are ingested and hatch miracidia and ultimately release cercariae. Metacercariae develop in the flesh of several species of freshwater fish. Ingested metacercariae hatch in the duodenum and migrate up the biliary tree.

A point source outbreak of this disease has been reported in 19 people who ate raw fish prepared from the white sucker Catostomus commersoni caught in a river north of Montreal. The illness was characterized by upper abdominal pain, low-grade fever, eosinophilia, and abnormal liver function tests. Ten days after ingestion of infected fish, eggs indistinguishable from those of O. viverrini were seen in the stools. The patients responded to treatment with praziquantel.

Further reading

Ezzat RF, et al. (2010). Endoscopic management of biliary fascioliasis: a case report. J Med Case Reports, 4, 83–6. [This article is free at http://www.ncbi.nlm.nih.gov/pubmed and has excellent images of F. hepatica seen at duodenoscopy in the duodenum and coming out of the bile duct.]Find this resource:

Hong ST, Fang Y. (2012). Clonorchis sinensis and clonorchiasis: an update. Parasitol Int, 61, 17–24.Find this resource:

Keiser J, Itzinger J. (2009). Food-borne trematodiases. Clin Microbiol Rev, 22, 466–83.Find this resource:

Lim JH. (2011). Liver flukes: the malady neglected. Korean J Radiol, 12, 269–79. [This article is free at http://www.ncbi.nlm.nih.gov/pubmed and has excellent illustrations of the parasite, histopathology, and radiology.]Find this resource:

Sripa B, et al. (2010). Food-borne trematodiases in Southeast Asia epidemiology, pathology, clinical manifestation and control. Adv Parasitol, 72, 305–50.Find this resource:

Websites

Centers for Disease Control and Prevention. http://www.dpd.cdc.gov/DPDx/HTML/Image_Library.htm

Korean Society for Parasitology. http://www.atlas.or.kr