INTRODUCTION — The three major liver flukes (trematodes) that infect humans are Clonorchis sinensis, Opisthorchis species, and Fasciola hepatica [1]. The North American liver fluke, Metorchis conjunctus, is a less common liver fluke. Liver fluke infections are acquired via ingestion of raw, undercooked, salted, dried, pickled, or smoked freshwater fish from endemic areas.
Issues related to clonorchiasis, opisthorchiasis, and M. conjunctus will be reviewed here. Fascioliasis is discussed separately. (See "Liver flukes: Fascioliasis".)
CLONORCHIASIS AND OPISTHORCHIASIS — Opisthorchis and Clonorchis infections are similar with respect to life cycle, clinical manifestations, diagnosis, treatment, and prevention (as discussed in the following sections).
Epidemiology
●Clonorchiasis – Clonorchiasis is caused by C. sinensis (or Opisthorchis sinensis), also known as the Chinese liver fluke. It is endemic in East Asia (mainly in China, Japan, Korea, Taiwan, and Vietnam) [2], as well as far eastern Russia (figure 1) [3-5]. Clonorchis is a parasite of fish-eating mammals; dogs and cats are the most common reservoirs [6]. More than 35 million people are infected worldwide, with 600 million at risk [7]. Prevalence rates in endemic areas vary widely; in different provinces of China, for example, the prevalence ranges from <1 to 57 percent [8]. One study in Korea noted a prevalence of 16 percent [9].
Reinfection rates are high in endemic areas. In one study including 436 individuals treated for clonorchiasis, the reinfection rate at 12 months was 40 percent [10].
●Opisthorchiasis – Opisthorchiasis is generally caused by Opisthorchis felineus or Opisthorchis viverrini. These are liver flukes of cats, dogs, and other fish-eating mammals, which serve as reservoir hosts.
•O. felineus occurs in Southeast Asia and in Central and Eastern Europe, particularly in Siberia and other parts of the former Soviet Union [11,12]. Prevalence rates are 40 to 95 percent in some areas, and it is estimated that more than 16 million people are infected [13].
•O. viverrini is endemic in Thailand, Vietnam, Cambodia, Laos, China, and Myanmar [14]. Prevalence rates of over 24 to 90 percent in villages in Thailand and 40 to 80 percent in Laos have been reported, and it is estimated that worldwide over 23 million people are infected, including 15 million in China [2,5,13,15].
●Infection outside endemic areas – Travelers to or immigrants from endemic areas may harbor the infection and import it to nonendemic areas. Surveys in the United States have shown that Southeast Asian immigrants may have liver fluke infection [16]. In addition, frozen, dried, or pickled fish that contain surviving metacercariae can be exported to nonendemic areas; therefore, occasionally infection occurs in individuals who have never traveled to endemic areas [17,18].
Life cycle and pathogenesis
●Outside the host – The life cycle begins with release of embryonated eggs in stool (figure 2). Eggs are ingested by a snail (first intermediate host), where miracidia are released and go through several developmental stages (sporocysts, rediae, and cercariae). The cercariae are released from the snail into fresh water and subsequently penetrate the flesh of freshwater fish (second intermediate host), where they encyst as metacercariae.
●Within the host – Animals or humans acquire infection via ingestion of raw, undercooked, salted, pickled, or smoked freshwater fish (such as carp or salmon). The metacercariae excyst in the host duodenum and ascend the biliary tract.
Maturation to adult flukes takes approximately one month. The adult flukes are hermaphroditic and generally reside in small- and medium-sized biliary ducts; occasionally, they reside in the gallbladder or pancreatic duct. They are dorsoventrally flattened, 10 to 23 mm in length, and the body has an anterior oral sucker and a ventral sucker at midbody. The adults can persist in situ for years; there is no tissue migration. Embryonated eggs are released into the host biliary ducts and subsequently into the stool.
●Pathogenesis of biliary injury – Initial metacercariae migration causes trauma to the bile duct epithelium, leading to ulceration and desquamation. Early infection may be associated with subcapsular bile duct dilatation, adenomatous hyperplasia of the bile duct epithelium (with or without periductal fibrosis), goblet cell metaplasia, and eosinophilic infiltration. Repeated exposures may provoke diffuse biliary involvement, including the large bile ducts and gallbladder.
Clinical manifestations
Risk of symptomatic illness — Most acutely infected individuals are asymptomatic. The risk of symptomatic infection increases with the duration and intensity of infection. Symptoms are rare in the setting of ‘light’ infection (20 to 200 adult flukes or up to 1000 eggs per gram of stool) [19]. Among individuals with ‘heavy’ infection (as many as 20,000 adult flukes), symptoms occur in approximately 5 to 10 percent of cases and the risk of severe hepatobiliary manifestations is increased more than three-fold [20,21].
Symptomatic infection is most common among older adults in endemic areas (given risk for ongoing exposure and increased worm burden with age); onset of symptoms may be delayed for many years following initial infection. Less commonly, symptomatic infection may develop within a few weeks following consumption of heavily infected undercooked fish.
Acute infection
●Manifestations common to all pathogens – Clinical manifestations of acute infection include right upper quadrant abdominal pain, anorexia, nausea, vomiting, diarrhea, weight loss, flatulence, and fatigue [22]. Additional signs and symptoms may include fever, ascites, hepatomegaly, lymphadenopathy, myalgia, arthralgia, and urticaria [1]. Acute symptoms usually last for two to four weeks.
Eggs generally become detectable in the stool three to four weeks after exposure. High levels of circulating eosinophils (10 to 20 percent) are common. Liver function tests may be elevated, often with a cholestatic pattern with elevated alkaline phosphatase and gamma-glutamyl transferase [23].
●Manifestations specific to O. felineus – Unique features of O. felineus infection include fever, chills, hepatosplenomegaly, abdominal tenderness, and high-grade eosinophilia (up to 40 percent) [24]. These symptoms occur early in infection and may be associated with primary exposure to a large dose of metacercariae.
Chronic infection and complications
●Late manifestations – Late manifestations of liver fluke infection may include biliary obstruction (as well as strictures and/or dilatation), stone formation, cholangitis, cholecystitis, liver abscess, pancreatitis, hepatitis, and cirrhosis. Signs and symptoms may include fatigue, abdominal discomfort, jaundice, anorexia, weight loss, and dyspepsia [25].
Elevated total bilirubin and alkaline phosphatase levels reflect obstruction; elevated transaminase levels reflect hepatic injury. Peripheral eosinophilia occurs in approximately half of cases and typically is mild (500 to 1000/microL) [26,27].
These manifestations occur as a result of chronic epithelial irritation, leading to hepatic fibrosis. In addition, immunosuppressive mechanisms may facilitate parasite persistence, allowing ongoing biliary inflammation [28].
●Cholangiocarcinoma – Patients with clonorchiasis or opisthorchiasis are at risk for cholangiocarcinoma, particularly in the setting of heavy infection [1,29]. Risk factors include diabetes and Helicobacter pylori infection [30-32]. Symptoms of cholangiocarcinoma include jaundice, weight loss, epigastric pain, abdominal mass, and ascites. (see "Epidemiology, risk factors, anatomy, and pathology of cholangiocarcinoma" and "Clinical manifestations and diagnosis of cholangiocarcinoma")
In one meta-analysis including 181 studies and 56 million people with food-borne trematode infection, the odds ratios for cholangiocarcinoma with clonorchiasis or opisthorchiasis were 6.1 (95% CI 4.3-8.7) and 4.4 (95% CI 1.0-18.5), respectively [33].
The mechanisms of carcinogenesis are uncertain; they may include chronic inflammation and mechanical damage to the bile duct epithelium, nitric oxide formation, genetic alterations, protein dysregulation, activation of drug-metabolizing enzymes, coinfection, changes in the biliary tract microbiome and parasitic production of oncogenic molecules [34-37].
Diagnosis
Clinical approach — The diagnosis of clonorchiasis or opisthorchiasis should be suspected in individuals with relevant epidemiologic exposure (consumption of raw or undercooked fish from endemic areas) and typical clinical manifestations (fatigue, abdominal discomfort, jaundice, anorexia, weight loss, dyspepsia), with or without eosinophilia. (See 'Epidemiology' above and 'Clinical manifestations' above.)
The diagnosis of clonorchiasis or opisthorchiasis may be established by identifying eggs in stool; eggs generally become detectable in the stool three to four weeks after exposure. In addition, ultrasonography should be pursued to evaluate the biliary tract and assess for findings warranting acute intervention (such as presence of biliary duct stones, cholangitis, cholecystitis, or abscess).
For patients with an indication for biliary decompression (such as biliary duct stones and/or cholangitis), the diagnosis may be made by identifying eggs or adult worms in bile. Occasionally, eggs are also recovered from other sites such as duodenal aspirates or gastric washings [1].
A diagnosis of clonorchiasis or opisthorchiasis should prompt evaluation of family members with stool microscopy and blood count (to evaluate for eosinophilia). For individuals with eosinophilia but negative stool microscopy, ultrasonography to evaluate for findings consistent with fluke infection is warranted; the presence of such findings supports a presumptive diagnosis of fluke infection, warranting treatment. (See 'Imaging' below and 'Treatment' below.)
Additional diagnostic tools (serologic, antigen, and molecular tests) have been developed but are not widely available.
Diagnostic tools
Microscopy
●Technique – The preferred microscopy method is the formalin ethyl-acetate concentration technique. Kato-Katz thick smears can also be used. (See "Approach to stool microscopy", section on 'Specimen collection and preparation'.)
●Egg identification – Eggs are detectable in the stool approximately four weeks following infection.
Distinguishing between Clonorchis and Opisthorchis eggs is difficult; both are oval in shape and measure approximately 20 to 30 microns by 15 microns (picture 1 and picture 2). Species differentiation is usually based upon geographic exposure and/or adult fluke morphology.
In light infections, eggs may not be present or may be detectable only in concentrated specimens. Other causes of false negative results include intermittent egg excretion and biliary duct obstruction (preventing release of eggs into the stool).
In the setting of suspected liver fluke infection but negative stool microscopy, serial stool samples should be examined; in addition, alternative diagnostic tools should be pursued if feasible. (See 'Serologic, antigen, and molecular tests' below.)
●Adult worm identification – Adult worms may be found at endoscopy or endoscopic retrograde cholangiopancreatography; they may also be passed in the stool following anthelminthic therapy [8].
•Adult C. sinensis worms are flat and elongated, measuring 10 to 25 mm long and 3 to 5 mm wide (picture 3).
•Adult O. felineus and O. viverrini worms are usually 8 to 12 mm long, but O. felineus tends to be wider (2 to 3 mm compared with 1 to 2 mm) (picture 4).
Imaging — Imaging tools for diagnosis of clonorchiasis or opisthorchiasis include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI).
●Ultrasonography – Ultrasound abnormalities may be observed in the setting of asymptomatic and symptomatic infection. In one study including 123 Korean patients with clonorchiasis, ultrasound abnormalities were observed in 49 percent of cases [38].
Ultrasound findings include gallbladder enlargement and/or sludge, bile duct dilatation, inflammation and/or fibrosis, and hepatomegaly [39]. Flukes within the gallbladder move in response to gentle palpation with the transducer over the gallbladder. Ultrasound may also detect aggregates of flukes as nonshadowing echogenic foci within bile ducts (image 1) [40].
In one study of including 316 Korean patients with clonorchiasis, four sonographic findings distinguished patients with active disease from controls: (1) increased periductal echogenicity (sensitivity and specificity: 35 and 91 percent, respectively), (2) floating echogenic foci in the gallbladder (sensitivity and specificity: 28 and 94 percent, respectively), (3) diffuse intrahepatic bile duct dilatation (sensitivity and specificity: 67 and 48 percent, respectively), and (4) gallbladder distention (sensitivity and specificity: 3 and 100 percent, respectively) [41].
●CT and MRI – CT and MRI facilitate evaluation for dilation and thickening of the small intrahepatic bile ducts; they are also useful tools for detection of fibrosis, calcification, and hyperplasia [42].
Serologic, antigen, and molecular tests
●Serology – Serologic testing for opisthorchiasis and clonorchiasis using an enzyme-linked immunosorbent assay (ELISA) is performed in some laboratories but is not widely available [43-45]. The assay cannot reliably distinguish between current and past infection and may cross-react with other parasitic infections [43].
More sensitive and specific antigen-based detection assays, including monoclonal antibody-based enzyme-linked immunosorbent assay (mAb-ELISA) and immunoblot assays, have been developed using somatic and excretory-secretory (ES) antigens [46,47]. Sensitivity and specificity vary depending on the antigen used and the intensity of infection.
Data suggest that mAb assays may able to detect light infection with only a few adult worms; in one study, immunoblot assays using C. sinensis-specific ES antigens demonstrated sensitivity and specificity of 76 and 95 percent, respectively [48,49].
A rapid diagnostic immunochromatographic kit for point-of-care diagnosis of opisthorchiasis and clonorchiasis using ES products from adult O. viverrini worms has demonstrated favorable sensitivity and specificity compared with ELISA (95 and 91 percent, respectively) [47].
●Antigen tests – Urine antigen detection is an emerging method for detection of opisthorchiasis and is a promising tool for diagnosis and mass screening [50]. In one study including more than 1000 people in Thailand, the prevalence of O. viverrini (determined by urine antigen detection) correlated well with stool antigen detection; both methods demonstrated 10 to 15 percent higher prevalence than stool microscopy [51]. Among patients with negative stool microscopy, urine and stool antigen were positive in 29 and 43 percent of cases, respectively. Another study showed higher sensitivity and negligible day-to-day variation of the urine antigen tests compared with fecal egg counts [52]. Antigen tests may decline or revert to negative approximately four weeks after treatment, suggesting that they may be helpful in differentiating current from past infection and for monitoring treatment outcomes [53,54].
●Molecular tests – Polymerase chain reaction (PCR)-based methods for detecting O. viverrini, O. felineus, and C. sinensis eggs in stool have been developed but are not commercially available [55-57]. Compared with standard stool microscopy, the sensitivity of PCR in specimens containing >1000, 200 to 1000, and <200 eggs per gram of stool, has been found to be 100 percent, 68 percent, and 50 percent, respectively. High specificity of tests is reported [58].
Differential diagnosis
●Other fluke infections – These include:
•Fascioliasis – Clinical manifestations of fascioliasis include fever, right upper quadrant pain, hepatomegaly, and occasional jaundice. Fascioliasis may be distinguished from infection due to other liver flukes by the presence of hypodense lesions on CT imaging as well as by stool microscopy and serology. (See "Liver flukes: Fascioliasis".)
•Schistosomiasis – Clinical manifestations of chronic schistosomiasis include signs of portal hypertension, abnormal liver function tests, and eosinophilia. The diagnosis is established by serology and/or microscopy. (See "Schistosomiasis: Epidemiology and clinical manifestations".)
•Strongyloidiasis – Clinical manifestations of strongyloidiasis include abdominal pain, diarrhea, anorexia, nausea, vomiting, and eosinophilia; strongyloidiasis may present with eosinophilia in the absence of other symptoms. The diagnosis is established by serology and/or microscopy. (See "Strongyloidiasis".)
•Ascariasis – Ectopic ascariasis can be a cause of extrahepatic biliary obstruction, with clinical manifestations of abdominal pain and jaundice. The diagnosis is established by serology, microscopy, and/or visualization via endoscopic retrograde cholangiopancreatography. (See "Ascariasis".)
●Acute viral hepatitis – Clinical manifestations of acute viral hepatitis include fever, right upper quadrant pain, and fatigue, in the absence of eosinophilia. The diagnosis of acute viral hepatitis is established via serology. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis".)
●Choledocholithiasis – Clinical manifestations of choledocholithiasis include right upper quadrant pain and liver function tests consistent with cholestasis (elevated bilirubin and alkaline phosphatase). The diagnosis is established via ultrasonography. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management".)
●Cholangiocarcinoma – Clinical manifestations of cholangiocarcinoma include jaundice, pruritus, clay-colored stools, dark urine, abdominal pain, weight loss, and fever. Liver function tests demonstrate a cholestatic picture. Diagnostic tools include magnetic resonance cholangiopancreatography and tumor markers. (See "Clinical manifestations and diagnosis of cholangiocarcinoma".)
●Primary sclerosing cholangitis – Clinical manifestations of primary sclerosing cholangitis may include fatigue, pruritus, jaundice, hepatomegaly, and splenomegaly. Liver function tests demonstrate a cholestatic picture. The diagnosis is established via cholangiography. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis".)
Treatment — Treatment is warranted for patients with positive stool microscopy, in the presence or absence of symptoms [40]. Treatment is also warranted for patients with a presumptive diagnosis of clonorchiasis or opisthorchiasis (based on relevant epidemiologic exposure, presence of eosinophilia, and ultrasonographic findings consistent with fluke infection), even in the setting of negative stool microscopy.
Goals of treatment include management of symptoms (if present), as well as minimizing the risk of chronic infection and associated complications, including cholangiocarcinoma. (See 'Chronic infection and complications' above.)
Anthelminthic therapy — Treatment of clonorchiasis or opisthorchiasis consists of anthelminthic therapy. Additional intervention may be needed depending on the nature of the clinical presentation.
●Preferred agent – Praziquantel is the preferred agent. Eggs typically disappear from the stool within a week of treatment. However, clinical symptoms may take months to resolve, and biliary ductal abnormalities may persist after treatment [59].
Treatment of clonorchiasis or opisthorchiasis consists of praziquantel (25 mg/kg orally three times daily for one to two days) [13,60]. We agree with the World Health Organization guidance, which favors two days of treatment; however, some regional treatment guidelines consist of one day of treatment. Cure rates are high (>90 percent) with either regimen but appear even higher with the two-day regimen (100 percent) [61-65]. A systematic review showed that the WHO-recommended praziquantel regimen (25 mg/kg three times a day for 2 days) had a high cure rate (98.5%; 85.4-99.9) in C. sinensis infection, and in O. viverrini infection, regimens of 75 mg/kg or 50 mg/kg of praziquantel given in a single day showed predicted cure rates of 93.8 percent (85.7-97.5) and 92.1 percent (64.9-98.6), respectively [66].
Adverse effects of praziquantel include headache, dizziness, insomnia, nausea, and vomiting.
Administration of praziquantel for two days is supported by two trials including 100 patients with clonorchiasis [60,61] as well as one trial including 25 patients with opisthorchiasis [62] in which cure rates of 100 percent were achieved (based on stool microscopy and clinical symptoms) [63].
Administration of praziquantel for one day is supported by a trial including 37 patients with clonorchiasis or opisthorchiasis randomly assigned to treatment with praziquantel (25 mg/kg/dose orally three times daily for one day) or placebo; the cure rate (based on stool microscopy) with this regimen was >90 percent [64].
For treatment of light infection due to opisthorchiasis (<1000 eggs per gram of stool by Kato-Katz technique), single-dose praziquantel (30 to 50 mg/kg) was similarly effective as the standard regimen with lower rates of adverse effects; additional study for moderate and heavy infection is needed [65,67].
A lower dose praziquantel regimen is less effective. In one study including 21 Vietnamese patients with clonorchiasis treated with praziquantel (25 mg/kg once daily for three days), the cure rate was only 29 percent [68]. Similarly, in a trial including 12 patients with opisthorchiasis treated with the same regimen, the cure rate was 44 percent [65].
●Alternative agents
•Albendazole – Albendazole (10 mg/kg orally [max dose 400 mg orally twice daily]) with fatty meal for seven days is a potential alternative regimen. In one study including 200 children with hookworm infection of whom 55 were coinfected with O. viverrini, the cure rate (based on stool microscopy) for single-dose albendazole was 33 percent [69]. In one case series of 86 patients with clonorchiasis who were tested after treatment with a four-day course of albendazole, the cure rate was 91 percent [70]. A systematic review of albendazole 400 mg twice daily for 5 or 7 days resulted in cure rates of 100 percent [66], although studies were of limited size.
•Tribendimidine – Tribendimidine may be at least as efficacious as praziquantel for treatment of opisthorchiasis [71-74]. In a randomized trial including more than 600 patients with O. viverrini infection treated with tribendimidine (single oral dose; 200 mg for children, 400 mg for adolescents and adults) or praziquantel (two doses; 50 mg/kg followed by 25 mg/kg, six hours apart), the cure rates (negative stool microscopy at three weeks follow-up) were 94 and 97 percent, respectively [73]. Adverse events were mild but were more frequent in the praziquantel group. A systematic review showed that a single dose of 400 mg tribendimidine had a predicted cure rate of 89.8 percent (77.5-95.8) [66].
●Additional interventions – Biliary decompression (endoscopic, percutaneous, or surgical) may be warranted in some circumstances; indications may include biliary duct stones and/or cholangitis.
In such cases, bile should be sent to evaluate for eggs and adult worms.
Issues related to management of complications (such as biliary obstruction, stone formation, cholangitis, cholecystitis, liver abscess, pancreatitis, hepatitis, and cirrhosis) are discussed separately (see related topics).
Follow-up — The optimal approach to monitoring for cholangiocarcinoma is uncertain; baseline ultrasonography abnormalities often persist following anthelminthic treatment. One study which followed individuals with O. viverrini infections and advanced periportal fibrosis (APF) for up to five years after praziquantel therapy found that about one third of patients (31 percent) had no relapse in APF, whereas 38 percent showed persistence or relapse of ultrasonic hepatobiliary abnormalities [75]. We favor annual ultrasonography following treatment of infection [76].
Further evaluation of the efficacy of follow-up screening is needed [77]. In one study including 347 Korean patients who underwent ultrasonography one year after completing treatment for clonorchiasis, most patients had persistent findings of periductal echogenicity and intrahepatic bile duct dilatation; floating echogenic foci in the gallbladder improved in about one third of cases [78]. In another study including 104 patients in Thailand with opisthorchiasis and advanced periductal fibrosis who underwent annual ultrasonography for five years after anthelminthic treatment, persistent or relapsed fibrosis was observed in 37 percent of cases; 5 cases of cholangiocarcinoma were observed [75].
Prevention — Prevention tools include:
●Education to reduce consumption of raw or undercooked fish – Transmission can be prevented by cooking; alternatively, fish may be frozen to internal temperature of -4°F for at least seven days [79]. Preparation methods that are not reliable to reduce transmission include salting, drying, pickling, and smoking [48]. Health literacy programs have also showed benefits [80].
●Improved hygiene to prevent water contamination.
●Mass drug administration − In regions where opisthorchiasis is endemic, mass treatment with praziquantel (40 mg/kg single dose) has been used, with cure rates (based on stool examination) ranging from 88 to 100 percent [53,65,81].
Some control programs in endemic areas have resulted in reduced prevalence; however, complete elimination may not be possible, particularly if domestic cat and dog reservoir hosts serve as a persistent reservoir of infection [48].
Vaccines are an area of ongoing study [82].
METORCHIS SPECIES — M. conjunctus is a liver fluke endemic to North America [83]. Most cases occur among native Canadian populations; stool surveys in these communities have demonstrated occasional asymptomatic human infection [84,85]. Metorchis belis occurs in Russia and Central and Eastern Europe; the geographic distribution overlaps with O. felineus [83]. Metorchis orientalis has been reported in Eastern Asia, specifically in China [86].
Metorchis spp are in the same family (Opisthorchiidae) as C. sinensis, O. viverrini, and O. felineus; all of these organisms have the same life cycle (figure 2) and seem to cause indistinguishable clinical symptoms, although data are limited due to the paucity of confirmed cases [5]. The different species cannot be distinguished morphologically or via light microscopy of eggs [83]; molecular methods are required for differentiation but are not available for routine use in clinical practice. Many fish-eating mammals (including dogs, fox, seals, and others) serve as definitive hosts. Aquatic snails serve as the first intermediate host; aquatic fish including the white sucker (Catostomus commersoni) serve as the second intermediate hosts. Humans are incidental hosts.
One outbreak of M. conjunctus among 19 Canadian patients was attributed to sushi prepared with raw white sucker fish [87]. Clinical manifestations (fever, anorexia, epigastric pain, and weight loss) and/or laboratory abnormalities (elevated serum transaminase concentration in 10 patients; eosinophilia in 15 patients) developed 1 to 15 days following ingestion of the raw fish. Stool microscopy demonstrated eggs among 10 patients; the eggs were indistinguishable from O. viverrini. Symptoms persisted for 3 to 28 days but responded promptly to treatment with praziquantel in all cases. It is uncertain whether prolonged infection or biliary complications can occur with M. conjunctus.
SUMMARY AND RECOMMENDATIONS
●Clonorchiasis and opisthorchiasis
•Epidemiology – Clonorchiasis and opisthorchiasis are liver fluke infections are acquired via ingestion of raw, undercooked, salted, dried, pickled, or smoked freshwater fish from endemic areas. Cats, dogs, and other fish-eating mammals serve as reservoir hosts (figure 2) (see 'Epidemiology' above):
-Clonorchiasis is caused by Clonorchis sinensis; it is endemic in China, Japan, Korea, Taiwan, and Vietnam.
Opisthorchiasis is caused by Opisthorchis felineus or Opisthorchis viverrini. O. felineus occurs in Southeast Asia and in Central and Eastern Europe; O. viverrini is endemic in Thailand, Vietnam, Cambodia, Laos, China, and Myanmar.
•Clinical manifestations (see 'Clinical manifestations' above):
-Acute infection – Most acutely infected individuals are asymptomatic. Symptomatic infection is most common among older adults in endemic areas (given risk for ongoing exposure and increased worm burden with age); onset of symptoms may be delayed for many years following initial infection.
-Chronic infection and complications – Late manifestations may include biliary obstruction (as well as strictures and/or dilatation), stone formation, cholangitis, cholecystitis, liver abscess, pancreatitis, hepatitis, and cirrhosis. In addition, such patients are at risk for cholangiocarcinoma, particularly in the setting of heavy infection.
•Diagnosis (see 'Diagnosis' above):
-The diagnosis of clonorchiasis or opisthorchiasis should be suspected in individuals with relevant epidemiologic exposure (consumption of raw or undercooked fish from endemic areas) and typical clinical manifestations (fatigue, abdominal discomfort, jaundice, anorexia, weight loss, dyspepsia), with or without eosinophilia.
-The diagnosis may be established by identifying eggs in stool, which generally become detectable three to four weeks after exposure (picture 1 and picture 2). In addition, ultrasonography should be pursued to evaluate the biliary tract and assess for findings warranting acute intervention (such as presence of biliary duct stones, cholangitis, cholecystitis, or abscess).
•Treatment – For treatment of clonorchiasis or opisthorchiasis in both symptomatic and asymptomatic individuals, we suggest treatment with praziquantel (25 mg/kg/dose orally three times daily for two days) rather than other treatment regimens (Grade 2C).
Additional intervention for management of complications may be needed depending on the nature of the clinical presentation. (See 'Treatment' above.)
•Follow up − The optimal approach to monitoring for cholangiocarcinoma is uncertain; baseline ultrasonography abnormalities often persist following anthelminthic treatment. We favor annual ultrasonography following treatment of infection. (See 'Follow-up' above.)
●Metorchis infection – Metorchis species can cause liver fluke disease in humans. The life cycles, morphology, and microscopy are comparable with those seen in clonorchiasis or opisthorchiasis. In confirmed cases, acute clinical manifestations include fever, anorexia, epigastric pain, and weight loss; eosinophilia is common. It is unknown whether prolonged infection or biliary complications can occur. Diagnosis consists of stool microscopy; treatment as for clonorchiasis or opisthorchiasis. (See 'Metorchis species' above.)
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