Continuing Education Activity

Clonorchis sinensis is also known as the Chinese liver fluke and is a fish-borne trematode causing the disease clonorchiasis. Low-income areas of Asian countries such as China, South Korea, and northern Vietnam are especially affected. The World Health Organization (WHO) therefore listed C. sinensis among the most neglected tropical diseases globally. C. sinensis is a common parasite of fish-eating mammals, including cats, dogs, and humans. Humans become infected by eating raw or undercooked freshwater fish in the form of fillets, sashimi, or congee that contain C. sinensis metacercariae. When infected, C. sinensis lives within the biliary system of humans. These parasites can cause serious complications if not found and treated early. This activity reviews the evaluation and treatment of liver flukes and addresses the role of the interprofessional team in evaluating and treating this condition

Objectives:

• Outline the typical presentation of a patient with Clonorchis sinensis infection.
• Review the evaluation of Clonorchis sinensis, identifying risk factors associated with the infection.
• Outline the treatment options for patients suspected of harboring C. sinensis.
• Explain the importance of the interprofessional team in identifying C. sinensis and providing the best possible care and education of the patient.

Introduction

Clonorchis sinensis is a trematode also known as the Chinese or Oriental liver fluke. This parasitic infection is most commonly found in Eastern Asia, including Korea, China, and Vietnam, but it can be endemic in far eastern regions of Russia. These liver flukes are common parasites of fish-eating mammals. Cats and dogs of endemic areas are the most common hosts,  but C. sinensis can be transmitted to humans who eat infected fish. When infected, C. sinensis can live for years within the biliary system of humans and result in a variety of symptoms, including cholecystitis, cholangitis, and cholangiocarcinoma. This can be extremely burdensome for Asian immigrants, who emigrated from an area of endemic infection and develop ongoing symptoms years after initial infection. In parts of Asia, liver flukes are a public health problem, and more than 200 million people are at risk of infection in these regions.[1][2]

Etiology

Causes of clonorchiasis are mostly limited to the ingestion of fish encysted with C. sinensis in endemic regions of the world, including East Asia. 

The Lifecycle of C. sinensis

Eggs of C. sinensis enter the water environment from feces. These eggs are then consumed by the first intermediate host, the freshwater snails, in which the eggs release miracidia which undergo a series of developmental stages to sporocyst, rediae, and subsequently cercariae. The cercariae are released from the snail and are free-swimming in the water until they penetrate a freshwater fish. These cercariae encyst then into the flesh of freshwater fish and continue to mature to metacercariae. The infected fish is then ingested by a higher mammal such as humans, where the metacercariae encyst as juvenile flukes in the duodenum. Hermaphroditic adult C. sinensis ascends through the ampulla of Vater into the bile system and can often be found in the intrahepatic bile ducts. Complete maturation can take up to a month. [3] The life cycle can take up to 3 months before eggs will show up in the sputum or feces of an infected adult.

Snails, including Bithynia fuchsiana, Alocinma longicornis, Parafossarulus striatulus, are important intermediate hosts. These snails are often found in the local waterways, ponds, lakes, and paddy fields. It is eating raw or uncooked freshwater fish (mostly of the Cyprinidae family) that can lead to parasitic infection, but contamination of utensils and food with Metacercariae is also a potential route of infection, which is especially seen in children and women.

Epidemiology

C. sinensis is predominantly endemic to the Eastern hemispheres of the world, mainly East Asia and parts of Russia. Previously, it was also prevalent in Japan, but it has virtually disappeared after the Second World War following the modernization of agriculture.[4][5]

Additionally, emigrants or travelers from endemic areas increase the risk of disease transmission to other countries.[6] It is estimated that about 15 to 20 million people are currently infected with C. sinensis, 13 million alone in China, which indicates a dramatic increase compared to an estimate of 7 million infections in the 1990s.[7][8] More than 200 million people are at risk of infection in these regions due to the frequent ingestion of improperly cooked fish; the World Health Organization (WHO) therefore listed C. sinensis among the most neglected tropical diseases globally.[9] Large fish are commonly less contaminated with metacercariae, but repetitive exposure through frequent ingestion can result in an overall accumulation of adults in the human bile ducts. Additionally, over 31 types of fish and shrimp are hosts of C. sinensis, many of which are common fish consumed by humans and are served in restaurants in endemic regions.[10][11] 

Qian et al. indicated in a recent study the presence of C. sinensis eggs in almost 20% of feces of 500 school children in the age of 10 to 17 years in the highly affected Hunan province of southeastern China.[12] Other affected areas in China include the Guangdong province, which borders Hong Kong and Macau, and the Guangxi province.[2][11] 

Men often have a better understanding of the existence of clonorchiasis, but because of still existing misconceptions (e.g., "alcohol can prevent infection") and deeply embedded cultural beliefs that eating raw fish is healthy.[13][6] Infection rates show a preference for males over females, with an infection rate increasing with age, climaxing in the 50s.[14][13] Other potential ways of infection include contamination of utensils and food with metacercariae, as cooked and uncooked food is rarely separated. This way of transmission is commonly responsible for the infection in children and women. 

Pathophysiology

C. sinensis is one of the most common parasitic infections in the world. In 2009, C. sinensis was classified as a carcinogen by the international agency for cancer research.[15] It is estimated that 25 to 35 per 100.000 cholangiocarcinomas are attributable to clonorchiasis in endemic areas.[8] The exact events leading to cholangiocarcinoma are unknown; several different mechanisms are believed to play a role. One mechanism includes mechanical injury related to damage to the bile duct mucosa related to the feeding activities of the parasite. Secondly, local accumulation of worms results in bile stasis favoring bacterial growth, inflammation, and subsequently, recurrent cholangitis. Thirdly, toxic effects of excretory-secretory products (ESPs) released by the parasite also result in inflammation.[16] 

History and Physical

The clinical consequences of infection are directly related to the intensity and duration of infection. The worm burden can be estimated by the number of eggs in feces which become detectable in stool after 3 to 4 weeks.[17] The more eggs are present; the more symptoms can be expected.[18][19] Symptoms occur about 10 to 30 days after ingesting an infected fish and are present for at least 2 to 4 weeks. Chronic symptoms are often observed in patients with a heavy burden of liver flukes. These chronic symptoms are generally a result of chronic mechanical and physical injuries of the bile ducts.

In the early phase of infection, most infected patients are considered to have an innocuous infection (less than 100 flukes) and rarely have symptoms. Patients with a very heavy parasitic load (>20 000) can present with symptoms compatible with acute cholangitis, including jaundice, right upper quadrant abdominal pain, nausea, vomiting, anorexia, malaise, and fevers. [6]  Chronic clonorchiasis can result in several symptoms involving the liver and biliary system. Cholelithiasis is commonly observed and is likely related to C. sinensis, predisposing to the formation of gallstones, especially calcium carbonate stones. C. sinensis induces hyperplastic changes of the gallbladder wall resulting in decreased gallbladder contractions and the subsequent precipitation of bilirubinate and mucin on the parasitic eggs.[20][21]

Furthermore, pancreatitis and liver abscesses appear more frequently in patients with clonorchiasis.[22] Chronic obstruction and strictures of the bile ducts can also result in bile stasis and recurrent ascending cholangitis mediated by Escherichia coli.[6] Clonorchis-associated cholangiocarcinoma is another complication of chronic inflammation and induced cellular proliferation and is often adenomatous in histology.[23] Children with a high parasitic load are at risk for potential developmental delays related to ongoing diarrhea, malnutrition, and anemia.[6]

Evaluation

The gold standard of diagnosis of C. sinensis is the detection of eggs in the stool which also provides insight into the intensity of infection.[24] Another marker of infection intensity includes bile and serum concentration of IgG4.[6] The absence of eggs in feces does not rule out clonorchiasis, as eggs are usually undetectable in stool during biliary obstruction.[25] Therefore, direct evidence of parasites can also be obtained in duodenal aspirates or biliary secretions via endoscopic retrograde cholangiopancreatography (ERCP).[7][3]

Standard diagnostic tests include a direct fecal smear via the Kato-Katz method, which is a method of preparing stool samples where stool is pressed through a mesh, and the remaining sample is a piece of cellophane soaked in glycerol which clears the stool from the eggs. The sensitivity of the test correlates with the intensity of infection, and the sensitivity of the test in low-intensity infections can be increased with repetitive assessments of stool samples. As differentiation between Clonorchis sinensis and Opisthorchis viverrine eggs is difficult (they appear morphologically similar), other factors like geographic exposure have to be considered.

Alternatively, the formalin-ether centrifuge sedimentation method concentrates the eggs in the feces and has better sensitivity than the Kato-Katz method, especially in suspected low-intensity cases.[26][14] Serodiagnostic tests like enzyme-linked immunosorbent assay (ELISA) are commonly used and are equally helpful for diagnosing C. sinensis. Specific antigens used in ELISA include ESPs and crude extract antigens, with the caveat that these assays can potentially cross-react with infections caused by other trematodes.[1]

Polymerase chain reaction (PCR) is also frequently used and has high sensitivity and specificity for diagnosing C. sinensis, but it might not be readily available. Newer diagnostic tools include loop-mediated isothermal amplification (LAMP), which targets C. sinensis DNA and is considered optimal for point of care diagnosis.[27][14] Despite these technical achievements within the last years, the underdiagnosis of C. sinensis is still a major issue due to the lack of diagnostic tools and training within the affected areas.[6] 

Imaging modalities like ultrasound, CT, and MRI are useful to determine the location, progression, and extent of the infection. On ultrasound, diffuse dilatation of intrahepatic bile ducts is commonly seen in patients infected with Clonorchis sinensis, but the finding by itself is too unspecific for diagnostic purposes and is significantly operator dependent.[28][29] Choi et al. indicated in a sonographic study with 457 subjects that enhanced periductal echogenicity and floating echogenic foci in the gallbladder are useful measures in the diagnosis of clonorchiasis.[30] CT imaging can help delineate the diagnosis of clonorchiasis, as it additionally shows a regular caliber of the unaffected larger bile ducts/extrahepatic ducts compared to the more frequently affected intrahepatic bile ducts.[22] MR cholangiographic imaging is also helpful in the diagnosis of C. sinensis. A classic sign of this imaging modality includes the "too many intrahepatic ducts"- sign resulting from parasitic obstruction of the smaller intrahepatic bile ducts in the periphery.[31]

Treatment / Management

The most effective treatment for clonorchiasis is praziquantel. The World Health Organization (WHO) recommends 25 mg/kg orally three times per day for 2 to 3 days or 40mg/kg in a single administration, which results in cure rates of above 90%.[32][33] Regional policies might vary, including higher dosing with less frequent administration, e.g., 75 mg/kg of praziquantel twice daily within 48 hours.[32]  In the case of heavy parasitic infections or the continuous presence of eggs in feces after treatment, re-treatment is necessary.[32] Associated side effects of praziquantel include abdominal discomfort, vomiting, and cephalgias.[34] 

Of note, the recovery period for pathological changes of the bile duct may be prolonged for weeks, and symptoms can persist despite adequate treatment.  As symptoms tend to be unspecific and large populations are unknowingly inhabited by the parasite, pilot studies elucidated the effects of mass treatments in endemic areas with praziquantel, indicating positive effects of(semi-)annual treatment with praziquantel reducing the prevalence from 59.5% in 2001 to 7.5% in 2004.[35] 

An alternative regimen includes albendazole (10mg/kg) for 5 to 7 days.[36][6] Patients’ family members and close contacts should also be tested for infection because it is more than likely that they may have eaten the same contaminated food or were exposed to metacercariae by contaminated surfaces.

According to recent studies, another alternative includes tribendimidine, a relatively new drug with promising cure rates and a favorable side effect profile.[37][32]

Researchers have been trying to develop a vaccine, but these have only been tested in animals to date.

Differential Diagnosis

The differential diagnosis includes acute hepatitis, cholecystitis, choledocholithiasis, cholangiocarcinoma, primary sclerosing cholangitis, primary biliary cholangitis, and other parasitic infections, including schistosomiasis, fascioliasis, and ascariasis.[1]

Prognosis

An initial prognosis can be made based on the number of eggs found in feces, as more eggs are indicative of more pronounced disease intensity.[17][18][19] Initial infections are often untreated as the majority of patients remain asymptomatic, or symptoms are non-specific. The reversibility of pathological changes induced by C. sinensis is largely dependent on the timing of initiation of treatment, meaning that when praziquantel treatment is delayed, the recovery period for pathological changes of the bile duct may be up to 12 weeks, and even longer or irreversible if the infection is severe and/or prolonged.[38]

As initial symptoms of C. sinensis are frequently unspecific, they can result in a missed diagnosis and the inhabitation of C. sinensis adult worms for many years.[19] Chronic complications like cholecystitis, cholangitis, or liver abscesses usually respond to symptomatic treatment. The prognosis of cholangiocarcinoma is sinister, with a median overall survival of fewer than 30 months.[39]

Complications

 In 2009, C. sinensis was classified as a carcinogen by the international agency for cancer research. The liver flukes reside within the biliary tree and cause obstruction, inflammatory irritation, and fibrosis resulting in the potential development of cholangiocarcinoma (CCA).[8] One study even reported Clonorchis sinensis as a risk factor for hepatic carcinoma, potentially synergistically occurring in a co-infected patient with HBV infection and/or alcohol use disorder.[40] As initial symptoms are often non-specific and missed for many years, histological changes like the epithelial proliferation of bile ducts and periductal fibrosis go unnoticed and can result in adenomatous hyperplasia giving rise to neoplastic changes.[19][41] 

Long-standing infection also increases the risk of strictures of the bile ducts, and together with the mechanical obstruction caused by the parasite itself, can result in recurrent pyogenic cholangitis, pancreatitis, and liver abscesses.[22] Regarding cholangiocarcinoma, C. sinensis infection increases the risk of intrahepatic and extrahepatic CCA.[42][41] Children with a high parasitic load are at risk for potential developmental delays related to ongoing diarrhea, malnutrition, and anemia.[6]

Deterrence and Patient Education

Preventing C. sinensis infection is heavily based on patient education and proper food preparation. Endemic areas promote education with public awareness programs, health guide booklets, and educating school children. These educational programs enforce proper food preparation and avoidance of undercooked or raw fish. Removal of farm animals from nearby fish farms and recognizing symptoms is also essential. These areas must undergo cultural changes to begin the decline of infection rates of C. sinensis, including replanting family farms to move farm animals from water sources and decreasing the consumption of raw fish in their diet.[43]

Enhancing Healthcare Team Outcomes

While most C. sinensis infections are asymptomatic with a parasite load of approximately 100, acute infections require a more detailed and rigorous management strategy with several medical teams on board. Patients with a heavy parasite load of approximately 20,000 are at a higher risk for chronic, long-term issues. Such risks include ascending cholangitis, cholangiocarcinoma, and hepatitis. Once it has become clear that a parasitic liver infection has developed, an interprofessional healthcare team including gastrointestinal (GI)/surgery, internal medicine, and infectious disease specialists must have a clear line of communication to begin therapy as soon as possible.

Specialty trained nurses in infection control and gastroenterology should provide patient and family education, monitor patients and provide status reports to the interprofessional team. Pharmacists evaluate the appropriateness of medications prescribed, assess drug-drug interactions, and participate in education. It is also important to accurately diagnose which parasite is the culprit of the current disease as there are several types of different parasitic liver infections. Clear communication between all involved specialties is vital to ensure that the patient and any close contacts are treated quickly and appropriately to avoid severe consequences. [Level 5]