Introduction

Did you know that more than 750 million people globally are at risk of contracting liver fluke infections, especially in Southeast Asia and the Western Pacific regions? These parasitic infections have been declared a global health concern, with the risk of severe health problems over time. They start by causing a brief illness, but when these infections become chronic, they can develop into one of the deadliest forms of bile duct cancer called cholangiocarcinoma. This cancer is very invasive, usually detected late, and often fatal.

Understanding this link between liver flukes and cholangiocarcinoma is not just a scientific interest, but a matter of public health safety. Such knowledge would help in early detection, quicker treatment, and better prevention, saving thousands of lives in these endemic areas. 

If you live in any of these regions or know someone who has developed this illness, then this article will walk you through what liver flukes are, how they spread, and why their association with cholangiocarcinoma matters so much.

Understanding liver fluke infections

What are liver flukes?

Liver flukes are tiny flatworms seen in the liver and bile ducts of humans and animals. They belong to a group called trematodes, which consists of several species. Three among them are the most common causes of disease in humans with a specific regional distribution.¹

• Opisthorchis viverrini (O. viverrini)
• Clonorchis sinensis (C. sinensis)
• Opisthorchis felineus (O. felineus)

Whilst the majority of cases are concentrated in South Asian Countries, due to extensive travelling and seafood importation from parts of Asia, many non-endemic regions have now reported these infections.²

How do people get infected?

People get infected with liver flukes by eating contaminated food and drinking unclean water. These parasites go through a complex life cycle dependent on humans as the definitive host and snails and fish as the intermediate host.³ 

The cycle starts when an infected human releases eggs into the environment through their stool. These eggs then enter freshwater, where they hatch and infect snails (the first intermediate host). The larva further develops inside the snails before being released into freshwater rivers. From there, they go on to infect the fish (the second intermediate host), where they form cysts in the muscles or just under the scales. This is the most infectious stage of the life cycle.^2,3 

Humans become infected when they eat these fish either in a raw or undercooked state, which is common in certain local dishes. These young parasites then enter the digestive system and travel to the bile duct region, where they mature into adult worms. Each worm releases about 50 eggs per stool into the environment, continuing the cycle.² In humans, these adult worms can grow up to 15 mm long⁴ and can survive for 10 to 26 years.²

Since they rely on freshwater snails and fish for survival and reproduction, their distribution is confined to certain regions. This is why these infections are closely associated with geographical locations and local food traditions.

Where are infections most common?

Liver fluke infections aren’t spread evenly around the world but rather are concentrated in regions where the parasite can thrive and where eating habits can make the transmission easier. Most cases are seen in Southeast Asia and the Western Pacific, though each of the major liver fluke species has its own geographical footprint.

• O. viverrini (Southeast liver fluke): Approximately 10 million people are affected, primarily in Thailand, Laos, Cambodia, and Vietnam
• C. sinensis (Chinese liver fluke): Seen mostly in China, Korea, some parts of Vietnam, and Russia, and previously Japan, infecting nearly 35 million
• O. felineus (Cat liver fluke): Specific to Russia, Belarus, Ukraine, Germany, and central Italy, with around 1.2 million people thought to be impacted^2,5

In fact, Khon Kaen province of Northeast Thailand has recorded the highest number of liver fluke infections, especially O. viverrini and cholangiocarcinoma, in the world.³

Why these places?

This is due to local food culture and dietary practices. In many rural communities, eating raw or fermented freshwater fish, especially cyprinoid fish, is an old tradition. Dishes like koi-pla, where raw or undercooked fish is mixed with spices, are considered a staple diet in these regions, with close ties to cultural identity and social life. This makes avoiding the risk quite difficult. In addition, poor sanitation practices and limited access to healthcare in rural areas worsen the problem, allowing infections to persist for generations in these regions.⁶

Knowing the regions most affected is important, but why it has become a serious health threat comes from understanding the damage caused by these parasites inside the body.

What happens in the body (pathology)?

When these worms enter the body, they begin a long-term relationship with the human host. Most infected people are asymptomatic, but some may experience symptoms like:

• Stomach pain 
• Nausea 
• Fever
• Vomiting 
• Anorexia 
• Diarrhoea 
• Skin rashes 

These symptoms are often dismissed as mild stomach issues.⁴

However, the real threat comes from chronic infection. As the worms feed and move around inside the bile ducts, they cause mechanical injury to the bile duct epithelium, leading to inflammation, thickening of the duct walls, and scarring. Over time, this slows down the bile flow, resulting in obstruction, gallstones, cholangitis, and liver damage.³

This repeated damage and repair increase the risk of cholangiocarcinoma, especially in heavily affected regions where people live with these infections for decades.³

Cholangocarcinoma: the cancer risk

What is cholangiocarcinoma (CCA)?

Cholangiocarcinoma is a highly fatal malignancy of the epithelial cells present along the biliary tract or even the liver tissue. It represents 10% to 20% of primary liver cancers worldwide.³ This cancer is very aggressive in nature and is known as a "silent killer" because it grows without showing any clinical symptoms. This makes detection quite late, mostly in the advanced stages, lowering its prognosis rate and making it really difficult to cure with reduced treatment options.²

Prevalence and risk factors

Cholangiocarcinoma mostly occurs at the age of 40 years and older globally. Men have higher chances of developing CCA than women, with most cases found in Northeast Thailand compared to other parts of the world.²

Literature has shown a few risk factors associated with the development of CCA, which are:

For endemic regions

• Liver fluke infections are mainly found in South Asian countries (major risk factor)

For non-endemic regions

• Inflammation caused by cholelithiasis, primary sclerosing cholangitis, and choledocholithiasis
• Hepatitis B viral infection ³

How liver fluke infections are linked to cholangiocarcinoma

Liver fluke infections have been associated with CCA for more than 50 years, with strong evidence showing concurrence of O. viverrini infection with CCA, especially in the Khon Kaen province of Northeast Thailand.⁶ The International Agency for Research on Cancer has officially declared O. viverrini as a cancer-causing agent, making it one of the few parasites in the world accepted as a carcinogen.²

Several pathways have been proposed explaining the mechanism behind liver flukes leading to CCA development.

Mechanical damage

Through their feeding and migrating behaviour, flukes cause mechanical injury to the bile duct epithelium. Their suckers cause tissue damage and eventually ulceration, where the eggs get trapped, resulting in granulomatous inflammation (a type of chronic inflammation involving the formation of granulomas). These repeated attacks can cause DNA damage and ultimately lead to CCA.

Metabolic products

Liver flukes release various chemicals into the bile. Some of these chemicals come from their outer surface (tegument), and some are excreted as waste products. These metabolic products can trigger strong immune responses in the body, causing the bile duct cells to multiply and change behaviour, becoming cancerous over time.

Immunologic factors

Both the physical damage done by the flukes and the body’s immune response to metabolic products cause a lot of inflammation and sometimes scarring around the ducts. This pushes the body to produce excess cytokines and nitrosamines, which can cause DNA damage and create an environment for CCA to develop.^3,6 

Diagnosis

For liver fluke infection

A stool screening test is recommended. This is relatively inexpensive and easily accessible for people living in endemic regions. However, they lack accuracy and can sometimes give negative results. In such cases, the PCR method is more reliable, along with abdominal ultrasound or CT scan.³

For cholangiocarcinoma

Diagnosing CCA is much harder, as early disease rarely shows any symptoms. By the time symptoms like stomach pain, jaundice, or weight loss appear, the cancer has already reached the advanced stage. 

Imaging tests like ultrasound, CT, or MRI can detect tumours, while a biopsy can confirm the diagnosis. A biomarker called carbohydrate antigen 19-9 (CA 19-9) can be used as a diagnostic tool for CCA.^1,3

Treatment

For liver fluke infection

• Praziquantel is the preferred drug for eradicating liver flukes
• When co-infection is suspected, tribendimidine is a drug that is effective in treating both liver flukes and intestinal roundworms

However, reinfection is quite common, so future vaccination methods might be able to solve this problem.³

For cholangiocarcinoma

• Surgical resection is the only recommended curative option, but most cases are diagnosed at an advanced stage where surgery is not possible³
• Liver transplantation is an option for small tumors, as recurrence risk increases for larger ones³
• Locoregional therapy is effective for those with locally advanced CCA who are not eligible for surgery¹
• Chemotherapy using cisplatin, gemcitabine, and paclitaxel may improve symptoms and quality of life, but it rarely stops the disease progression³

Preventative strategies

• Adopt proper cooking practices, as cooking effectively kills the infective stages of the parasite.
• Avoid eating raw or lightly fermented dishes like koi-pla, and substitute it for fully cooked fish.
• Improve sanitation measures with proper disposal of human waste.
• Organise health awareness programs explaining how food habits can lead to liver fluke infections and cholangiocarcinoma.
• Carry out mass screening for liver fluke infections in endemic regions and provide immediate praziquantel treatment to those infected. ³

Summary

Liver fluke infection is still a major health problem in endemic areas, especially in Northeast Thailand, with a strong association with the development of cholangiocarcinoma. People usually become infected by eating worm-infested raw or undercooked freshwater fish. These parasites enter the body and cause chronic inflammation and harmful changes in the bile duct, leading to this deadly cancer. The most effective way to stop this is through a combined approach of proper cooking practices, health education to change dietary habits, improved sanitation measures, and periodic deworming in high-risk areas. Breaking this cycle of infection is necessary to prevent the progression from liver fluke infection to cholangiocarcinoma.