Liver parasites: A global endemic and journey from infestation to intervention

Abstract

Parasites have coexisted with humans throughout history, forming either symbiotic relationships or causing significant morbidity and mortality. The liver is particularly vulnerable to parasitic infections, which can reside in, pass through, or be transported to the liver, leading to severe damage. This editorial explores various parasites that infect the liver, their clinical implications, and diagnostic considerations, as discussed in the article “Parasites of the liver: A global problem?”. Parasites reach the liver primarily through oral ingestion, mucosal penetration, or the bloodstream, with some larvae even penetrating the skin. Hepatic parasites such as cestodes (Echinococcus), trematodes (Clonorchis, Opisthorchis), nematodes (Ascaris), and protozoa (Entamoeba histolytica) can also cause systemic infections like visceral leishmaniasis, malaria, cryptosporidiosis, and toxoplasmosis. Chronic infections like clonorchiasis and opisthorchiasis are linked to persistent hepatobiliary inflammation, potentially progressing to cholangiocarcinoma, a fatal bile duct cancer, particularly prevalent in Southeast Asia. The global nature of liver parasite infestations is alarming, with hundreds of millions affected worldwide. However, control over treatment quality remains suboptimal. Given the significant public health threat posed by these parasites, international medical organizations must prioritize improved diagnosis, treatment, and preventive measures. Strengthening educational efforts and enhancing healthcare provider training are critical steps toward mitigating the global impact of parasitic liver diseases.

Key Words: Liver flukes; Nematodes; Cestodes; Trematodes; Protozoa; Parasites

Core Tip: Liver parasites are a hidden global threat, driving severe conditions like recurrent cholangitis, cirrhosis, liver failure, and even cancer. As climate change and globalization fuel their spread, especially in Asia, Europe and Africa, timely diagnosis is often missed due to limited awareness. This editorial shines a spotlight on these overlooked infections, offering a vital guide for clinicians to better recognize and combat hepatic parasites. This is a call to action for the global hepatology community to address these rising dangers and to safeguard public health.

INTRODUCTION

Parasites have coexisted with humans since the beginning of time. Some of them form symbiotic bonds with their hosts, while others are responsible for causing serious morbidity and mortality[1]. The liver appears to be highly appealing to various parasites, which might either reside within the organ, transit through it during their life cycle, or be transported to the liver, resulting in its damage[2]. In this editorial, we will discuss various parasites that infect the liver, their clinical implications and comment on diagnostic aspects discussed in the article “Parasites of the liver: A global problem?”[3].

A range of mechanisms facilitate the transmission of parasites to the liver, predominantly through oral ingestion and mucosal penetration of the gastrointestinal tract or via the portovenous bloodstream. Additionally, certain larvae are capable of directly penetrating the skin to reach the liver. These hepatic parasites include cestodes (Echinococcus), trematodes (Clonorchis, Opisthorchis), nematodes (Ascaris) and protozoa (Entamoeba histolytica). Certain hepatic parasites can also induce systemic infections, such as visceral leishmaniasis (VL), malaria, cryptosporidiosis and toxoplasmosis[4].

Since the liver receives its blood supply from the portal vein and the hepatic artery, it is more vulnerable to infections, especially those entering through the gastrointestinal tract. Fungal infections are also seen in immunocompromised individuals, often appearing as opportunistic infections in human immunodeficiency virus (HIV) patients. The distribution and epidemiology of these infections vary widely across different geographic regions. All parasites have their unique presentation and the disease is managed accordingly. Accurate diagnosis necessitates a thorough patient history, clinical examination, and comprehensive investigations. While some parasites present with overt disease symptoms, others may only cause subtle, asymptomatic disturbances in liver enzyme levels. Therefore, careful assessment is important[5].

CESTODES-TAPEWORMS

Hepatic echinococcosis, commonly referred to as hydatid disease of the liver, encompasses infections caused by six distinct species of the Echinococcus genus. The most prevalent of these are Echinococcus granulosus (E. granulosus), which is responsible for cystic echinococcosis (CE), and Echinococcus multilocularis (E. multilocularis), which causes alveolar echinococcosis (AE). Additionally, Echinococcus vogeli and Echinococcus oligarthrus, although rare, are known to induce polycystic echinococcosis. Recent studies have introduced two new species, Echinococcus felidis and Echinococcus shiquicus; however, available data on these novel species remain limited[6].

CE is attributed to the larval stage (metacestode) of E. granulosus, with its life cycle primarily occurring in dogs and other canids. The global health impact of CE is considerable, affecting an estimated 1.2 million individuals and resulting in 3.6 million disability-adjusted life years lost. In humans, the clinical manifestations of CE can vary widely, from asymptomatic infection to severe, potentially life-threatening disease. Common symptoms of hydatid cysts include upper abdominal discomfort and decreased appetite. Clinical examination may reveal hepatomegaly, a palpable abdominal mass or abdominal distension. Ultrasound is typically effective in diagnosing hydatid cysts. For cases involving subdiaphragmatic cysts, disseminated disease, extra-abdominal involvement, or cysto-biliary fistulae, computed tomography and magnetic resonance imaging can provide additional diagnostic clarity[7].

According to data from Pakistan, the mortality rate is 2.8%, with 13.2% of the population affected by morbidity. Notably, 67.9% of the cases are from rural areas of Pakistan, and 19.8% involve Afghan refugees. Additionally, 25.4% of individuals were found to have extrahepatic and hepatic cysts. Hepatic CE is increasingly emerging as a significant health concern in Central Asia, largely due to the displacement of infected populations[8].

E. multilocularis is a diminutive cestode, ranging from 1.2 mm to 4.5 mm, with definitive hosts including wild carnivores such as red and arctic foxes, as well as domestic dogs and cats. The metacestode of this parasite develops within the liver, forming an alveolar structure comprised of multiple vesicles encased in aggregates of granulomas. Human AE represents a severe and emergent disease, with a poor prognosis if left untreated or when diagnosed at a late stage[6].

Taeniasis is another widespread helminthic disease caused by Taenia species, including Taenia solium, Taenia saginata, and Taenia asiatica. While these parasites usually infect the small intestine, rare cases of abnormal migration to the liver, gall bladder, biliary tree, and pancreas have been reported, leading to significant morbidity[9,10].

Table 1 summarizes the clinical, diagnostic and treatment aspects of Echinococcosis[6,7].

Table 1 Clinical features of cestodes.

Parasite	Ref.	Global distribution	Hosts	Symptoms and complications	Diagnosis	Treatment
Echinococcus granulosus	Rinaldi et al[7]	Eurasia, Africa, Australia, South America	Dogs, herbivores, humans	Abdominal pain, hepatic cysts commonly, rarely pulmonary cysts	US, CT scan, ELISA and indirect hemagglutination, newer cystic fluid lipoprotein antigen	Albendazole 15 mg/kg/day in 2 divided doses, praziquantel once/week 40 mg/kg surgery, puncture, aspiration, instillation, reaspiration
Echinococcus multilocularis	Nunnari et al[6]	North America, Asia	Carnivores	Early symptoms of fatigue, weight loss, followed by portal hypertension, ascites splenomegaly	US, CT, IHA, ELISA, raised levels of IgG1 and IgG4 antibodies	Surgical resection, albendazole 15 mg/kg/day and mebendazole 40 mg/kg/day

CT: Computed tomography; ELISA: Enzyme-linked immunosorbent assay; IHA: Indirect hemagglutination; US: Ultrasound.

TREMATODES- LIVER FLUKES

Trematodes, commonly known as flukes, are capable of causing significant global morbidity and mortality due to their potential to induce fibrosis, cirrhosis, and even cancer. Human fascioliasis primarily occurs in rural regions where sheep and cattle farming are prevalent. The flukes most commonly responsible for this condition are Fasciola hepatica and Fasciola gigantica[4]. Fascioliasis progresses through two distinct phases. The acute (hepatic) phase typically starts 6 weeks to 12 weeks after ingesting metacercariae from contaminated water, marked by a high fever, right upper quadrant pain, hepatomegaly, and sometimes jaundice. The chronic (biliary) phase usually develops about 6 months later, as the flukes settle in the bile ducts, and can last for a decade or more. Though often without symptoms, it can occasionally cause chronic upper abdominal pain, nausea, vomiting, and other gastrointestinal issues. Severe cases may result in chronic bile duct obstructions, recurrent jaundice, cholelithiasis, pancreatitis, or ascending cholangitis[11]. Numerous cases have been documented, presenting with abdominal pain, anorexia, abnormal liver function tests, and peripheral eosinophilia, occasionally leading to the formation of liver abscesses[12,13].

The small liver flukes belonging to the families Clonorchis and Opisthorchis are predominantly distributed throughout Asia[4]. Clonorchiasis and opisthorchiasis are marked by persistent infections that cause chronic hepatobiliary inflammation, notably periductal fibrosis, which can be identified through ultrasonography. Over time, this chronic inflammation may progress to cholangiocarcinoma (CCA), an often fatal bile duct cancer. In Thailand, opisthorchiasis-related CCA claims up to 20000 lives annually, underscoring its significant public health impact. The socioeconomic consequences for low middle income families and communities are substantial. Therefore hygiene practices and eradication measures are encouraged[14].

Schistosomiasis is caused by Schistosoma mansoni (S. mansoni), Schistosoma japonicum (S. japonicum), and Schistosoma hematobium (S. hematobium). S. mansoni and S. japonicum are found in the intestinal venules, where their eggs are deposited in the liver, resulting in liver fibrosis and related symptoms. S. hematobium resides in the venules of the urinary bladder and ureters, leading to granulomatous inflammation. Infections with S. japonicum cause eggs to travel to the portal vein and settle in the liver’s periportal areas, where they degenerate, calcify, and induce granulomas and fibrosis. S. mansoni infections create periportal fibrosis that can progress to Symmers’ pipe-stem fibrosis, often giving the liver a “turtle back” appearance. Unlike S. japonicum, S. mansoni eggs do not calcify. This fibrotic process replaces portal venous tracts with scar tissue, causing liver enlargement, portal hypertension, spleen enlargement, and varicose veins in the esophagus. The eggs can also migrate to other organs like the spleen, lungs, kidneys, and heart, causing additional granulomatous lesions[15]. Table 2 summarizes trematodes clinical manifestations and treatment[16-19].

Table 2 Clinical features of trematodes.

Parasite	Ref.	Global distribution	Hosts	Symptoms and complications	Diagnosis	Treatment
Fasciola hepatica	Peters et al[4]; Bargues and Mas-Coma[16]	Asia, Americas, Africa, Europe, Oceania	Lymnaea galba (water snail)	Abdominal pain, fever, nausea, urticaria, biliary tract obstruction, eosinophilia, jaundice, focal hepatic lesion	Stool microscopy, CT, antibodies, US, ERCP	Triclabendazole 10 mg/kg × 2 doses 12 hours apart, nitazoxanide 500 mg twice a day for 7 days
Fasciola gigantica	Peters et al[4]; Bargues and Mas-Coma[16]	Asia, Africa[4]	Lymnaea radix (water snail)[16]	Constitutional and hepatobiliary symptoms the same as Fasciola hepatica	Stool microscopy, CT, antibodies, US, ERCP	Triclabendazole 10 mg/kg × 2 doses 12 hours apart, nitazoxanide 500 mg twice a day for 7 days
Clonorchis sinesis	Locke et al[17]	East Asia	Freshwater fish (mainly cyprinidae family)	Calcium carbonate gallstones, pancreatitis, liver abscess, recurrent ascending cholangitis, cholangiocarcinoma	Stool microscopy, bile and serum IgG4, ERCP, ELISA, CT	Praziquantel 25 mg/kg orally 3 times a day, tribendimidine single dose of 400 mg, surgery or biliary stenting in case of cholangiocarcinoma
Ophisthorchis viverrine	Liau et al[18]	Southeast Asia	Freshwater snails (bithynia), Freshwater fish (cyprinidae)	Cholangitis, cholecystitis, periductal fibrosis, cholangiocarcinoma	Stool microscopy, urine antigen detection, US, CT, ERCP	Praziquantel 25 mg/kg orally 3 times a day, tribendimidine single dose of 400 mg
Schistosoma manson	Colley et al[19]	Africa, Middle East, Americas	Freshwater snails (biomphalaria species)	Symmers pipestem liver fibrosis, portal hypertension, gastroesophageal varices	Stool microscopy, US, circulating cathodic antigen assay	Praziquantel 20 mg/kg PO TID for 1 day
Schistosoma japonicum	Colley et al[19]	Asia	Freshwater snails (oncomelania species)	Periportal fibrosis, rectal bleeding, cerebral schistosomiasis (meningoencephalitis)	Stool microscopy, circulating cathodic antigen assay	Praziquantel 20 mg/kg PO TID for 1 day

CT: Computed tomography; ELISA: Enzyme-linked immunosorbent assay; ERCP: Endoscopic retrograde cholangiopancreatography; PO: Per oral; TID: Three times a day; US: Ultrasound.

NEMATODES- ROUND WORMS

Nematodes consist of both plant and animal parasites, subsequently affecting humans as well as agricultural products[20]. Ascaris Lumbricoides, a nematode transmitted through the soil, is one of the most common pathological parasites in humans globally[21]. A survey conducted in Lahore, Pakistan showed higher prevalence of disease in areas of low socioeconomic and demographic standing. The pathogen is transferred not only through soil but also via contaminated water, crops, and pet animals. The rate of infection is higher in children, as they are more susceptible to unhygienic practices[22]. The lifecycle inside hosts begins with the larvae entering the circulation through the intestinal mucosa. Adult worms then primarily effect the hepatobiliary and pulmonary systems[21].

Pulmonary manifestations include Loeffler syndrome characterized by eosinophilia. Other respiratory symptoms include wheezing, dyspnea, cough, and hemoptysis. Abdominal complications include but are not limited to cholecystitis, cholangitis, pancreatitis, small bowel obstruction and volvulus[21]. The worms repeatedly span the hepatic and biliary ducts, resulting in obstructive cholecystitis and recurrent pyogenic cholangitis. Moreover, debris from dead worms forms gallbladder sludge and calculi. Hence, biliary colic is a common presenting complaint[23].

Like other helminths, Ascaris has constitutional features like iron deficiency anemia, anorexia and weight loss. If the parasite load is high, they might emerge from openings in the nose, mouth, vagina, anus, or ears. Toxins that are produced can result in facial edema, conjunctivitis, rashes, paraplegia and meningitis[22].

Albendazole is the first line treatment and mebendazole is second line. In cases of bowel obstruction, surgical resection of the bowel is performed[21]. Table 3 explains nematode infestation and management.

Table 3 Clinical features of nematodes.

Parasite	Ref.	Global distribution	Host	Symptoms and complications	Diagnosis	Treatment
Ascaris Lumbricoides	de lima et al[21]; Ali et al[22]	Sub-Saharan Africa, Latin America, China, East Asia	Humans (transmitted by fecal oral route)	Anorexia, diarrhea, pneumonitis and, cholangitis, small bowel obstruction, intussusception	Stool microscopy (can be negative in early infection), CBC, sputum analysis, US, CT, ERCP	Albendazole 400 mg PO once, mebendazole 100 mg PO 12 hours for 3 days, ivermectin 150-200 μg/kg, laparotomy if bowel obstruction present

CBC: Complete blood count; CT: Computed tomography; ERCP: Endoscopic retrograde cholangiopancreatography; PO: Per oral; US: Ultrasound.

PROTOZOA

Protozoa make a substantial contribution to global disease burden. Statistics by the World Health Organization show 67.2 million infections, corresponding to 492000 disability adjusted life years caused by intestinal parasites[24]. Entamoeba histolytica, Cryptosporidium spp, Giardia and Trichomonas vaginalis are some of the common disease-causing protozoa. Clinical manifestations vary from asymptomatic to severe gastrointestinal and/or genitourinary disease. While disease prevalence is remarkably higher in areas with unsanitary conditions and low socioeconomic status, these parasites are still a subject of distress in developed countries such as the North American states. Recreational water bodies and public drinking sources have been linked with major disease outbreaks, resulting in a higher proportion of infections in children as compared to adults. Zoonotic transmission also takes place with cattle being one of the major hosts for Giardia and Cryptosporidium[25].

Entamoeba has seven different species out of which only Entamoeba histolytica is pathogenic for the hosts. It inhabits the intestines in the form of trophozoites that multiply to either cause disease or form mature cysts, which are shed into the host’s stool. The cysts are then transmitted through a fecal-oral route by means of contaminated food and water[26]. Carriers are usually asymptomatic, while in cases of disease, intestinal amoebiasis is the most common manifestation. Symptoms include dysentery, weight loss and abdominal pain. Complications include extraintestinal involvement such as liver abscess, transudative pleural effusions, brain abscess, empyema, and pericarditis. The latter two are rarely seen with the rupture of the liver abscess[27].

A South Asian study found that Entamoeba histolytica caused 68% of liver abscess cases. While most patients respond to antibiotics and supportive care, many eventually require needle aspiration. The international hydropower association entamoeba titer confirms the diagnosis of amebic liver abscess. Factors such as advanced age, abscess size greater than 5 cm, involvement of both liver lobes, and symptoms lasting longer than 7 days increase the likelihood of requiring aspiration[28]. Table 4 summarizes protozoas.

Table 4 Clinical features of protozoas.

Parasite	Ref.	Global distribution	Host	Symptoms and complications	Diagnosis	Treatment
Entamoeba Histolytica	Guillén[26]; Chou and Austin[27]	Central and South America, Africa, Asia	Humans	Asymptomatic, dysentery, liver abscess, amoebic brain abscess	Stool microscopy, stool antigen detection, stool molecular studies, colonoscopy, abscess drain aspirate culture and sensitivity	Metronidazole 500-750 mg PO TID for 5-10 days, luminal agents such as paromomycin 25-35 mg/kg/day PO 6 hourly, Drain placement in liver abscess

PO: Per oral; TID: Three times a day.

SYSTEMIC INVOLVEMENT

Certain parasites have systemic effects, causing disseminated infection, simultaneously involving the liver and other organs. These are discussed below; although liver involvement is rare, it can be fatal.

VL is a widespread protozoan infection caused by the parasites Leishmania donovani (L. donovani) and Leishmania infantum (L. infantum). The primary mode of transmission is through the bite of phlebotomine sand flies, though rare transmission routes include blood transfusions, intravenous drug use, organ transplants, congenital infection, and laboratory accidents. The zoonotic form of VL caused by L. infantum is found in the Mediterranean region, China, the Middle East, and South America, with dogs as the main host. The anthroponotic form caused by L. donovani is common in eastern Africa and Asia[29].

The disease can range from asymptomatic to severe and life-threatening. Common symptoms include chronic fever, weight loss, and enlargement of the liver and spleen, often accompanied by pancytopenia. Without treatment, VL is almost always fatal. Traditionally, diagnosis has relied on directly visualizing the parasite through microscopy (using Giemsa staining) or culturing it from invasive samples such as spleen, bone marrow, lymph node aspirates, or liver biopsy. Diagnosing VL in immunocompromised individuals, especially those with HIV, can be particularly challenging. This is due to atypical presentations where parasites might be found in unusual locations (like the intestines or oral ulcers) rather than in the expected sites, resulting in negative bone marrow or spleen aspirates. A significant advancement has been the development of the rK39-based rapid diagnostic test, which is affordable and easy to use, playing a key role in the regional VL elimination efforts in the Indian subcontinent[29].

Pentavalent antimonials, including glucantime and pentostam, continue to be the primary treatments for various forms of leishmaniasis in many endemic regions, despite their significant side effects. Amphotericin B deoxycholate and its liposomal version are highly effective against leishmaniasis, but they must be given intravenously because they are poorly absorbed when taken orally. Currently, miltefosine is the only oral medication approved for treating VL[30].

Malaria is a protozoan disease spread by female Anopheles mosquitoes, resulting from an infection with Plasmodium parasites. Out of over 120 known Plasmodium species, only five are responsible for malaria in humans: Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), Plasmodium ovale (P. ovale), Plasmodium malariae (P. malariae), and Plasmodium knowlesi (P. knowlesi). It is endemic in 86 countries, including all of sub-Saharan Africa, significant areas of South-East Asia, the Eastern Mediterranean, the Western Pacific, and the Americas. While malaria is primarily transmitted through mosquito bites, it can occasionally be spread through other means such as blood transfusions, organ transplants, or congenital transmission, though these methods contribute minimally to the overall burden[31]. Because stagnant water is a breeding ground for mosquitoes, Pakistan experienced a sharp increase in cases during the catastrophic flood that hit the country in June 2022. The World Health Organization reported that by August 2022, the number of cases had already exceeded the total reported for the entire year of 2021[32].

Clinical presentation most commonly consists of periodic fever paroxysms that align with the parasite’s life cycle in red blood cells: Every 24 hours for P. knowlesi, every 48 hours for P. falciparum, P. vivax, and P. ovale, and every 72 hours for P. malariae. Initial symptoms can be generic, such as malaise, fatigue, joint and muscle pain, headache, abdominal discomfort, nausea, vomiting, or orthostatic hypotension. Severe malaria is a complex, multi-system illness often identified by a combination of cerebral malaria, severe malarial anemia, and acidosis/hyperlactatemia (often presenting as respiratory distress). Other possible symptoms include hypoglycemia, acute kidney injury, jaundice, repeated seizures, pulmonary edema, significant bleeding, high parasite levels, or shock[31].

Cryptosporidiosis is mostly restricted to immunocompromised individuals, such as those with HIV, and children less than 5 years of age. In low- and middle-income countries, the most prevalent risk factor is inadequate hygiene, followed by exposure to animals, overcrowded living conditions, unsafe drinking water, and the presence of diarrhea in the household[33]. As an infection that primarily affects the gastrointestinal tract, the gut microbiome plays a significant role in the index of disease severity. Clinical symptoms include but are not limited to profuse watery diarrhea, dehydration and muscle wasting[34]. They can sometimes extend beyond the gastrointestinal tract and may affect the respiratory system, leading to cough, croup, shortness of breath, hoarseness, and wheezing. The effects on children can be especially severe, causing malnutrition, stunted growth, and impaired cognitive development[35].

Toxoplasma gondii is a widespread microorganism found globally, with higher infection rates in tropical regions. An increased risk of infection has also been observed in China, Indonesia, and Russia. Humans can become infected through several pathways, including oral ingestion of contaminated food and water (containing oocysts), consuming raw or undercooked meat from pigs and sheep, which are the primary sources, carrying tissue cysts, eggs, or milk (containing tachyzoites), as well as through organ transplantation, blood transfusion, or vertical transmission[36].

The disease can be acute or chronic, manifesting as an active infection at any age. Congenital infection often leads to fetal death, premature birth, intrauterine growth retardation, fever, pneumonia, hepatosplenomegaly and thrombocytopenia. Neurologic involvement commonly presents as chorioretinitis, meningoencephalitis, hydrocephaly and microcephaly. Retinal toxoplasmosis is acknowledged as a leading cause of blindness in various regions across the globe[37]. These rare liver parasites cause mild derangement of liver enzymes that is sometimes asymptomatic but may rarely cause fatal disease. These systemic involvements of parasites cause significant disease burden globally and warrants urgent attention by the physicians.

CONCLUSION

The global burden of liver parasites is an urgent public health concern, exacerbated by climate change and increased international travel. These parasites, capable of causing severe hepatic diseases such as cholangitis, cirrhosis, liver failure, and cancer, often go undiagnosed due to a lack of awareness among clinicians. This delayed recognition contributes to the rising incidence of these infections, particularly in regions like Europe where they are becoming increasingly more common. Effective management and control of hepatic parasitic infections require a multifaceted approach, including improved diagnostic capabilities, heightened clinician awareness, and targeted public health initiatives. Public health programs should be arranged to spread awareness regarding hygiene practices and proper food handling. These parasitic infections can easily be prevented by avoiding undercooked meat and seafood, drinking clean water, careful hand washing and not swimming in fresh water like lakes and ponds. This could significantly reduce medical costs by preventing hospital admissions and avoiding expensive procedures like drains, endoscopic retrograde cholangio-pancreatography, and surgeries. The global nature of this issue demands coordinated efforts from international health organizations to prioritize these neglected diseases. More prospective data and studies are required to know the exact disease burden. By enhancing educational outreach and bolstering healthcare infrastructure, we can better protect populations from the devastating effects of liver parasites and reduce the significant morbidity and mortality associated with these infections.