Parasites of the liver – epidemiology, diagnosis and clinical management in the European context October 22, 2024 – Posted in: Uncategorized

Summary

Parasites in the liver cause significant global morbidity and mortality, as they can lead to recurrent cholangitis, cirrhosis, liver failure and cancer. Due to climate change and globalisation, their incidence is increasing, especially in Europe. The correct diagnosis of a hepatic parasite is often delayed because clinicians are unfamiliar with respective entities. Therefore, in this review, we aim to provide clinicians with a comprehensive clinical picture of hepatic parasites and to bring these neglected parasitic liver diseases to the wider attention of hepatology stakeholders in Europe and around the world.

Keywords

1. Liver parasites
2. alveolar echinococcosis
3. cystic echinococcosis
4. Echinococcus multilocularis
5. Echinococcus granulosus
6. hydatid disease
7. schistosomiasis
8. fascioliasis
9. liver flukes
10. ascariasis
11. amoebiasis

Introduction

The liver is crucially involved in various parasitic infections. For orally transmitted parasites, such as Echinococcus spp., liver flukes, Ascaris lumbricoides and Entamoeba histolytica, it is the first solid organ encountered after mucosal penetration, either directly or via portal-venous blood flow. Other parasites reach the liver after the larvae penetrate the skin (schistosomiasis). Recently, it has been argued that the liver offers a favourable immunological environment for parasites, as tolerance instead of immunity is the preferred immunological response to exogenous microorganisms.¹ In addition, parasites have evolved complex mechanisms to alter the host’s immune response to overcome defence mechanisms. This allows for parasitic maturation (flukes) or proliferation (Echinococcus spp., amoebiasis) in the hepatic tissue. Although hepatic parasites cause a significant global burden of disease, therapeutic options are limited and vaccines are not expected to be available soon because of both the complex immunological context and the low economic incentive. Furthermore, the clinical presentation is often non-specific or asymptomatic, hampering diagnosis. In this review, we want to provide clinical guidance by discussing the most important parasitic infections of the liver, with the main epidemiological focus on Europe. Other parasitic infections such as visceral leishmaniasis, malaria, cryptosporidiosis or toxoplasmosis can also affect the liver, however, they usually cause a systemic inflammation and are hence not the main focus of this review. Table 1 summarises differential diagnoses of hepatic parasites from a clinical perspective, while parasitological details are listed in Table 2.

Symptom	Differential diagnosis
Upper abdominal discomfort	AE, CE, fascioliasis, small liver fluke disease, schistosomiasis, ascariasis, amoebiasis
Severe abdominal pain	fascioliasis, small liver fluke disease
Malabsorption	Ascariasis (children)
Dysentery	Amoebiasis
Fever	Schistosomiasis (Katayama fever), amoebiasis (ALA), fascioliasis/CE/AE in case of cholangitis
Cough	Ascariasis, schistosomiasis
Eosinophilia	CE, small liver fluke disease, fascioliasis
Biliary obstruction, jaundice, cholangitis	AE, CE, fascioliasis, small liver fluke disease, ascariasis
Portal hypertension	AE, schistosomiasis
Possible complications
Cancer	Small liver fluke disease (CCC), schistosomiasis (bladder, potentially HCC)
Cholelithiasis	Small liver fluke disease
Biliary pancreatitis	Small liver fluke disease, fascioliasis, ascariasis
Fibrosis	Schistosomiasis, small liver fluke disease
Cirrhosis	Very late-stage schistosomiasis, small liver fluke disease
Hepatomegaly	Schistosomiasis
Appendicitis	Ascariasis
Liver abscess	Amoebiasis
Cystobiliary fistula	CE
Liver failure	Late AE, late schistosomiasis
Liver impairment in imaging
Focal hepatic lesion	AE, CE, amoebiasis, (fascioliasis)
Diffuse parenchymal liver disease	Schistosomiasis, (early fascioliasis)
Dilated (intrahepatic) bile ducts	Small liver fluke disease, fascioliasis, ascariasis

Table 1

Differential diagnoses of hepatic parasites according to their clinical presentations, possible complications and the appearance of characteristic liver impairment on imaging.

AE, alveolar echinococcosis; ALA, amoebic liver abscess; CCC, cholangiocarcinoma; CE, cystic echinococcosis; HCC, hepatocellular carcinoma.

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Species	Geographic distribution	Intermediate hosts	Definite hosts	Incubation period	Adult size in mm	Prepatent period∗	Life span∗	Clinical features	Complications	Diagnostic methods	Standard Treatment
Cestodes
Echinococcus granulosus sensu lato	Worldwide. Different genotypes G1–10 with diff. human pathogenicity	Different herbivores (sheep, cattle, camel, pig and others, humans are accidental)	Carnivores (mainly dogs)	Not exactly known, years	3–7	n.a.	Not exactly known	Slow growing cysts in various organs (70% liver, 20% lung, and others)	1.Fistulation, e.g. cystobiliary or cystobronchial2.Anaphylaxis due to cyst rupture3.Mass effect, esp. when cerebral or bone involvement	1.Imaging, US most important for CE-classification2.Serologic tests3.microscopy of fluid or histopathology	Albendazole∗∗ p.o. 10–15 mg/kg/d, split into 2 doses, or alternatively: Mebendazole 40–50 mg/kg/d, split into 3 doses, both with fatty meal
Echinococcus multilocularis	Northern hemisphere	Rodents, humans are accidental	Carnivores, Europe mainly: red fox, also dogs	Not exactly known, 10–15 years	2–5	n.a.	Not exactly known	Infiltrate growing liver lesion often involving vessels and biliary tree causing abdominal discomfort/pain, possibly jaundice	1.Cholestatic jaundice or vascular thrombosis of the portal vein or vena cava2.Infiltration of neighbouring organs	1.Imaging (first US followed by (PET)-CT- or MRI scan with serologic testing2.PCR or histopathology in clinical specimen (liver biopsy)
Trematodes
Fasciola hepatica	Asia, Americas, Europe, Africa, Oceania	Water snail (family Lymnaeidae)	Mainly sheep, cattle, goats	Around 2 weeks	20–30	10–12 weeks	up to 13 years	Abdominal pain, fever	Biliary obstruction	Stool microscopy, Serum antibody ELISA	Triclabendazole∗∗ p.o. 10 mg/kg BID Nitazoxanide 500 mg BID for 7 days
Fasciola gigantica	Asia, Africa				25–75	10–16 weeks		Abdominal pain, fever		Stool microscopy, Serum antibody ELISA
Clonorchis sinensis	in East and Southeast Asia, Russia, India	Water snail, fish, crustaceans	mainly dogs, cats, swines		10–25	2–3 weeks	Up to 20 years	Asymptomatic or abdominal pain	Cholangiocellular carcinoma, biliary obstruction	Stool microscopy, Serum antibody ELISA, stool antigen	Praziquantel∗∗∗ p.o. 75 mg/kg/day, split into 3 doses for 2 days
Opisthorchis viverrini	Southeast Asia	Water snail, fish, crustaceans	Cats, dogs		8–12		Up to 25 years			Stool microscopy, Serum antibody ELISA
Opisthorchis felineus	Eastern Europe, Central Asia	Water snail, fish, crustaceans	Cats, dogs, foxes							Stool microscopy, Serum antibody ELISA
Schistosoma mansoni	Africa, South America, Caribbean	Water snails	Humans, non-human primates	4–87 days	6–20	4–6 weeks	3–10 years	Symptomatic only through complications	Portal fibrosis, hepatosplenic schistosomiasis, HCC	Stool microscopy, (stool antigen detection usually negative in ALA), serum antibody ELISA, (serum/aspirate antigen test and PCR from aspirate as available)	Praziquantel∗∗∗ p.o. 40 mg/kg OD for 3 days
Schistosoma intercalatum	Central and West Africa		humans	14–84 days	11–14
Schistosoma japonicum	China, Indonesia, South-East Asia		Humans, wild mammals		10–30						Praziquantel∗∗∗ p.o. 60 mg/kg OD for 3 days
Schistosoma mekongi	Laos, Cambodia		Humans, dogs		12–15
Nematodes
Ascaris lumbricoides	Asia, Africa and Latin America	None (soil maturation)	humans	2–7 days	Females up to 40 cm, males up to 25 cm	ca. 70 days	1–2 years	Respiratory and abdominal symptoms, malabsorption	Cholangitis, pancreatitis,	Stool microscopy, adult worms can be macroscpical identified, coproantigen, (Serology) US	Albendazole p.o. 400 mg once∗∗, mebendazole p.o. 100 mg BD for 3 d (or 500 mg once)∗∗ or ivermectin p.o. 150–200 μg/kg once
Protozoa
Entamoeba histolytica	Africa, Asia and Latin America	None	humans	2–4 weeks	0.25–0.4	n.a.	n.a.	Abdominal pain, (bloody) diarrhoea, tenesma	Amoebic liver abscess (ALA)	Stool microscopy, Serum antibody ELISA (stool antigen detection usually negative in ALA, serum/aspirate antigen test and PCR from aspirate as available)	Metronidazole p.o. 500–750 mg TDS for 7–10 days, followed by paromomycin p.o. 500 mg TDS for 7 days

Table 2

Summary of clinical features of hepatic parasites.

ALA, amoebic liver abscess; CE, cystic echinococcosis; HCC, hepatocellular carcinoma; PET, positron emission tomography; US, ultrasound.

∗

In humans.

∗∗

Benznidazoles have to be taken with fatty meal to reach efficient plasma levels.

∗∗∗

To be taken with or directly after food.

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Hepatopathic helminths

Cestodes of the liver: Echinococcus spp.

Human echinococcoses are zoonoses caused by the larval forms (metacestodes) of the cestode species (spp.) of the genus Echinococcus. Cystic echinococcosis (CE), caused by E. granulosus sensu lato, exceeds alveolar echinococcosis (AE), caused by E. multilocularis, in prevalence and geographic distribution. AE is restricted to the northern hemisphere within temperate climate zones.^2–5 Central Asia has the highest prevalence of both diseases. In Europe, CE is endemic in Mediterranean and Eastern countries, while AE occurs in Western-Central, Baltic, and Eastern countries, as depicted in Fig. 1.^6,7

Echinococcoses have a substantial global public health impact. Both AE and CE are considered orphan diseases, yet account for approximately 871,000 disability-adjusted life years (DALYs), which is still assumed to be a large underestimate.^7–9 Despite their non-tropical distribution, echinococcoses are considered neglected tropical diseases (NTDs).¹⁰ Due to scant data, diagnosis and treatment are guided by expert consensus, primarily the recommendations of the WHO-IWGE (Informal Working Group on Echinococcosis),¹¹ which are currently under revision. An ‘international consensus on terminology to be used in the field of echinococcosis’ was recently published to harmonise terminology on a global level.¹²

Key point

Migration, globalisation and climate change have led to an expansion of endemic areas (e.g. for AE) and emerging cases outside endemic areas (e.g. for CE and schistosomiasis), resulting in delayed diagnosis and mismanagement.

Echinococcus spp. depend on different mammals to complete their life cycles: adult worms live in the small intestines of carnivores, their definite hosts, such as dogs or foxes. Matured eggs are released with their faeces and can be ingested by a suitable intermediate host (e.g. small rodents for E. multilocularis and ungulates for E. granulosus), where the eggs hatch and the larvae penetrate the intestinal wall. After migration in the host’s circulation and further maturation, Echinococcus spp. develop as lesions in different organs. The consumption of cyst-containing organs re-infects definite hosts and closes the parasitic life cycle. Humans act as so-called accidental intermediate hosts, acquiring the infection by ingestion of infective eggs and represent a dead-end host.¹³ Based on this life cycle, public health approaches for protecting the vulnerable population require basic hygiene regarding animal contact, sheep vaccination (CE), deworming domestic dogs (CE and AE) or fox-baiting with praziquantel (AE), as well as screening based on risk factors.

Although often discussed together, CE and AE are distinct chronic diseases with different clinical features and treatment approaches. CE is generally considered benign, with clearly delimited cystic lesions; yet it has a substantial medical and economic impact because of its cosmopolitan distribution.^7,14 In contrast, AE develops as lesions formed by micro-cysts, appearing more solid and tumour-like, with the potential to infiltrate and metastasise, for which it is termed a malignant parasitosis.¹⁵ Therefore, diagnostic and clinical management should be carefully distinguished and left to specialist care. In this review, we discuss aspects of the (changing) epidemiology, clinical features, diagnostics and treatment of CE and AE in the European context.

Key point

Echinococcoses are emerging diseases in Europe. Imaging (ultrasound) is crucial, with CE cysts being more pathognomonic than AE lesions. CEUS can be used to differentiate between AE and malignancy.

Echinococcus granulosus sensu lato (cystic echinococcosis)

Epidemiology

Human CE is highly endemic in pastoral communities where close contact between humans, livestock and dogs is common (Fig. 1).^6,16,17 The true prevalence of CE is difficult to estimate due to underreporting and underdiagnosis of asymptomatic infections.^18–20 In Central Europe, autochthonous E. granulosus transmission is rare due to strictly regulated meat processing and inspection. Thus, the majority of reported cases are imported from South-Eastern Europe and the Middle East.^21–23 Due to its relatively low prevalence in Western countries, clinicians are often unfamiliar with CE, leading to potential mismanagement. Therefore, cases from endemic areas with suspicious cysts should be referred for further investigation.²⁴

Clinical features

Approximately 60–75% of CE cases are incidental findings, especially during the early stages of infection.^18,20,25 Most CE cases are diagnosed in adulthood. CE cysts can occur in all organs, but mostly affect the liver (70%), lungs (20–30%) or both.²⁵ Depending on site and size of manifestations, symptoms result from compression or displacement of healthy tissue.²⁶ Accordingly, patients may present with upper abdominal discomfort and biliary obstruction caused by cystobiliary fistula, leading to jaundice and/or cholangitis. Further complications include cyst rupture, inducing fever, urticaria, eosinophilia and anaphylaxis.^14,16,27 The case fatality rate of CE is reported to be 2–4%.²⁵

Key point

A multidisciplinary treatment approach should be followed to avoid complications, as well as overtreatment. Cysts in active stages should be evaluated for interventional and/or medical treatment, inactive lesions should not be treated.

Diagnostics

The diagnosis of CE is primarily based on imaging techniques. Serology can be useful to confirm the diagnosis of CE in unclear cases, but has a variable sensitivity: false-negative results are frequent in case of young, inactive or extrahepatic cysts; a positive serology does not correlate with viability, as it can persist for years even after curative surgery and is hence inappropriate for follow-up.^28,29

Ultrasound is the standard investigation for the diagnosis of hepatic CE.¹¹ Pathognomonic features of CE cysts on ultrasound are listed in Fig. 2.^18,30 This classification – based on the morphology, size, number and localisation of cyst(s) – can differentiate between active, transitional and inactive cysts and guides further management.³¹ Other imaging techniques used for hepatic CE lesions include MRI and CT, which are mainly used for pre-operative evaluation or in case of complications; they play a secondary role for the diagnosis and follow-up of patients with CE.^32,33 Ultimately, if a case remains unclear, parasitological confirmation can be achieved by cytological examination of cyst material for brood capsules or protoscoleces, or by molecular analysis.¹¹ Benzimidazole (BMZ) pretreatment is required prior to cyst puncture for suspected CE, and precautions should be taken to avoid possible anaphylaxis.³⁴

Treatments

Clinical decision-making for uncomplicated liver CE is based on ultrasound staging.¹¹ Hepatic CE treatment is aimed at complete elimination of viable parasitic cells and prevention of recurrence, with the end goal of minimising mortality and morbidity. To achieve these aims, no “one-size-fits-all” approach exists, and the appropriate clinical management must be based on disease-specific characteristics (cyst stage, number, size, site and presence of complications, Fig. 2) and the patient’s clinical conditions, as well as local medical and surgical expertise. There are currently 4 different management options available: a) surgery, b) percutaneous treatment, c) medical treatment with anthelmintic drugs (BMZ, possibly combined with praziquantel), and d) watch and wait for inactive cysts. Surgery is the first therapeutic choice for large and complicated cysts, i.e. cysts at risk of rupture or if fistulation or infection occurs. For CE2 and CE3b cysts, surgery should be evaluated.^11,35 For CE1 and CE3a cysts, percutaneous treatment is an option, aiming at the destruction of the germinal layer, either by performing PAIR (puncture, aspiration, injection and re-aspiration) or through the evacuation of the entire endocyst (modified catheterisation technique). Excluding cysto-biliary fistulae before injecting any scolicidal agent is mandatory to prevent complications.³⁶ Further findings restricting the feasibility of percutaneous aspiration are a subcapsular or extrahepatic localisation, as it increases the risk of leakage and dissemination into the adjacent cavity, CE2 and CE3a stage, and a previous history of hypersensitivity after cyst manipulation. Small cysts may respond to medical therapy alone and thus do not justify the procedure-related risk.³⁷ Medical treatment with BMZ, preferably albendazole (ABZ), is used to induce cyst inactivation, resulting in CE4 cyst resemblance, and is most effective in small CE1 and CE3a cysts, but often fails in the case of large cysts. Recurrence is most commonly observed in conservatively treated CE2 and CE3b cysts. BMZs are only parasitostatic, hence, regular sonographic follow-up is required to promptly detect recurrence or reactivation.²⁴ If a solid stage is reached spontaneously, reactivation is rare.³⁸ Despite the mentioned drawbacks, BMZ treatment remains the main treatment option in disseminated or inoperable CE.

Key point

The WHO classification for CE on ultrasound is a powerful tool that clinicians should be familiar with.

In case of invasive procedures, prophylactic BMZ is required to avoid secondary echinococcosis potentially arising from spillage of viable larvae (brood capsules or protoscoleces). BMZ should be administered at least 1 day before and continued for at least 1–3 months after the procedure.^11,35 Praziquantel might enhance the effect of ABZ and is therefore recommended in some centres for peri-interventional prophylaxis.³⁹

Echinococcus multilocularis (alveolar echinococcosis)

Epidemiology and clinical impact

Human alveolar echinococcosis (AE) is the most lethal parasitic zoonosis in Europe. If left untreated, the 10-year mortality rate can reach 90%.⁴⁰ AE is considered an emerging disease, with an annual incidence of approximately 18,000 cases globally, of which 91% occur in China.^6,7,41,42 In Europe, cases in the hitherto endemic area of Central Europe (France, Switzerland, Germany and Austria) are increasing in number. Moreover, the geographical distribution is expanding to countries previously considered AE-free like Poland, Slovakia, Hungary and the Baltic region,^43–48 challenging respective health care systems.²¹

Key risk factors for acquiring AE in Europe are being a farmer, owning a dog or cat or having a kitchen garden.^49–51 Furthermore, the incidence of AE is higher among immunodeficient patients, who often show atypical presentations.⁵² A genetic susceptibility associated with an altered immune response has been observed.^53,54

Clinical presentation

Due to the slow growth of AE larvae, the first symptoms can arise after several years of latency (5–15). European patients are often older than 50 years and AE in children is rare.^55–59 Interestingly, in China, the average age at first diagnosis is significantly younger than in Europe, and disease is often advanced, requiring a more invasive treatment approach.⁶ Early symptoms are mostly non-specific including fatigue, abdominal pain or jaundice. One-third of all cases are asymptomatic and diagnosed incidentally.⁵⁸ Upon diagnosis, parasitic liver lesions are often extensive and infiltrate neighbouring structures, limiting treatment options.^40,55 Common complications are portal vein thrombosis with consecutive portal hypertension, biliary duct obstruction with a risk for cholangitis and bacterial superinfection in advanced lesions with considerable necrosis.^40,58 Since AE has the potential to metastasise, further symptoms depend on the organs involved.

Diagnosis

Diagnosis of AE is multimodal, based on clinical presentation along with epidemiological data, typical imaging signs, and serological tests.¹¹ One finding on its own might be misleading, as, for example, most seropositive people identified by epidemiological screening in Germany and France never developed active disease.^60–62 Serologic and histologic or molecular confirmation is central.^11,63 A 2-step approach is recommended, using a high sensitivity screening test followed by a more specific confirmatory test, resulting in both high sensitivity and specificity of nearly 100%.⁶³ Still, there might be cross-reactivity with CE resulting in misinterpretation. Confirmation of AE can be achieved by histopathological examination including specific immunohistochemistry or nucleic acid detection in a clinical sample.⁶⁴ An ultrasound-guided core-needle biopsy is an effective diagnostic tool to achieve a definitive diagnosis of hepatic AE.⁶⁵ Based on the respective findings, AE can be classified as possible, probable or confirmed, defining the requirement for treatment (Table 3).

Key point

AE is associated a high mortality if left untreated, hence early diagnosis is crucial, requiring at least imaging and serological testing. Staging is mandatory to guide treatment, using CT, MRI or preferably PET-CT scan.

WHO case definition
Label	Definition	Treatment recommendation
Possible	Epidemiology + Imaging OR Serology	No, regular follow-up
Probable	Epidemiology + Imaging AND Serology	Yes
Confirmed	Epidemiology + Imaging AND Serology AND histological confirmation/positive nucleic acid sequence from clinical specimen	Yes
WHO staging
Hepatic localisation	PX	Primary tumour cannot be assessed
	P0	No detectable tumour in the liver
	P1	Peripheral lesions without proximal vascular and/or biliary involvement
	P2	Central lesions with proximal vascular and/or biliary involvement of one lobe∗
	P3	Central lesions with hilum vascular or biliary involvement of both lobes and/or with involvement of 2 hepatic veins
	P4	Any liver lesion with extension along the vessels∗∗ and the biliary tree
Extrahepatic involvement of neighbouring organs	Diaphragm, lung, pleura, pericardium, heart, gastric and duodenal wall, adrenal glands, peritoneum, retroperitoneum, parietal wall, pancreas, regional lymph nodes, kidney
	NX	Not evaluable
	N0	No regional involvement
	N1	Regional involvement of contiguous organs or tissues
Distant metastasis	Lung, distant lymph nodes, spleen, CNS, orbital, bone, skin, muscle, kidney, distant peritoneum, retroperitoneum
	MX	Not completely evaluated
	M0	No metastasis (chest radiography and cerebral computed tomography)
	M1	Metastasis

Treatment recommendation
Classification	Surgery	Interventional therapy	Drug therapy	Follow-up
P1N0M0	Radical resection (R0)	—	Adjuvant BMZ for 2 years	•Serology + ultrasound every 6–24 months•MRI or PET/CT every 2–4 years•considered healed after 10 years without recurrence (PET/CT)
P2N0M0	Radical resection (R0)	—	Adjuvant BMZ for 2 years	•Serology + ultrasound every 6–24 months•MRI or PET/CT every 2–4 years•considered healed after 10 years without recurrence (PET/CT)
P3N0/N1M0	In selected cases	if needed	Continuously	•Serology + ultrasound every 6–12 months•MRI or PET/CT every 2 years•Re-evaluate staging/eligibility for surgery
P4N0/N1M0/M1	In selected cases	if needed	Continuously	•Serology + ultrasound every 6–12 months•MRI or PET/CT every 2 years•Re-evaluate staging/eligibility for surgery

Table 3

WHO case definition, staging and recommended treatment for alveolar echinococcosis, adopted from (11) and based on the authors’ experience.

BMZ, benzimidazole; CNS, central nervous system; PET, postrion emission tomography.

∗

The plane projecting between the bed of the gall bladder and the inferior vena cava divides the liver into 2 lobes.

∗∗

Inferior vena cava, portal vein and arteries.

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The morphology of AE lesions in different imaging modalities is shown in Fig. 3. Ultrasound is an important tool, yet, unlike in CE, findings are not pathognomonic for AE. Its main significance lies in the early detection of an often irregular lesion with a mixed echogenic pattern, calcification and an undefined margin, triggering further diagnostics. Other lesions show a resemblance with haemangiomas or metastases. Contrast-enhanced ultrasound (CEUS) may facilitate the confirmation of AE, since respective lesions do not show central contrast enhancement. In contrast to CE, AE lacks a cystic appearance.⁶⁶ Therefore, sonographic diagnosis is often challenging for clinicians unfamiliar with the disease.^66,67 A CT, particularly for heavily calcified lesions, or MRI scan of the abdomen are the imaging techniques of choice.^58,68–72 In analogy to the TNM-classification, a PNM-classification can be deduced from imaging to guide treatment (Table 3). Staging is completed by a chest x-ray and a cerebral CT. Alternatively, [18F]-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) can be combined with a full-body CT scan. FDG enrichment surrounding AE lesions is interpreted as larval metabolic activity^73,74 and can serve as a follow-up tool. The role of PET-MRI is currently under evaluation.⁷⁵

Treatment

A multidisciplinary and personalised approach are key to optimise the treatment of AE. BMZ treatment and surgery are the cornerstones of management; a stage-specific approach is recommended, using the PNM-classification^11,76 (Table 3) adapted from¹¹ and based on the current clinical experience of the authors. The curative approach consists of radical surgery, completely removing all lesions including satellite lesions, followed by a 2-year course of BMZ. Evidence for pre-operative BMZ administration is lacking, but from the authors’ experience, remarkable regression of AE liver lesions under strict BMZ treatment can be seen, allowing for complete surgical resection after months or even years (unpublished data).

After resection, the surgical specimens should be graded according to the resection margin from R0 to R2 (Table 3). The highest cure rates were achieved with a resection margin of more than 1 mm and adjuvant BMZ treatment.^66,77 Cure can be assumed after surgery and a recommended follow-up period of 10 years, if parasitic lesions remain undetectable, preferably using a PET/CT scan.^11,78,79

However, upon diagnosis, AE is inoperable in most patients because of the involvement of liver vessels or bile ducts; these patients therefore require long-term, mostly life-long BMZ treatment.^11,58 Under sufficient BMZ treatment, FDG-uptakes should decrease or even vanish, corresponding to suppressed periparasitic inflammatory activity.^76,80,81

Orthotopic liver transplantation is rarely used in Europe and reserved for inoperable cases with liver failure or recurrent life-threatening cholangitis in the absence of extrahepatic AE localisations. Early re-administration of BMZ after liver transplantation is essential to avoid relapse resulting from immunosuppression.^82,83 Palliative surgery for parasitic mass reduction is no longer recommended, as it often results in late biliary complications.⁸⁴

Follow-up and complications

All patients with AE should be monitored by ultrasound at frequent intervals and by PET/CT and/or MRI every 2–3 years to evaluate disease recurrence or progression.⁷⁹ Monitoring serology after surgery and/or BMZ therapy is useful, as surgical removal of the lesion may result in seronegativity.⁸⁵ After several years of BMZ treatment in stable AE without complications, a structured treatment interruption can be discussed.^74,76,81

Biliary complications, such as obstruction causing jaundice and cholangitis, are common in AE and occur in 10–30% of patients.⁸⁶ In particular, late biliary complications (after more than 3 years of treatment) are associated with high mortality.⁸⁷ Patients with acute complications might require hospitalisation for endoscopic interventions and antibiotic treatments.⁸⁸

Another unresolved challenge is how best to treat inoperable patients in whom BMZ leads to hepatotoxicity. New treatment options are urgently needed for these patients; drug-repurposing (e.g. mefloquine), as well as new formulations of BMZ, are under investigation.⁸⁹ Currently, amphotericin B can be administered as an experimental approach.⁹⁰ Nitazoxanide failed to show efficacy.⁵⁵ Immunotherapy using PD1 (programmed cell death 1) inhibitors⁹¹ and by inhibiting the polo-like kinase EmPlk1 have been investigated in vitro, but so far the results are not promising.⁹²

Prognosis and outlook

Prognosis has improved significantly following the introduction of BMZs in the 1980s, resulting in a nearly normal life-expectancy in Europe, mostly under long-term BMZ treatment.^{56,58,93–95} Early diagnosis, based on imaging and serological markers, can increase the number of resectable lesions.⁵⁸ From a One Health perspective, i.e. a multi-sectored holistic perspective focusing on the health of the environment, animals and people, the distribution of praziquantel-containing baits for foxes effectively reduced the egg-load in the environment, assumingly reducing the human risk of AE.⁹⁶

Trematodes of the liver

Trematodes, or flukes, are flatworms which contain a snail in their life cycle. They cause significant global morbidity and mortality, as they can lead to fibrosis, cirrhosis and cancer. In recent years, foodborne trematodes, in particular, have been on the rise, with an increase both in incidence and geographical distribution (Fig. 4 and 5). Currently, trematodes lead to 200,000 illnesses annually and over 7,000 deaths, causing more than 2 million DALYs.^97–99 This might be attributable to growing awareness and availability of diagnostic methods, such as ultrasound, and possibly to aquatic food becoming more popular with global consumers.^1,99

Faciola hepatica and Fasciola gigantica

Fascioliasis can be caused by the flatworms Fasciola hepatica and Fasciola gigantica. It is a widely spread zoonosis (Fig. 4) and ruminants serve as natural definite hosts. Human fascioliasis mainly occurs in rural areas where sheep and cattle husbandry is common. The animals’ excreta contain eggs that, if released into freshwater, hatch and infect water snails, the intermediate host. After maturation and multiplication, larvae are released into the water and develop into metacercariae, which encyst and attach to aquatic plants. With the ingestion of respective plants, the larvae reach the small intestine, penetrate the wall and migrate through the peritoneum and hepatic tissue to the bile ducts, where they mature and produce eggs, closing the infectious cycle. Human infections are caused by undercooked water plants (e.g. watercress), plants that need frequent irrigation and are manured with animal excreta and, to a lesser extent, by contaminated drinking water.¹⁰⁰

Based on the pathophysiology, fascioliasis can be divided into 2 stages: in an acute phase (the first 2 to 4 months of infection), larvae migrate through the peritoneal cavity and penetrate the liver capsule causing local inflammation. Symptoms include upper abdominal pain, fever, nausea, rash or arthralgia in some cases. The second stage is marked by adult parasites settling in the extrahepatic bile ducts and gallbladder, which can be asymptomatic or cause malaise, abdominal discomfort or biliary tract obstruction.

During the acute phase, common findings are elevated liver enzymes and eosinophilia. Imaging techniques often lack distinct pathological findings and might reveal hepatomegaly or focal liver lesions.¹⁰¹ Serum antibody tests can be applied from 2 weeks after infection with sufficient sensitivity. In chronic infections, a possibly motile parasite might be detected sonographically in the gallbladder or main bile ducts.^101,102 After a prepatent period of 10 to 16 weeks, eggs can be detected in bile or stool with varying sensitivity.

Fascioliasis is curable and, if treated, does not usually cause long-term complications. The treatment of choice is single-dose triclabendazole or nitazoxanide for 1 week. Severe infections may require 2 doses. In case of a biliary duct obstruction, an endoscopic retrograde cholangiopancreatography-(ERCP) can be considered to extract the flukes.¹⁰³

Clonorchis sinensis, Opisthorchis viverrini and Opisthorchic felineus

The so-called small liver flukes of the families Clonorchis and Opisthorchis are mainly spread in Asia (Fig. 4). Eggs are excreted into freshwater in the faeces of dogs, cat, birds, reptiles or other definitive hosts. Larvae hatch and infect water snails, the first intermediate host, where they multiply. They ultimately leave the snail and penetrate the skin of their second intermediate host, mainly fish, where they encyst within the muscular tissue. After consumption, the larvae are released within the definitive host’s digestive tract and migrate to the liver using the bile duct. Humans act as accidental definitive hosts and infections occur after consumption of poorly cooked fish.^97,104,105 Thus, populations that depend on fishing as a livelihood are particularly affected.¹⁰⁶ Salting, drying, marinating or short-term freezing does not affect the viability of the larvae.

In the acute phase, clinical features depend on the fluke load and span from asymptomatic infections to upper abdominal pain. After maturation of the flukes in the chronic phase of the disease, abdominal symptoms can either resolve or persist with potentially severe complications such as cholelithiasis, cholangitis and pancreatitis. Clonorchis sinensis has been putatively associated with recurrent pyogenic cholangitis, a disease only seen in South-East Asia and therefore also called Oriental cholangiohepatitis.¹⁰⁷ The most important long-term consequences, especially after recurrent infections, are cirrhosis and cholangiocarcinoma.^108,109 Mechanical irritation and persistent inflammation presumably lead to dysplasia in the biliary duct cells.^111–113 In their meta-analysis, Xia et al. (2015) found the odds for cholangitis were almost 16 times higher in patients with liver fluke infection and 5 times higher for cholangiocarcinoma.¹⁰⁸ The latter, in particular, causes a high burden of disease, with 1 in 6 individuals infected with O. viverrini developing a cholangiocellular carcinoma in endemic areas.¹¹⁴ Patients often present with eosinophilia; diagnostic methods involve stool microscopy, serological antibody testing (with limited sensitivity and specificity), and imaging techniques such as ultrasound, CT or MRI scan. The treatment of choice for both clonorchiasis and opisthorchiasis is praziquantel. In endemic areas, preventive chemotherapy with repeated single-dose praziquantel at a community-level is recommended.¹¹⁵

Key point

For schistosomiasis, serologic screening and praziquantel treatment in migrants from endemic countries is recommended.

Schistosoma mansoni and Schistosoma japonicum

According to the WHO, approximately 240 million people are infected with schistosomes globally. As a water-based NTD, endemic areas are found in tropical and subtropical climate zones on every continent, mainly in Sub-Saharan Africa and South America (Fig. 5). The infectious cycle requires freshwater contact: different water snails, the intermediate hosts, release cercariae into the water which penetrate human skin, migrate through the lungs as immature schistosomulae and mature in the liver, to finally settle in abdominal vessels.¹ Schistosoma mansoni is the main species causing liver pathology, and to a lesser extent S. japonicum. Both species settle in the mesenteric vessels and excrete eggs that penetrate the intestinal wall and hatch; if released into freshwater, they penetrate a suitable freshwater snail, closing the life cycle.¹¹⁶ Eggs can either get stuck during penetration or enter the venous circulation and reach other organs, primarily the liver and rarely the central nervous system or lungs, where they cause chronic inflammation. Liver pathology is marked by a chronic granulomatous inflammation resulting in hepatic fibrosis and, eventually, hepatosplenic schistosomiasis (HSS). Data on the prevalence of HSS are scarce, but for example, the incidence of periportal fibrosis among the population at risk in rural Tanzania ranges between 24 and 40%.^117,118

Apart from a possible dermatitis resulting from larval penetration, the first symptoms usually occur 4–6 weeks after infection with the first shedding of eggs. This causes a strong immune reaction resulting in a flu-like syndrome called Katayama fever, which is more likely seen in immunonaïve travellers than in the native population. However, the native population is prone to chronic schistosomiasis, depending on the worm burden. Entrapped eggs can cause a vast array of symptoms, depending on the species and organ involved, like abdominal pain, haematuria or infertility. In the liver, inflammation causes hepatomegaly in early stages, followed by the so-called ‘Symmer’s pipestem’ fibrosis of the portal system and granulomatous thrombophlebitis in later stages. Ultimately, HSS results in portal hypertension with respective complications. Early HSS is often asymptomatic, while in later stages, impaired liver function, portal branch occlusion and variceal bleeding are observed.¹¹⁹ The prevalence of oesophageal varices varies from 12% to 80% and variceal bleeding is the main cause of death.¹²⁰ Co-infection with HIV, malaria or hepatitis increases the risk of HCC, as well as the general mortality of affected patients.¹²¹ Whether HSS itself can be considered a pre-cancerosis is currently unclear.¹²²

Diagnostic methods involve stool microscopy; however, sensitivity may be low. Coproantigen or blood-based PCR may be more sensitive, the latter being the only diagnostic option in Katayama fever. Specific antibodies appear 3 months after infection and are the diagnostic method of choice for travellers. Late stages of schistosomiasis can be seronegative and without detectable eggs or antigens. HSS is commonly diagnosed sonographically, based on patterns of periportal fibrosis.^123,124 The role of elastosonography in HSS is still a matter of debate.¹²⁵ Liver biopsy is not recommended.

The treatment of choice is praziquantel. Due to its safety profile and favourable cost-effectiveness ratio, it should be administered generously in suspected cases or as repeated drug mass administration in endemic areas. Since praziquantel is only effective against adult worms, repeated treatment might be required, especially as reinfection is frequent in endemic areas. Regarding HSS, praziquantel neither reverses liver fibrosis nor its already established complications. Specific management is equivalent to that of portal hypertension, including screening for oesophageal varices in high-risk patients.¹²⁰

In the European context, serological screening is advised for people reporting freshwater contact in endemic areas followed by treatment in case of a positive result.¹²⁶ Additional screening for co-infections, such as hepatitis, is highly recommended.

Nematodes of the liver: Ascaris lumbricoides

Currently, 800 million people worldwide are infected with Ascaris lumbricoides.¹²⁷ The geographical distribution of ascariasis is linked to low socio-economic development, with insufficient hygiene practices due to poor housing and sanitation promoting the parasite life cycle.^1,128,129 Ingestion of food or material contaminated with mature eggs from human faeces is the main route of infection. Larvae hatch in the duodenum, migrate to the liver and lungs where they are coughed up and swallowed, again reaching the digestive tract. Adult worms develop in the small intestines and produce eggs which are released into the environment in the absence of a sewage system. After maturation in the soil, eggs can contaminate plants (vegetables) which serve as the source of infection.¹²⁹

Clinical characteristics depend on the stage of infection. During larval migration, respiratory symptoms with eosinophilia are frequently observed. Once juvenile or adult worms reach the small intestine, patients can remain asymptomatic or suffer from abdominal pain, nausea and malabsorption, which occurs more frequently in children or with a high worm load. Stool microscopy can reveal eggs and serological antibody testing is available. For complications such as biliary, intestinal or pancreatic duct obstructions, and appendicitis, ultrasound is the diagnostic method of choice to detect adult worms.^129,130 Similar to Clonorchis sinensis, ascariasis has been suggested to contribute to recurrent pyogenic cholangitis.¹⁰⁷

Albendazole, mebendazole and ivermectin are effective for the treatment of ascariasis. According to a recent Cochrane review, all drugs are equally effective with a single dose being as effective as multiple doses.¹³¹ Complications might require interventions such as ERCP or surgery in case of intestinal obstruction or appendicitis.^129,130

Protozoan parasites: Entamoeba histolytica

Amoebiasis is caused by the protozoa Entamoeba histolytica and occurs in humans and primates. The burden of disease is considerable, with an estimated 50 million infections and 55,000 deaths annually.⁹ Globally, impoverished communities with insufficient sanitary facilities are most affected, as E. histolytica is mainly transmitted via the faecal-oral route. In Europe, amoebiasis is predominantly seen in travellers returning from endemic areas. Amoebiases can be asymptomatic (90%) or cause gastrointestinal symptoms that range from abdominal discomfort to severe dysentery or even megacolon and perforation.¹³² Most infections remain intestinal; however, the potential to lyse tissue followed by haematogenous spread allows E. histolytica to infect other organs, mostly the liver (2 to 5% of cases) followed by the lungs, brain and heart, particularly in immunocompromised patients. Middle-aged men and individuals with low socio-economic status are at increased risk. In the liver, inflammation and necrosis of hepatocytes result in an amoebic liver abscess (ALA).¹³³ The majority of cases become symptomatic within 2–4 weeks after exposure, however, latency can last for years. Symptoms consist of high fever, upper abdominal pain, leucocytosis, usually without eosinophilia, and elevated liver transaminases.¹³⁴ Gastrointestinal symptoms occur in only 10–35% of cases. Ultrasound is highly sensitive, yet has limited specificity because of the resemblance to pyogenic liver abscesses (PLAs).¹³⁵ In ALA, the sensitivity of microscopy of faeces (<10%) and liver aspirates (<25%) is low, while antigen testing in fresh stool is usually negative.¹³⁶ Serum antibodies are detectable in 85–95% of invasive infections, but might result from previous infection, especially in endemic areas.^134,136 To prove active infection, antigen testing from serum and PCR from aspirates (as well as urine, saliva or blood) have been applied with high sensitivity before treatment initiation.^137,138

Initial treatment of suggestive findings should, based on empirical considerations (e.g. travel history), cover both ALA and PLA, combining antiparasitics and antibiotics. Firstline treatment for ALA is metronidazole or tinidazole, followed by paromomycin for its luminal effect to clear persisting parasites, resulting in cure rates of about 85%. Possible complications are abscess rupture and, rarely, thrombosis of the vena cava, portal or hepatic vein. Therapeutic aspiration using percutaneous catheter drainage should be considered in case of abscesses larger than 5 cm, localisation in the left lobe, bacterial superinfection or failure of a conservative approach.¹³⁹

Conclusions

For European clinicians, knowing clinical features and the epidemiological background is key to initiate appropriate diagnostics for hepatic parasites. Importantly, AE and CE may be considered emerging public health issues in Europe. Fascioliasis is an endemic disease in Europe as well, yet with less public health impact. Regarding returning travellers, right upper abdominal pain is suspicious of ALA and, in case of flu-like symptoms and freshwater contact, Katayama fever should be considered, according to epidemiology.

Chronic infections with the parasites discussed in this review can cause severe morbidity and mortality, such as malignancies (schistosomiasis, small liver flukes), portal hypertension (schistosomiasis), biliary obstruction and recurrent cholangitis (ascariasis, small liver flukes, AE, CE) and, ultimately, liver failure. Therefore, most importantly for everyday routine, further investigations should be carried out if echinococcoses are suspected. Screening for schistosomiasis should be guided by a patient’s history.

Finally, almost all hepatic parasites count as food- and waterborne NTDs. Therefore, long-term control requires a One Health approach combining individual treatment, public health measures, food chain safety and animal health interventions for diseases with animal reservoirs.

Source : Journal of hepatology