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Parasites of the liver – epidemiology, diagnosis and clinical management in the European context

  • Author Footnotes
    † These authors contributed equally.
    Lynn Peters
    Footnotes
    † These authors contributed equally.
    Affiliations
    University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Albert-Einstein-Allee 23, 89081 Ulm, Germany
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  • Author Footnotes
    † These authors contributed equally.
    Sanne Burkert
    Footnotes
    † These authors contributed equally.
    Affiliations
    University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Albert-Einstein-Allee 23, 89081 Ulm, Germany
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  • Beate Grüner
    Correspondence
    Corresponding author. Address: University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Albert-Einstein-Allee 23, 89081 Ulm, Germany, Tel.: +49731/500-45551, fax: +49731/500-45555.
    Affiliations
    University Hospital of Ulm, Department of Internal Medicine III, Division of Infectious Diseases, Albert-Einstein-Allee 23, 89081 Ulm, Germany
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  • Author Footnotes
    † These authors contributed equally.
Published:February 23, 2021DOI:https://doi.org/10.1016/j.jhep.2021.02.015

      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

      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.
      • Deslyper G.
      • Doherty D.G.
      • Carolan J.C.
      • Holland C.V.
      The role of the liver in the migration of parasites of global significance.
      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.
      Table 1Differential diagnoses of hepatic parasites according to their clinical presentations, possible complications and the appearance of characteristic liver impairment on imaging.
      SymptomDifferential diagnosis
      Upper abdominal discomfortAE, CE, fascioliasis, small liver fluke disease, schistosomiasis, ascariasis, amoebiasis
      Severe abdominal painfascioliasis, small liver fluke disease
      MalabsorptionAscariasis (children)
      DysenteryAmoebiasis
      FeverSchistosomiasis (Katayama fever), amoebiasis (ALA), fascioliasis/CE/AE in case of cholangitis
      CoughAscariasis, schistosomiasis
      EosinophiliaCE, small liver fluke disease, fascioliasis
      Biliary obstruction, jaundice, cholangitisAE, CE, fascioliasis, small liver fluke disease, ascariasis
      Portal hypertensionAE, schistosomiasis
      Possible complications
       CancerSmall liver fluke disease (CCC), schistosomiasis (bladder, potentially HCC)
       CholelithiasisSmall liver fluke disease
       Biliary pancreatitisSmall liver fluke disease, fascioliasis, ascariasis
       FibrosisSchistosomiasis, small liver fluke disease
       CirrhosisVery late-stage schistosomiasis, small liver fluke disease
       HepatomegalySchistosomiasis
       AppendicitisAscariasis
       Liver abscessAmoebiasis
       Cystobiliary fistulaCE
       Liver failureLate AE, late schistosomiasis
      Liver impairment in imaging
       Focal hepatic lesionAE, CE, amoebiasis, (fascioliasis)
       Diffuse parenchymal liver diseaseSchistosomiasis, (early fascioliasis)
       Dilated (intrahepatic) bile ductsSmall liver fluke disease, fascioliasis, ascariasis
      AE, alveolar echinococcosis; ALA, amoebic liver abscess; CCC, cholangiocarcinoma; CE, cystic echinococcosis; HCC, hepatocellular carcinoma.
      Table 2Summary of clinical features of hepatic parasites.
      SpeciesGeographic distributionIntermediate hostsDefinite hostsIncubation periodAdult size in mmPrepatent period
      In humans.
      Life span
      In humans.
      Clinical featuresComplicationsDiagnostic methodsStandard Treatment
      Cestodes
      Echinococcus granulosus sensu latoWorldwide. Different genotypes G1–10 with diff. human pathogenicityDifferent herbivores (sheep, cattle, camel, pig and others, humans are accidental)Carnivores (mainly dogs)Not exactly known, years3–7n.a.Not exactly knownSlow growing cysts in various organs (70% liver, 20% lung, and others)
      • 1.
        Fistulation, e.g. cystobiliary or cystobronchial
      • 2.
        Anaphylaxis due to cyst rupture
      • 3.
        Mass effect, esp. when cerebral or bone involvement
      • 1.
        Imaging, US most important for CE-classification
      • 2.
        Serologic tests
      • 3.
        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 multilocularisNorthern hemisphereRodents, humans are accidentalCarnivores, Europe mainly: red fox, also dogsNot exactly known, 10–15 years2–5n.a.Not exactly knownInfiltrate 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 cava
      • 2.
        Infiltration of neighbouring organs
      • 1.
        Imaging (first US followed by (PET)-CT- or MRI scan with serologic testing
      • 2.
        PCR or histopathology in clinical specimen (liver biopsy)
      Trematodes
      Fasciola hepaticaAsia, Americas, Europe, Africa, OceaniaWater snail (family Lymnaeidae)Mainly sheep, cattle, goatsAround 2 weeks20–3010–12 weeksup to 13 yearsAbdominal pain, feverBiliary obstructionStool microscopy, Serum antibody ELISATriclabendazole
      Benznidazoles have to be taken with fatty meal to reach efficient plasma levels.
      p.o. 10 mg/kg BID Nitazoxanide 500 mg BID for 7 days
      Fasciola giganticaAsia, Africa25–7510–16 weeksAbdominal pain, feverStool microscopy, Serum antibody ELISA
      Clonorchis sinensisin East and Southeast Asia, Russia, IndiaWater snail, fish, crustaceansmainly dogs, cats, swines10–252–3 weeksUp to 20 yearsAsymptomatic or abdominal painCholangiocellular carcinoma, biliary obstructionStool microscopy, Serum antibody ELISA, stool antigenPraziquantel
      To be taken with or directly after food.
      p.o. 75 mg/kg/day, split into 3 doses for 2 days
      Opisthorchis viverriniSoutheast AsiaWater snail, fish, crustaceansCats, dogs8–12Up to 25 yearsStool microscopy, Serum antibody ELISA
      Opisthorchis felineusEastern Europe, Central AsiaWater snail, fish, crustaceansCats, dogs, foxesStool microscopy, Serum antibody ELISA
      Schistosoma mansoniAfrica, South America, CaribbeanWater snailsHumans, non-human primates4–87 days6–204–6 weeks3–10 yearsSymptomatic only through complicationsPortal fibrosis, hepatosplenic schistosomiasis, HCCStool microscopy, (stool antigen detection usually negative in ALA), serum antibody ELISA, (serum/aspirate antigen test and PCR from aspirate as available)Praziquantel
      To be taken with or directly after food.
      p.o. 40 mg/kg OD for 3 days
      Schistosoma intercalatumCentral and West Africahumans14–84 days11–14
      Schistosoma japonicumChina, Indonesia, South-East AsiaHumans, wild mammals10–30Praziquantel
      To be taken with or directly after food.
      p.o. 60 mg/kg OD for 3 days
      Schistosoma mekongiLaos, CambodiaHumans, dogs12–15
      Nematodes
      Ascaris lumbricoidesAsia, Africa and Latin AmericaNone (soil maturation)humans2–7 daysFemales up to 40 cm, males up to 25 cmca. 70 days1–2 yearsRespiratory and abdominal symptoms, malabsorptionCholangitis, pancreatitis,Stool microscopy, adult worms can be macroscpical identified, coproantigen, (Serology) USAlbendazole p.o. 400 mg once
      Benznidazoles have to be taken with fatty meal to reach efficient plasma levels.
      , mebendazole p.o. 100 mg BD for 3 d (or 500 mg once)
      Benznidazoles have to be taken with fatty meal to reach efficient plasma levels.
      or ivermectin p.o. 150–200 μg/kg once
      Protozoa
      Entamoeba histolyticaAfrica, Asia and Latin AmericaNonehumans2–4 weeks0.25–0.4n.a.n.a.Abdominal pain, (bloody) diarrhoea, tenesmaAmoebic 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
      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.

      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.
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      Global distribution of alveolar and cystic echinococcosis.
      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.
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      The global burden of alveolar echinococcosis.
      Figure thumbnail gr1
      Fig. 1Worldwide distribution of Echinococcoses.
      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.
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      The global burden of alveolar echinococcosis.
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      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      Despite their non-tropical distribution, echinococcoses are considered neglected tropical diseases (NTDs).
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      Due to scant data, diagnosis and treatment are guided by expert consensus, primarily the recommendations of the WHO-IWGE (Informal Working Group on Echinococcosis),
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      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      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.
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      International consensus on terminology to be used in the field of echinococcoses.
      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.
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      Ecology and life cycle patterns of Echinococcus species.
      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.
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      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.
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      The echinococcoses.
      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.
      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).
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      Echinococcosis: advances in the 21st century.
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      The true prevalence of CE is difficult to estimate due to underreporting and underdiagnosis of asymptomatic infections.
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      The first meeting of the European Register of Cystic Echinococcosis (ERCE).
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      Cystic echinococcosis in a single tertiary care center in rome, Italy.
      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.
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      Alveolar and cystic echinococcosis in Europe: old burdens and new challenges.
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      Autochthonous cystic echinococcosis in patients who grew up in Germany.
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      Evaluation of direct costs associated with alveolar and cystic echinococcosis in Austria.
      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.
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      Cystic echinococcosis of the liver: a primer for hepatologists.

      Clinical features

      Approximately 60–75% of CE cases are incidental findings, especially during the early stages of infection.
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      Prevalence of abdominal cystic echinococcosis in rural Bulgaria, Romania, and Turkey: a cross-sectional, ultrasound-based, population study from the HERACLES project.
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      Cystic echinococcosis in a single tertiary care center in rome, Italy.
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      WHO/OIE manual on echinococcosis in humans and animals.
      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.
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      WHO/OIE manual on echinococcosis in humans and animals.
      Depending on site and size of manifestations, symptoms result from compression or displacement of healthy tissue.
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      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.
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      The case fatality rate of CE is reported to be 2–4%.
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      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.
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      Immunoblotting with human native antigen shows stage-related sensitivity in the serodiagnosis of hepatic cystic echinococcosis.
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      Cystic echinococcosis.
      Ultrasound is the standard investigation for the diagnosis of hepatic CE.
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      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      Pathognomonic features of CE cysts on ultrasound are listed in Fig. 2.
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      • Akinci D.
      • Chipeva R.
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      Prevalence of abdominal cystic echinococcosis in rural Bulgaria, Romania, and Turkey: a cross-sectional, ultrasound-based, population study from the HERACLES project.
      ,
      • Ran B.
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      Differentiation between hepatic cystic echinococcosis types 1 and simple hepatic cysts: a retrospective analysis.
      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.
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      The WHO informal working group on echinococcosis. The Coordinating Board of the WHO-IWGE.
      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.
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      Diagnosing and staging of cystic echinococcosis: how do CT and MRI perform in comparison to ultrasound?.
      ,
      • Hosch W.
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      MR imaging for diagnosing cysto-biliary fistulas in cystic echinococcosis.
      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.
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      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      Benzimidazole (BMZ) pretreatment is required prior to cyst puncture for suspected CE, and precautions should be taken to avoid possible anaphylaxis.
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      Current management of cystic echinococcosis: a survey of specialist practice.
      Figure thumbnail gr2
      Fig. 2WHO classification of cystic echinococcosis and recommended treatments.
      Adapted from Rinaldi F et al. Cystic echinococcosis of the liver: A primer for hepatologists, World J Hepatol 2014 6(5)293–305.

      Treatments

      Clinical decision-making for uncomplicated liver CE is based on ultrasound staging.
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      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.
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ,
      • Tamarozzi F.
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      Acceptance of standardized ultrasound classification, use of albendazole, and long-term follow-up in clinical management of cystic echinococcosis: systematic review.
      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.
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      • Göçmen A.
      Liver hydatid disease: long-term results of percutaneous treatment.
      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.
      • Smego R.A.
      • Bhatti S.
      • Khaliq A.A.
      • Beg M.A.
      Percutaneous aspiration-injection-reaspiration drainage plus albendazole or mebendazole for hepatic cystic echinococcosis: a meta-analysis.
      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.
      • Rinaldi F.
      • Brunetti E.
      • Neumayr A.
      • Maestri M.
      • Goblirsch S.
      • Tamarozzi F.
      Cystic echinococcosis of the liver: a primer for hepatologists.
      If a solid stage is reached spontaneously, reactivation is rare.
      • Stojkovic M.
      • Rosenberger K.D.
      • Steudle F.
      • Junghanss T.
      Watch and wait management of inactive cystic echinococcosis – does the path to inactivity matter – analysis of a prospective patient cohort.
      Despite the mentioned drawbacks, BMZ treatment remains the main treatment option in disseminated or inoperable CE.
      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.
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ,
      • Tamarozzi F.
      • Nicoletti G.J.
      • Neumayr A.
      • Brunetti E.
      Acceptance of standardized ultrasound classification, use of albendazole, and long-term follow-up in clinical management of cystic echinococcosis: systematic review.
      Praziquantel might enhance the effect of ABZ and is therefore recommended in some centres for peri-interventional prophylaxis.
      • Alvela-Suárez L.
      • Velasco-Tirado V.
      • Belhassen-Garcia M.
      • Novo-Veleiro I.
      • Pardo-Lledías J.
      • Romero-Alegría A.
      • et al.
      Safety of the combined use of praziquantel and albendazole in the treatment of human hydatid disease.

      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%.
      • Kern P.
      Clinical features and treatment of alveolar echinococcosis.
      AE is considered an emerging disease, with an annual incidence of approximately 18,000 cases globally, of which 91% occur in China.
      • Wen H.
      • Vuitton L.
      • Tuxun T.
      • Li J.
      • Vuitton D.A.
      • Zhang W.
      • et al.
      Echinococcosis: advances in the 21st century.
      ,
      • Torgerson P.R.
      • Keller K.
      • Magnotta M.
      • Ragland N.
      The global burden of alveolar echinococcosis.
      ,
      • Romig T.
      • Dinkel A.
      • Mackenstedt U.
      The present situation of echinococcosis in Europe.
      ,
      • Davidson R.K.
      • Romig T.
      • Jenkins E.
      • Tryland M.
      • Robertson L.J.
      The impact of globalisation on the distribution of Echinococcus multilocularis.
      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,
      • Schweiger A.
      • Ammann R.W.
      • Candinas D.
      • Clavien P.A.
      • Eckert J.
      • Gottstein B.
      • et al.
      Human alveolar echinococcosis after fox population increase, Switzerland.
      • Nahorski W.L.
      • Knap J.P.
      • Pawłowski Z.S.
      • Krawczyk M.
      • Polański J.
      • Stefaniak J.
      • et al.
      Human alveolar echinococcosis in Poland: 1990–2011.
      • Bružinskaite R.
      • Marcinkute A.
      • Strupas K.
      • Sokolovas V.
      • Deplazes P.
      • Mathis A.
      • et al.
      Alveolar echinococcosis, Lithuania [5].
      • Kolářová L.
      • Matějů J.
      • Hrdý J.
      • Kolářová H.
      • Hozáková L.
      • Žampachová V.
      • et al.
      Human alveolar echinococcosis, Czech republic, 2007–2014.
      • Schneider R.
      • Aspöck H.
      • Auer H.
      Unexpected increase of alveolar echincoccosis, Austria, 2011.
      • Dezsényi B.
      • Strausz T.
      • Makrai Z.
      • Csomor J.
      • Danka J.
      • Kern P.
      • et al.
      Autochthonous human alveolar echinococcosis in a Hungarian patient.
      challenging respective health care systems.
      • Deplazes P.
      • Gottstein B.
      • Junghanss T.
      Alveolar and cystic echinococcosis in Europe: old burdens and new challenges.
      Key risk factors for acquiring AE in Europe are being a farmer, owning a dog or cat or having a kitchen garden.
      • Kern P.
      • Ammon A.
      • Kron M.
      • Sinn G.
      • Sander S.
      • Petersen L.R.
      • et al.
      Risk factors for alveolar echinococcosis in humans.
      • Piarroux M.
      • Piarroux R.
      • Knapp J.
      • Bardonnet K.
      • Dumortier J.
      • Watelet J.
      • et al.
      Populations at risk for alveolar echinococcosis, France.
      • Conraths F.J.
      • Probst C.
      • Possenti A.
      • Boufana B.
      • Saulle R.
      • La Torre G.
      • et al.
      Potential risk factors associated with human alveolar echinococcosis: systematic review and meta-analysis.
      Furthermore, the incidence of AE is higher among immunodeficient patients, who often show atypical presentations.
      • Chauchet A.
      • Grenouillet F.
      • Knapp J.
      • Richou C.
      • Delabrousse E.
      • Dentan C.
      • et al.
      Increased incidence and characteristics of alveolar echinococcosis in patients with immunosuppression-associated conditions.
      A genetic susceptibility associated with an altered immune response has been observed.
      • Godot V.
      • Harraga S.
      • Beurton I.
      • Deschaseaux M.
      • Sarciron E.
      • Gottstein B.
      • et al.
      Resistance/susceptibility to Echinococcus multilocularis infection and cytokine profile in humans. I. Comparison of patients with progressive and abortive lesions.
      ,
      • Eiermann T.H.
      • Bettens F.
      • Tiberghien P.
      • Schmitz K.
      • Beurton I.
      • Bresson-Hadni S.
      • et al.
      HLA and alveolar echinococcosis.

      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.
      • Kern P.
      • Bardonnet K.
      • Renner E.
      • Auer H.
      • Pawlowski Z.
      • Ammann R.W.
      • et al.
      European echinococcosis registry: human alveolar echinococcosis, Europe, 1982-2000.
      • Piarroux M.
      • Piarroux R.
      • Giorgi R.
      • Knapp J.
      • Bardonnet K.
      • Sudre B.
      • et al.
      Clinical features and evolution of alveolar echinococcosis in France from 1982 to 2007: results of a survey in 387 patients.
      • Kern P.
      • Wen H.
      • Sato N.
      • Vuitton D.A.
      • Gruener B.
      • Shao Y.
      • et al.
      WHO classification of alveolar echinococcosis: principles and application.
      • Grüner B.
      • Kern P.
      • Mayer B.
      • Gräter T.
      • Hillenbrand A.
      • Barth T.E.F.
      • et al.
      Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany.
      • Jonaitytė E.
      • Judickas M.
      • Tamulevičienė E.
      • Šeškutė M.
      Alveolar echinococcosis in children.
      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.
      • Wen H.
      • Vuitton L.
      • Tuxun T.
      • Li J.
      • Vuitton D.A.
      • Zhang W.
      • et al.
      Echinococcosis: advances in the 21st century.
      Early symptoms are mostly non-specific including fatigue, abdominal pain or jaundice. One-third of all cases are asymptomatic and diagnosed incidentally.
      • Grüner B.
      • Kern P.
      • Mayer B.
      • Gräter T.
      • Hillenbrand A.
      • Barth T.E.F.
      • et al.
      Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany.
      Upon diagnosis, parasitic liver lesions are often extensive and infiltrate neighbouring structures, limiting treatment options.
      • Kern P.
      Clinical features and treatment of alveolar echinococcosis.
      ,
      • Kern P.
      • Bardonnet K.
      • Renner E.
      • Auer H.
      • Pawlowski Z.
      • Ammann R.W.
      • et al.
      European echinococcosis registry: human alveolar echinococcosis, Europe, 1982-2000.
      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.
      • Kern P.
      Clinical features and treatment of alveolar echinococcosis.
      ,
      • Grüner B.
      • Kern P.
      • Mayer B.
      • Gräter T.
      • Hillenbrand A.
      • Barth T.E.F.
      • et al.
      Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany.
      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.
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      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.
      • Romig T.
      • Kratzer W.
      • Kimmig P.
      • Frosch M.
      • Gaus W.
      • Flegel W.A.
      • et al.
      An epidemiologic survey of human alveolar echinococcosis in southwestern Germany.
      • Jensen B.
      • Reuter S.
      • Kratzer W.
      • Naser K.
      • Kächele V.
      • Kimmig P.
      • et al.
      Long-term seropositivity against Echinococcus multilocularis in an epidemiological follow-up study in southwestern Germany (Römerstein).
      • Bresson-Hadni S.
      • Laplante J.J.
      • Lenys D.
      • Rohmer P.
      • Gottstein B.
      • Jacquier P.
      • et al.
      Seroepidemiologic screening of Echinococcus multilocularis infection in a european area endemic for alveolar echinococcosis.
      Serologic and histologic or molecular confirmation is central.
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ,
      • Siles-Lucas M.
      • Casulli A.
      • Conraths F.J.
      • Müller N.
      Laboratory diagnosis of Echinococcus spp. in human patients and infected animals.
      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%.
      • Siles-Lucas M.
      • Casulli A.
      • Conraths F.J.
      • Müller N.
      Laboratory diagnosis of Echinococcus spp. in human patients and infected animals.
      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.
      • Barth T.F.E.
      • Herrmann T.S.
      • Tappe D.
      • Stark L.
      • Grüner B.
      • Buttenschoen K.
      • et al.
      Sensitive and specific immunohistochemical diagnosis of human alveolar echinococcosis with the monoclonal antibody Em2G11.
      An ultrasound-guided core-needle biopsy is an effective diagnostic tool to achieve a definitive diagnosis of hepatic AE.
      • Bulakci M.
      • Ilhan M.
      • Bademler S.
      • Yilmaz E.
      • Gulluoglu M.
      • Bayraktar A.
      • et al.
      Efficacy of ultrasound-guided core-needle biopsy in the diagnosis of hepatic alveolar echinococcosis: a retrospective analysis.
      Based on the respective findings, AE can be classified as possible, probable or confirmed, defining the requirement for treatment (Table 3).
      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.
      Table 3WHO case definition, staging and recommended treatment for alveolar echinococcosis, adopted from (11) and based on the authors’ experience.
      WHO case definition
      LabelDefinitionTreatment recommendation
      PossibleEpidemiology + Imaging OR SerologyNo, regular follow-up
      ProbableEpidemiology + Imaging AND SerologyYes
      ConfirmedEpidemiology + Imaging AND Serology AND histological confirmation/positive nucleic acid sequence from clinical specimenYes
      WHO staging
      Hepatic localisationPXPrimary tumour cannot be assessed
      P0No detectable tumour in the liver
      P1Peripheral lesions without proximal vascular and/or biliary involvement
      P2Central lesions with proximal vascular and/or biliary involvement of one lobe
      The plane projecting between the bed of the gall bladder and the inferior vena cava divides the liver into 2 lobes.
      P3Central lesions with hilum vascular or biliary involvement of both lobes and/or with involvement of 2 hepatic veins
      P4Any liver lesion with extension along the vessels
      Inferior vena cava, portal vein and arteries.
      and the biliary tree
      Extrahepatic involvement of neighbouring organsDiaphragm, lung, pleura, pericardium, heart, gastric and duodenal wall, adrenal glands, peritoneum, retroperitoneum, parietal wall, pancreas, regional lymph nodes, kidney
      NXNot evaluable
      N0No regional involvement
      N1Regional involvement of contiguous organs or tissues
      Distant metastasisLung, distant lymph nodes, spleen, CNS, orbital, bone, skin, muscle, kidney, distant peritoneum, retroperitoneum
      MXNot completely evaluated
      M0No metastasis (chest radiography and cerebral computed tomography)
      M1Metastasis
      Treatment recommendation
      ClassificationSurgeryInterventional therapyDrug therapyFollow-up
      P1N0M0Radical 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)
      P2N0M0Radical 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/N1M0In selected casesif neededContinuously
      • Serology + ultrasound every 6–12 months
      • MRI or PET/CT every 2 years
      • Re-evaluate staging/eligibility for surgery
      P4N0/N1M0/M1In selected casesif neededContinuously
      • Serology + ultrasound every 6–12 months
      • MRI or PET/CT every 2 years
      • Re-evaluate staging/eligibility for surgery
      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.
      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.
      • Kratzer W.
      • Gruener B.
      • Kaltenbach T.E.M.
      • Ansari-Bitzenberger S.
      • Kern P.
      • Fuchs M.
      • et al.
      Proposal of an ultrasonographic classification for hepatic alveolar echinococcosis: echinococcosis multilocularis Ulm classification-ultrasound.
      Therefore, sonographic diagnosis is often challenging for clinicians unfamiliar with the disease.
      • Kratzer W.
      • Gruener B.
      • Kaltenbach T.E.M.
      • Ansari-Bitzenberger S.
      • Kern P.
      • Fuchs M.
      • et al.
      Proposal of an ultrasonographic classification for hepatic alveolar echinococcosis: echinococcosis multilocularis Ulm classification-ultrasound.
      ,
      • Sulima M.
      • Nahorski W.
      • Gorycki T.
      • Wołyniec W.
      • Wąż P.
      • Felczak-Korzybska I.
      • et al.
      Ultrasound images in hepatic alveolar echinococcosis and clinical stage of the disease.
      A CT, particularly for heavily calcified lesions, or MRI scan of the abdomen are the imaging techniques of choice.
      • Grüner B.
      • Kern P.
      • Mayer B.
      • Gräter T.
      • Hillenbrand A.
      • Barth T.E.F.
      • et al.
      Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany.
      ,
      • Reuter S.
      • Nüssle K.
      • Kolokythas O.
      • Haug U.
      • Rieber A.
      • Kern P.
      • et al.
      Alveolar liver echinococcosis: a comparative study of three imaging techniques.
      • Kantarci M.
      • Bayraktutan U.
      • Karabulut N.
      • Aydinli B.
      • Ogul H.
      • Yuce I.
      • et al.
      Alveolar echinococcosis: spectrum of findings at cross-sectional imaging.
      • Kodama Y.
      • Fujita N.
      • Shimizu T.
      • Endo H.
      • Nambu T.
      • Sato N.
      • et al.
      Alveolar echinococcosis: MR findings in the liver.
      • Azizi A.
      • Blagosklonov O.
      • Lounis A.
      • Berthet L.
      • Vuitton D.A.
      • Bresson-Hadni S.
      • et al.
      Alveolar echinococcosis: correlation between hepatic MRI findings and FDG-PET/CT metabolic activity.
      • Graeter T.
      • Kratzer W.
      • Oeztuerk S.
      • Haenle M.M.
      • Mason R.A.
      • Hillenbrand A.
      • et al.
      Proposal of a computed tomography classification for hepatic alveolar echinococcosis Retrospective Study.
      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
      • Reuter S.
      • Schirrmeister H.
      • Kratzer W.
      • Dreweck C.
      • Reske S.N.
      • Kern P.
      Pericystic metabolic activity in alveolar echinococcosis: assessment and follow-up by positron emission tomography.
      ,
      • Caoduro C.
      • Porot C.
      • Vuitton D.A.
      • Bresson-Hadni S.
      • Grenouillet F.
      • Richou C.
      • et al.
      The role of delayed 18F-FDG PET imaging in the follow-up of patients with alveolar echinococcosis.
      and can serve as a follow-up tool. The role of PET-MRI is currently under evaluation.
      • Lötsch F.
      • Waneck F.
      • Auer H.
      • Kaczirek K.
      • Karanikas G.
      • Ramharter M.
      FDG-PET/MRI in alveolar echinococcosis.
      Figure thumbnail gr3
      Fig. 3Display of different imaging techniques of alveolar echinococcosis.
      Imaging characteristics of AE differ widely. The following table shows the variation in findings for the different modalities. Importantly, in contrast to CE, neither US nor CT morphologies determine consecutive treatment. However, the depicted findings should raise suspicion and prompt further investigation for AE. A) Ultrasound images and classification
      • Kratzer W.
      • Gruener B.
      • Kaltenbach T.E.M.
      • Ansari-Bitzenberger S.
      • Kern P.
      • Fuchs M.
      • et al.
      Proposal of an ultrasonographic classification for hepatic alveolar echinococcosis: echinococcosis multilocularis Ulm classification-ultrasound.
      ; B) CT and PET-CT. The CT-scan and the respective 18FDG-PET-CT scan (with 2-deoxy-2-[fluorine-18]fluoro-D-glucose) are displayed before treatment initiation and after two years of treatment with albendazole. The reduction in 18-FDG uptake refers to a reduced immunological activity surrounding the lesion and can be interpreted as a response to the administered treatment.

      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
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ,
      • Reuter S.
      • Buck A.
      • Manfras B.
      • Kratzer W.
      • Seitz H.M.
      • Darge K.
      • et al.
      Structured treatment interruption in patients with alveolar echinococcosis.
      (Table 3) adapted from
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      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.
      • Kratzer W.
      • Gruener B.
      • Kaltenbach T.E.M.
      • Ansari-Bitzenberger S.
      • Kern P.
      • Fuchs M.
      • et al.
      Proposal of an ultrasonographic classification for hepatic alveolar echinococcosis: echinococcosis multilocularis Ulm classification-ultrasound.
      ,
      • Joliat G.R.
      • Melloul E.
      • Petermann D.
      • Demartines N.
      • Gillet M.
      • Uldry E.
      • et al.
      Outcomes after liver resection for hepatic alveolar echinococcosis: a single-center cohort study.
      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.
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ,
      • Buttenschoen K.
      • Carli Buttenschoen D.
      • Gruener B.
      • Kern P.
      • Beger H.G.
      • Henne-Bruns D.
      • et al.
      Long-term experience on surgical treatment of alveolar echinococcosis.
      ,
      • Kadry Z.
      • Renner E.C.
      • Bachmann L.M.
      • Attigah N.
      • Renner E.L.
      • Ammann R.W.
      • et al.
      Evaluation of treatment and long-term follow-up in patients with hepatic alveolar echinococcosis.
      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.
      • Brunetti E.
      • Kern P.
      • Vuitton D.A.
      Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans.
      ,
      • Grüner B.
      • Kern P.
      • Mayer B.
      • Gräter T.
      • Hillenbrand A.
      • Barth T.E.F.
      • et al.
      Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany.
      Under sufficient BMZ treatment, FDG-uptakes should decrease or even vanish, corresponding to suppressed periparasitic inflammatory activity.
      • Reuter S.
      • Buck A.
      • Manfras B.
      • Kratzer W.
      • Seitz H.M.
      • Darge K.
      • et al.
      Structured treatment interruption in patients with alveolar echinococcosis.
      ,
      • Stumpe K.D.M.
      • Renner-Schneiter E.C.
      • Kuenzle A.K.
      • Grimm F.
      • Kadry Z.
      • Clavien P.A.
      • et al.
      F-18-fluorodeoxyglucose (FDG) positron-emission tomography of Echinococcus multilocularis liver lesions: prospective evaluation of its value for diagnosis and follow-up during benzimidazole therapy.
      ,
      • Ammann R.W.
      • Stumpe K.D.M.
      • Grimm F.
      • Deplazes P.
      • Huber S.
      • Bertogg K.
      • et al.
      Outcome after discontinuing long-term benzimidazole treatment in 11 patients with non-resectable Alveolar echinococcosis with negative FDG-PET/CT and anti-EmII/3-10 serology.
      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.
      • Bresson-Hadni S.
      • Koch S.
      • Miguet J.P.
      • Gillet M.
      • Mantion G.A.
      • Heyd B.
      • et al.
      Indications and results of liver transplantation for Echinococcus alveolar infection: an overview.
      ,
      • Bresson-Hadni S.
      • Koch S.
      • Beurton I.
      • Vuitton D.A.
      • Bartholomot B.
      • Hrusovsky S.
      • et al.
      Primary disease recurrence after liver transplantation for alveolar echinococcosis: long-term evaluation in 15 patients.
      Palliative surgery for parasitic mass reduction is no longer recommended, as it often results in late biliary complications.
      • Buttenschoen K.
      • Gruener B.
      • Carli Buttenschoen D.
      • Reuter S.
      • Henne-Bruns D.
      • Kern P.
      Palliative operation for the treatment of alveolar echinococcosis.

      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.
      • Kadry Z.
      • Renner E.C.
      • Bachmann L.M.
      • Attigah N.
      • Renner E.L.
      • Ammann R.W.
      • et al.
      Evaluation of treatment and long-term follow-up in patients with hepatic alveolar echinococcosis.
      Monitoring serology after surgery and/or BMZ therapy is useful, as surgical removal of the lesion may result in seronegativity.
      • Tappe D.
      • Frosch M.
      • Sako Y.
      • Itoh S.
      • Grüner B.
      • Reuter S.
      • et al.
      Close relationship between clinical regression and specific serology in the follow-up of patients with alveolar echinococcosis in different clinical stages.
      After several years of BMZ treatment in stable AE without complications, a structured treatment interruption can be discussed.
      • Caoduro C.
      • Porot C.
      • Vuitton D.A.
      • Bresson-Hadni S.
      • Grenouillet F.
      • Richou C.
      • et al.
      The role of delayed 18F-FDG PET imaging in the follow-up of patients with alveolar echinococcosis.
      ,
      • Reuter S.
      • Buck A.
      • Manfras B.
      • Kratzer W.
      • Seitz H.M.
      • Darge K.
      • et al.
      Structured treatment interruption in patients with alveolar echinococcosis.
      ,
      • Ammann R.W.
      • Stumpe K.D.M.
      • Grimm F.
      • Deplazes P.
      • Huber S.
      • Bertogg K.
      • et al.
      Outcome after discontinuing long-term benzimidazole treatment in 11 patients with non-resectable Alveolar echinococcosis with negative FDG-PET/CT and anti-EmII/3-10 serology.
      Biliary complications, such as obstruction causing jaundice and cholangitis, are common in AE and occur in 10–30% of patients.
      • Graeter T.
      • Ehing F.
      • Oeztuerk S.
      • Mason R.A.
      • Haenle M.M.
      • Kratzer W.
      • et al.
      Hepatobiliary complications of alveolar echinococcosis: a long-term follow-up study.
      In particular, late biliary complications (after more than 3 years of treatment) are associated with high mortality.
      • Frei P.
      • Misselwitz B.
      • Prakash M.K.
      • Schoepfer A.M.
      • Prinz Vavricka B.M.
      • Müllhaupt B.
      • et al.
      Late biliary complications in human alveolar echinococcosis are associated with high mortality.
      Patients with acute complications might require hospitalisation for endoscopic interventions and antibiotic treatments.
      • Ambregna S.
      • Koch S.
      • Sulz M.C.
      • Grüner B.
      • Öztürk S.
      • Chevaux J.B.
      • et al.
      A European survey of perendoscopic treatment of biliary complications in patients with alveolar echinococcosis.
      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.
      • Lundström-Stadelmann B.
      • Rufener R.
      • Hemphill A.
      Drug repurposing applied: activity of the anti-malarial mefloquine against Echinococcus multilocularis.
      Currently, amphotericin B can be administered as an experimental approach.
      • Reuter S.
      • Buck A.
      • Grebe O.
      • Nüssle-Kügele K.
      • Kern P.
      • Manfras B.J.
      Salvage treatment with amphotericin B in progressive human alveolar echinococcosis.
      Nitazoxanide failed to show efficacy.
      • Kern P.
      • Bardonnet K.
      • Renner E.
      • Auer H.
      • Pawlowski Z.
      • Ammann R.W.
      • et al.
      European echinococcosis registry: human alveolar echinococcosis, Europe, 1982-2000.
      Immunotherapy using PD1 (programmed cell death 1) inhibitors
      • Wang J.
      • Jebbawi F.
      • Bellanger A.P.
      • Beldi G.
      • Millon L.
      • Gottstein B.
      Immunotherapy of alveolar echinococcosis via PD-1/PD-L1 immune checkpoint blockade in mice.
      and by inhibiting the polo-like kinase EmPlk1 have been investigated in vitro, but so far the results are not promising.
      • Schubert A.
      • Koziol U.
      • Cailliau K.
      • Vanderstraete M.
      • Dissous C.
      • Brehm K.
      Targeting Echinococcus multilocularis stem cells by inhibition of the polo-like kinase EmPlk1.

      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.
      • Piarroux M.
      • Piarroux R.
      • Giorgi R.
      • Knapp J.
      • Bardonnet K.
      • Sudre B.
      • et al.
      Clinical features and evolution of alveolar echinococcosis in France from 1982 to 2007: results of a survey in 387 patients.
      ,
      • Grüner B.
      • Kern P.
      • Mayer B.
      • Gräter T.
      • Hillenbrand A.
      • Barth T.E.F.
      • et al.
      Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany.
      ,
      • Ammann R.W.
      • Ilitsch N.
      • Marincek B.
      • Freiburghaus A.U.
      Effect of chemotherapy on the larval mass and the long-term course of alveolar echinococcosis.
      • Ammann R.W.
      • Renner E.C.
      • Gottstein B.
      • Grimm F.
      • Eckert J.
      • Renner E.L.
      Immunosurveillance of alveolar echinococcosis by specific humoral and cellular immune tests: long-term analysis of the Swiss chemotherapy trial (1976-2001).
      • Torgerson P.R.
      • Schweiger A.
      • Deplazes P.
      • Pohar M.
      • Reichen J.
      • Ammann R.W.
      • et al.
      Alveolar echinococcosis: from a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years.
      Early diagnosis, based on imaging and serological markers, can increase the number of resectable lesions.
      • Grüner B.
      • Kern P.
      • Mayer B.
      • Gräter T.
      • Hillenbrand A.
      • Barth T.E.F.
      • et al.
      Comprehensive diagnosis and treatment of alveolar echinococcosis: a single-center, long-term observational study of 312 patients in Germany.
      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.
      • König A.
      • Romig T.
      • Janko C.
      • Hildenbrand R.
      • Holzhofer E.
      • Kotulski Y.
      • et al.
      Integrated-baiting concept against Echinococcus multilocularis in foxes is successful in southern Bavaria, Germany.

      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.
      • Jayasena D.D.
      • Kim H.J.
      • Yong H.I.
      • Park S.
      • Kim K.
      • Choe W.
      • et al.
      • Hotez P.J.
      • Molyneux D.H.
      • Fenwick A.
      • Kumaresan J.
      • Sachs S.E.
      • Sachs J.D.
      • et al.
      Control of neglected tropical diseases.
      • King S.
      • Scholz T.
      Trematodes of the family Opisthorchiidae: a minireview.
      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.
      • Deslyper G.
      • Doherty D.G.
      • Carolan J.C.
      • Holland C.V.
      The role of the liver in the migration of parasites of global significance.
      ,
      • King S.
      • Scholz T.
      Trematodes of the family Opisthorchiidae: a minireview.
      Figure thumbnail gr4
      Fig. 4Worldwide distribution of liver flukes.

      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.
      • Mas-Coma S.
      • Bargues M.D.
      • Valero M.A.
      Human fascioliasis infection sources, their diversity, incidence factors, analytical methods and prevention measures.
      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.
      • Preza O.
      • Klapa I.
      • Tsiakalos A.
      • Cokkinos D.D.
      • Chatziioannou A.
      Fascioliasis: a challenging differential diagnosis for radiologists.
      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.
      • Preza O.
      • Klapa I.
      • Tsiakalos A.
      • Cokkinos D.D.
      • Chatziioannou A.
      Fascioliasis: a challenging differential diagnosis for radiologists.
      ,
      • Mas-Coma S.
      • Bargues M.D.
      • Valero M.A.
      Diagnosis of human fascioliasis by stool and blood techniques: update for the present global scenario.
      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.
      • Saba R.
      • Korkmaz M.
      • Inan D.
      • Mamikoǧlu L.
      • Ö Turhan
      • Günseren F.
      • et al.
      Human fascioliasis.

      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.
      • Jayasena D.D.
      • Kim H.J.
      • Yong H.I.
      • Park S.
      • Kim K.
      • Choe W.
      • et al.
      ,
      • Keiser J.
      • Utzinger J.
      Food-borne trematodiases.
      ,
      • Allegranzi B.
      • Nejad S.B.
      • Combescure C.
      • Graafmans W.
      • Attar H.
      • Donaldson L.
      • et al.
      Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis.
      Thus, populations that depend on fishing as a livelihood are particularly affected.
      • Parkin D.M.
      The global health burden of infection-associated cancers in the year 2002.
      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.
      • Huang M.H.
      • Chen C.H.
      • Yen C.M.
      • Yang J.C.
      • Yang C.C.
      • Yeh Y.H.
      • et al.
      Relation of hepatolithiasis to helminthic infestation.
      The most important long-term consequences, especially after recurrent infections, are cirrhosis and cholangiocarcinoma.
      • Xia J.
      • Jiang S.
      • Peng H.-J.
      Association between liver fluke infection and hepatobiliary pathological changes: a systematic review and meta-analysis.
      ,
      • Saijuntha W.
      • Sithithaworn P.
      • Kaitsopit N.
      • Andrews R.H.
      • Petney T.N.
      Liver flukes: clonorchis and opisthorchis.
      Mechanical irritation and persistent inflammation presumably lead to dysplasia in the biliary duct cells.
      • Sripa B.
      • Kaewkes S.
      Localisation of parasite antigens and inflammatory responses in experimental opisthorchiasis.
      • Zheng S.
      • Zhu Y.
      • Zhao Z.
      • Wu Z.
      • Okanurak K.
      • Lv Z.
      Liver fluke infection and cholangiocarcinoma: a review.
      • Su S.B.
      • Zhang J.F.
      • Huang F.F.
      • Cen Y.
      • Jiang H.X.
      Large numbers of interleukins-22- and -17A-producing T helper cells in cholangiocarcinoma related to liver fluke infection.
      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.
      • Xia J.
      • Jiang S.
      • Peng H.-J.
      Association between liver fluke infection and hepatobiliary pathological changes: a systematic review and meta-analysis.
      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.
      • Haswell-Elkins M.R.
      • Sithithaworn P.
      • Elkins D.
      Opisthorchis viverrini and cholangiocarcinoma in Northeast Thailand.
      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.
      • Jong E.C.
      • Wasserheit J.N.
      • Johnson R.J.
      • Carberry W.L.
      • Agosti J.
      • Dunning S.
      • et al.
      Praziquantel for the treatment of clonorchis/opisthorchis infections: report of a double-blind, placebo-controlled trial.
      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.
      • Deslyper G.
      • Doherty D.G.
      • Carolan J.C.
      • Holland C.V.
      The role of the liver in the migration of parasites of global significance.
      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.
      • Burke M.L.
      • Jones M.K.
      • Gobert G.N.
      • Li Y.S.
      • Ellis M.K.
      • McManus D.P.
      Immunopathogenesis of human schistosomiasis.
      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%.
      • Mazigo H.D.
      • Nuwaha F.
      • Dunne D.W.
      • Kaatano G.M.
      • Angelo T.
      • Kepha S.
      • et al.
      Schistosoma mansoni infection and its related morbidity among adults living in selected villages of Mara region, north-western Tanzania: a cross-sectional exploratory study.
      ,
      • Kaatano G.M.
      • Min D.Y.
      • Siza J.E.
      • Yong T.S.
      • Chai J.Y.
      • Ko Y.
      • et al.
      Schistosoma mansoni-Related hepatosplenic morbidity in adult population on Kome Island, Sengerema district, Tanzania.
      Figure thumbnail gr5
      Fig. 5Global distribution of schistosomiasis.
      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.
      • Strauss E.
      Hepatosplenic schistosomiasis: a model for the study of portal hypertension.
      The prevalence of oesophageal varices varies from 12% to 80% and variceal bleeding is the main cause of death.
      • Gunda D.W.
      • Kilonzo S.B.
      • Manyiri P.M.
      • Peck R.N.
      • Mazigo H.D.
      Morbidity and mortality due to schistosoma mansoni related periportal fibrosis: could early diagnosis of varices improve the outcome following available treatment modalities in Sub saharan Africa? A scoping review.
      Co-infection with HIV, malaria or hepatitis increases the risk of HCC, as well as the general mortality of affected patients.
      • Shaker Y.
      • Samy N.
      • Ashour E.
      Hepatobiliary schistosomiasis.
      Whether HSS itself can be considered a pre-cancerosis is currently unclear.
      • Filgueira N.A.
      • Saraiva C.M. de A.
      • Jucá N.T.
      • Bezerra M.F.
      • Lacerda C.M.
      Schistosomal liver fibrosis and hepatocellular carcinoma – case series of patients submitted to liver transplantation.
      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.
      • Masi B.
      • Perles-Barbacaru T.A.
      • Bernard M.
      • Viola A.
      Clinical and preclinical imaging of hepatosplenic schistosomiasis.
      ,
      • Silva L.C.S.
      • Andrade L.M.
      • de Queiroz L.C.
      • Voieta I.
      • Azeredo L.M.
      • Antunes C.M.F.
      • et al.
      Schistosoma mansoni: magnetic resonance analysis of liver fibrosis according to WHO patterns for ultrasound assessment of schistosomiasis-related morbidity.
      The role of elastosonography in HSS is still a matter of debate.
      • Carvalho Santos J.
      • Dória Batista A.
      • Maria Mola Vasconcelos C.
      • Souza Lemos R.
      • Romão de Souza Junior V.
      • Dessein A.
      • et al.
      Liver ultrasound elastography for the evaluation of periportal fibrosis in schistosomiasis mansoni: a cross-sectional study.
      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.
      • Gunda D.W.
      • Kilonzo S.B.
      • Manyiri P.M.
      • Peck R.N.
      • Mazigo H.D.
      Morbidity and mortality due to schistosoma mansoni related periportal fibrosis: could early diagnosis of varices improve the outcome following available treatment modalities in Sub saharan Africa? A scoping review.
      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.
      (DTG) DG für T und IG
      Leitlinie: diagnostik und Therapie der Schistosomiasis (Bilharziose) Ziele und Kontext.
      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.
      • Pullan R.L.
      • Smith J.L.
      • Jasrasaria R.
      • Brooker S.J.
      Global numbers of infection and disease burden of soil transmitted helminth infections in 2010.
      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.
      • Deslyper G.
      • Doherty D.G.
      • Carolan J.C.
      • Holland C.V.
      The role of the liver in the migration of parasites of global significance.
      ,
      • Sultan Khuroo M.
      Ascariasis.
      ,
      • O’Lorcain P.
      • Holland C.V.
      The public health importance of Ascaris lumbricoides.
      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.
      • O’Lorcain P.
      • Holland C.V.
      The public health importance of Ascaris lumbricoides.
      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.
      • O’Lorcain P.
      • Holland C.V.
      The public health importance of Ascaris lumbricoides.
      ,
      • Khuroo M.S.
      • Rather A.A.
      • Khuroo N.S.
      • Khuroo M.S.
      Hepatobiliary and pancreatic ascariasis.
      Similar to Clonorchis sinensis, ascariasis has been suggested to contribute to recurrent pyogenic cholangitis.
      • Huang M.H.
      • Chen C.H.
      • Yen C.M.
      • Yang J.C.
      • Yang C.C.
      • Yeh Y.H.
      • et al.
      Relation of hepatolithiasis to helminthic infestation.
      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.
      • Conterno L.O.
      • Turchi M.D.
      • Corrêa I.
      • Monteiro de Barros Almeida R.A.
      Anthelmintic drugs for treating ascariasis.
      Complications might require interventions such as ERCP or surgery in case of intestinal obstruction or appendicitis.
      • O’Lorcain P.
      • Holland C.V.
      The public health importance of Ascaris lumbricoides.
      ,
      • Khuroo M.S.
      • Rather A.A.
      • Khuroo N.S.
      • Khuroo M.S.
      Hepatobiliary and pancreatic ascariasis.

      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.
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      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.
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      Amebiasis.
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      In ALA, the sensitivity of microscopy of faeces (<10%) and liver aspirates (<25%) is low, while antigen testing in fresh stool is usually negative.
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      Serum antibodies are detectable in 85–95% of invasive infections, but might result from previous infection, especially in endemic areas.
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      Laboratory diagnostic techniques for Entamoeba species.
      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.
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      ,
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      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.
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      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.

      Abbreviations

      AE, alveolar echinococcosis; ALA, amoebic liver abscess; CE, cystic echinococcosis; CEUS, contrast-enhanced ultrasound; ERCP, endoscopic retrograde cholangiopancreatography; FDG, fluorodeoxyglucose; HSS, hepatosplenic schistosomiasis; NTD, neglected tropical diseases; PAIR, puncture, aspiration, injection and re-aspiration; PET, positron emission tomography; PLA, pyogenic liver abscesses.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Conceptualisation: LP, SB, BG. Writing: LP (Fasciolia, Clonorchis, Opisthorchis, Ascaris), SB (Schistosomae, Entaemoeba), BG (AE, CE). Editing: LP, SB, BG; Supervision: BG.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work. refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      We would like to thank Francesca Tamarozzi, MD, PhD, Prof. Dr. med Peter Kern, and Dr. med. Benjamin Hagemann for providing valuable input and figures. We thank Prof. Dr. med. Wolfgang Kratzer, Prof. Dr. med. Ambros Beer and Dr. med. Nina Eberhardt, as well as Prof. Dr. med. Andreas Hillenbrand for illustrative material. Last but not least, we thank our patients and our institution for supporting our research.

      Supplementary data

      The following is the supplementary data to this article:

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