Alveolar Echinococcosis: Symptoms, diagnosis, treatment

• Spotlight
• Symptoms
• Case definition
• Diagnosis
• Staging and follow-up
• Treatment
• Prognosis
• Major references

Spotlight

Symptoms

Primary parasitic lesions are almost always located in the liver. For many years, patients may be asymptomatic, then unspecific symptoms like epigastric pain, fever, weight loss, fatigue, or abnormal findings on routine laboratory parameters may initiate thorough medical examination. Often, incidental detection of hemangioma-like structures in the liver or an irregular, already large lesion in the liver ultrasound are suggestive of alveolar echinococcosis. Depending on its localization in the liver, the parasitic tissue infiltrates the bile ducts and/or hepatic vessels, and may infiltrate adjacent organs and be spread via blood or lymph. Complications related to liver lesions are diverse, i.e. cholestasis, jaundice, cholangitis, symptoms of liver abscess, septicaemia, portal hypertension, bleeding from oesophageal varices, Budd-Chiari syndrome. When the lesions extend to neighbouring organs and when distant metastases are present, symptoms of the affected region prevail (vena cava, diaphragm, adrenal gland, pancreas, lung, brain, skin, bones, etc.). The disease manifestations therefore encompass a wide spectrum which requires careful review of all findings, involving several medical disciplines.
 
 

Case definition

The Working Group of the network EurEchinoReg developed the following case definition for alveolar echinococcosis:
Diagnosis is confirmed by:

- positive histopathology, if available.
Specimens obtained by surgical removal or in puncture material. Needle biopsy is not recommended because of possible dissemination. PCR techniques are not yet validated.

- positive morphological findings by imaging techniques.
For verification consultation of a reference centre may be necessary. Alveolar echinococcosis affects primarily the liver in 98% of cases.

+/- positive serological findings. Serology may be negative in 10-20% of cases.
Positive serology without suggestive imaging findings does not qualify for alveolar echinococcosis case definition.

(Published in Final Report to the European Commission "EurEchinoReg: European Network for Concerted Surveillance of Alveolar Echinococcosis". 1999)
 
 

Diagnosis

Histopathology

The diagnosis is made by histopathology. However, the morphological proof is not easy and may not be feasible in every case; collection of specimens and parasitological examination should be done under the guidance of experienced investigators. The parasitic lesions are surrounded by a typical granulomatous reaction with infiltrating mononuclear cells, epithelioid cells and giant cells. Observation of parasitic vesicles with a PAS + laminated layer is a key point for diagnosis. It is sometimes difficult to differentiate between remnants of larvae of E. granulosus (causative agent of cystic echinococcosis) and larvae of E. multilocularis (alveolar echinococcosis); however effort should be made to differentiate between both diseases whenever possible since both epidemiological and prognostic characteristics are markedly different.

Imaging techniques

Liver ultrasound (US) and/or abdominal computer tomography (CT-scan) are sensitive methods to identify lesions of E. multilocularis and to differentiate between alveolar and cystic echinococcosis. MR imaging is advisable under selected circumstances either to confirm diagnosis or to more precisely assess extension to neighbouring or distant organs. Alveolar echinococcosis presents itself as an inhomogeneous lesion in the affected liver; it appears hyperechoic with less reflective margins. Calcifications with the typical "shadow" at US examination are found regularly and are very well identified using CT-scan. When the disease progresses, "cystic" hypoechoic lesions develop and, finally, a central necrosis with cavitation appears which is often falsely interpreted as a manifestation of cystic echinococcosis. Ultrasound images often resemble those of primary liver carcinoma, cholangiocarcinoma, other types of calcified liver lesions or liver metastases. Differentiation of alveolar echinococcosis from degenerating or dead cysts of cystic echinococcosis can be difficult and requires expertise. Lesions at a very early stage may look like hemangiomas of the liver. Further work-up requires MR Imaging and serology. Finally, small isolated calcified clusters may represent "died-out" lesions of an abortive infection. These individuals never presented any clinical symptoms nor signs indicating a viable parasitic lesion.

Serology

Serologic tests, i.e. the detection of antibodies which are developed against the parasite some time after the infection, are supportive to confirm the diagnosis. Different techniques are available, among them, Elisa for IgG detection, IHAT and Western Blot are used with purified or recombinant antigens. However, serology may be negative in 10 to 20% of cases. Cross-reactivity with crude antigens of E. granulosus occurs frequently. Interpretation of test results can be difficult, especially in geographic regions where both diseases are prevalent. In endemic areas of alveolar echinococcosis, individuals with "died-out lesions" suggestive for "abortive alveolar echinococcosis" have a positive serology. Serology thus needs to be interpreted with caution; all clinical and morphological findings must be taken into account by an experienced investigator. In endemic areas, 2% of the population react positive for Echinococcus serology despite negative imaging findings. Further diagnosis work-up using imaging techniques as well as serology once a yaer is recommended.

Clinical, morphological and serological expression of AE may vary widely among individuals because of the broad range of locations, size, parasite activity, and host response. Thus, three forms of AE can be identified according to these findings.
 

Form of AE	Clinical signs and symptoms	Imaging	Serology	Histopathology + molecular tools
Active AE	+ or -	Typical lesions and evidence of progression	+ or -	+
Regressive AE	+ or -	Typical lesions and evidence of regression	+ or -	+
Abortive AE	-	calcifications	+	n.a.

+: positive; -: negative

The institutions cooperating within the EurEchinoReg network are prepared to give advice for confirmatory tests and the interpretation of ambiguous results. Special questions will be answered by internationally recognized experts in each of the European countries (see Contacts).
 

Staging and follow-up

It is extremely helpful to exactly record the anatomical extent of the parasitic infestation at the time of first diagnosis: liver lobe and segments, involvement of the adjacent organs, and occurrence of distant metastases. A staging system of alveolar echinococcosis adapted from tumor staging (TNM) of liver cancer was developed by members of the EurEchinoReg.

PNM classification

The PNM system for describing the anatomical extent of alveolar echinococcosis is based on the assessment of three components at the time of diagnosis:

P = Hepatic Localization of the Parasite
N = Extrahepatic Involvement of Neighbouring Organs
M =Absence or Presence of Distant Metastases

P =     Hepatic Localization of the Parasite
PX    primary tumor cannot be assessed
P0    no detectable tumor in the liver
P1    peripheral lesions without proximal vascular and/or biliar involvement
P2    central lesions with proximal vascular and/or biliar involvement of one lobe*
P3    central lesions with  hilar vascular and/or biliar involvement of both lobes and/or with involvement of two hepatic veins
P4    any liver lesion with extension along the vessels** and the biliary tree

N = Extrahepatic Involvement of Neighbouring Organs
[diaphragm, lung, pleura, pericardium, heart, gastric and duodenal wall, adrenal glands, peritoneum, retroperitoneum, parietal wall (muscles, skin, bone), pancreas, regional lymph nodes, liver ligaments, kidney]
NX    not evaluable
N0    no regional involvement
N1    regional involvment of contiguous organs or tissues

M =Absence or Presence of Distant Metastases
[lung, distant lymph nodes, spleen, CNS, orbita, bone, skin, muscle, kidney, distant peritoneum and retroperitoneum]
MX    not completely evaluated
M0    no metastasis***
M1    metastasis

Note:    *    For classification, the plane projecting between the bed of the gallbladder and the inferior vena cava divides the liver in two lobes.
            **    Vessels means inferior vena cava, portal vein and arteries.
            *** Chest X-ray and cerebral CT negative.
 
 

Treatment

1. Alveolar echinococcosis can be cured by a radical resection of the complete parasitic lesion from the liver and/or other affected organs. Assessment of resectability is therefore the prerequisite for surgery. Surgery is feasible at an early stage of the disease, only. After curative surgery, concomitant treatment with benzimidazoles is recommended for 2 years (see below).

2. For patients with inoperable lesions, a continuous long-term medication with benzimidazoles is obligatory. The two derivatives albendazole and mebendazole have been in use since more than 20 years. Their effect is parasitostatic but not parasitocidal.

3. Interventional procedures i.e. biliary drainage, stent implantation or dilation of bile ducts or blood vessels, etc. are recommended in some cases to relieve symptoms of the affected region and to limit complications and sequelae.

4. Palliative surgery has been performed in some cases to reduce the parasitic mass and to improve the efficacy of chemotherapy. Hereafter, long-term, mostly lifelong chemotherapy is necessary. Unfortunately, relapses are very common in all these cases, and specific complications (i.e. stenosis of bile ducts, intrahepatic bile duct stones, bacterial or fungal superinfection) occur very often after surgery. Indications of palliative surgery should be examined on a case by case basis by a multidisciplinary team.

5. In cases with chronic liver failure or severe liver dysfunction, liver transplantation has been performed (45 cases in Europe from 1986 to 2000). However, immunosuppressive therapy preventing graft rejection can cause regrowth of residual lesions in extrahepatic locations and can even lead to re-infection of the transplant. It is therefore recommended to assess the indication for liver transplantation by an experienced interdisciplinary team. Association of chemotherapy and a careful post-transplantation follow-up are mandatory.

Guidelines for diagnosis and treatment of alveolar echinococcosis have been published in Bulletin of the WHO, 1996, 74(3): 231 - 242 by the WHO Informal working Group on Echinococcosis. Reprint requests to Prof. Peter Kern (Ulm, Germany), or Prof. Dominique A. Vuitton (Besançon, France) (see Contacts).
 
 

Prognosis

For most patients, alveolar echinococcosis is a chronic disease which requires a long-term, mostly lifelong chemotherapy with regular medical supervision. A regular follow-up of patients should include the assessment of the status of the disease and the evaluation of side-effects of the drugs. Studies have shown that untreated patients have a 10-years´ survival rate not exceeding 10%. Today, the combination therapy (chemotherapy, interventional measures and surgery at an early stage) leads to a survival rate of more than 80% in experienced centres.
 
 

Authors:

 

Solange Bresson-Hadni	Liver Diseases Unit, University Hospital of Besançon, France.
Peter Kern	Sektion Infektiologie und Klinische Immunologie, Med. Universitätsklinik und Poliklinik Ulm, Germany and Echinococcosis Working Group of the Paul-Ehrlich-Society
Wolfgang Kratzer	Abteilung Innere Medizin I, Med. Universitätsklinik und Poliklinik Ulm, Germany
Stefan Reuter	Sektion Infektiologie und Klinische Immunologie, Med. Universitätsklinik und Poliklinik Ulm, Germany
Dominique A. Vuitton	WHO Collaborating Center for Prevention and Treatment of Human Echinococcosis, University of Franche-Comté, Besançon, France.

In English :

2. Bresson-Hadni S, Vuitton DA, Bartholomot B et al. A twenty-year history of alveolar echinococcosis: analysis of a series of 117 patients from eastern France. Eur J Gastroenterol Hepatol 2000; 12: 327-336.

3. Eckert J, Conraths FJ, Tackmann K. Echinococcosis: an emerging or re-emerging zoonosis? International Journal for Parasitology 2000; 30: 1283 - 1294

4. Liance M, Janin V, Bresson-Hadni S, Vuitton DA, Houin R, Piarroux R. Immunodiagnosis of Echinococcus infections: Confirmatory testing and species differentiation by a new commercial Western blot. Journal of Clinical Microbiology 2000; 38: 3718 - 3721

5. Reuter S, Jensen B, Buttenschoen K et al. Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature. J Antimicr Chem 2000; 46: 451-456.

6. Reuter S, Nüssle K, Kolokyhas O et al. Alveolar liver echinococcosis : a comparative study of three imaging techniques. Infection 2001; 29: 119- 125

7. Romig T, Kratzer W, Kimmig P, Frosch M, Gaus W et al. An epidemiologic survey of human alveolar echinococcosis in southwestern Germany. Am J Trop Med Hyg 1999; 61: 566-573

8. Siles-Lucas M, Gottstein B. Review: Molecular tools for the diagnosis of cystic and alveolar echnococcosis. Tropical Medicine and International Health 2001; 6: 463 - 475

9. WHO Informal Working Group on Echinococcosis. Guidelines for treatment of cystic and alveolar echinococcosis in humans. Bull WHO 1996; 74: 231-242.

10. WHO/OIE manual on echinococcosis in humans and animals: a public health problem of global concern. Eds: Eckert J, Gemmell MA, Meslin FX, Pawlowski ZS. OIE, Paris, 2001, 265 pp, ISBN 92-9044-522-X
 

In French:

2. Bresson-Hadni S et Vuitton DA. Infections non virales du foie (monographie). Les échinococcoses. Rev Prat, 2001, sous presse

3. Vuitton DA. Vers un traitement "médical" des échinococcoses ? La lettre de l'Infectiologue, 2000;15:343-350

4. Vuitton DA, Bresson-Hadni S, Liance M et al. L'échinococcose alvéolaire humaine : hasard épidémiologique ou fatalité immunologique ? Gastroenterol Clin Biol 1990;14:124-130.

5. Vuitton DA, Godot V, Harraga S, Liance M, Beurton I, Bresson-Hadni S. Les échinococcoses: un modèle parasitaire pour la compréhension des maladies allergiques? Rev Fr Allergol Immunol Clin 2001;41:285-93.
 
 

In German:

2. Kern P, Kratzer W, Reuter S. Alveoläre Echinokokkose. Diagnose. Dtsch Med Wochenschr 2000; 125: 59-62

3. Kern P, Kratzer W, Reuter S. Alveoläre Echinokokkose. Therapie. Dtsch Med Wochenschr 2000; 125: 87-89

4. Reuter S, Kratzer W, Kurz S, et al. Chemotherapie der alveolären Echinokokkose mit Benzimidazolen. Med Klin 1998; 93: 463 - 467