Perspective Chapter: Prospects for Pharmacological Therapy of Hepatic Alveolar Echinococcosis

Abstract

Often misdiagnosed as liver cancer at first, the Alveolar hydatid disease or hepatic alveolar echinococcosis is an uncommon but potentially harmful variant of the disease also synonymously known as Echinococcus multilocularis (E. Multilocularis). The major area being drastically affected is the liver, from where its later advances into the lung and brain, typically fatal if left untreated. Even if surgery is still the recommended course of treatment for the condition, drug therapy cannot be thwarted off and remains essential and vital for individuals with disease extremity. This chapter therefore aims to present a framework through which FDA-approved drugs and nano drug delivery technologies collaborate to manage progressive hepatic alveolar echinococcosis.

1. Introduction

Echinococcosis is amongst those neglected diseases that the World Health Organisation (WHO) intends to manage or mitigate by the year 2050. Significant inclinations toward overhauling the treatment, management and control of Echinococossis originate from limitations of current diagnostic techniques, toxicity and low efficacy of medication options, usually suboptimal surgical procedures and other factors [1]. As the name implies, this chapter seeks to outline the latest clinical findings regarding the management of Hepatic Alveolar Echinococcosis (HAE) also just known as Alveolar Echinococcosis (AE).

2. Physiology of transmission

During its life cycle, the parasitic worm primarily picks out a carnivore like dogs and their prey (rodents) to act as its definitive and intermediate hosts. Despite not being actively engaged in the propagation of the illness, humans can nonetheless serve as intermediate hosts in certain situations. The maturation of adult worms and the release of eggs in the faeces of the definitive host as mentioned above are the variables that are involved in the transmission phenomena. After being consumed by a person (through food or water), the eggs later hatch and reach the liver via the lymphatic channels. This locus is significant in terms of the eggs developing into larvae and later metastasizing into other organs of the host [1].

3. Prevalence

Alveoli echinococcosis has been a significant problem in northern Japan, China, Tibet and other parts of Central Asia [2, 3, 4, 5, 6, 7]. In much of Europe, both definite and intermediate hosts have now been reported to be significantly more vulnerable to the infection [8, 9]. Until recent findings from parts of Mexico, AE was not regarded as a major human hazard in North America [10]. Nonetheless, over the past 10 years, human infections have been identified in North America and other parts of Canada [11, 12].

4. Clinical indications

The liver is where a high proportion of the disease’s primary lesions are sited, out of which many may differ to manifest for up to 15 years. Trauma to the hepatic blood vessels or bile ducts emerges as disease symptomatology [13]. The delay in disease identification was caused by both false imaging results and acute clinical symptoms, pointing to a problem (incorrect therapeutic management) that could not be easily overlooked [14]. It has been determined that elevated levels of biological response modifiers such as interleukins and genetic variations in antigen presenting cells such as the human leukocyte antigen are positively correlated with the onset or progression of the disease in humans [15, 16]. The occurrence of AE and its rapid progression have also been linked to acquiring therapeutic immunosuppression, which results from immunosuppressant administration necessary during a liver transplant [17].

5. Diagnosis

Visual tests (CT scans), imaging techniques and serology are amongst the most widely employed methodologies for the confirmation of the parasite. Other than these prominent ones, southern blotting and polymerase chain reactions (PCR) are the molecular techniques involved in the diagnosis of the disease. Discussed below are the most widely employed diagnostic methods for AE.

5.1 Imaging techniques

In order to offer physicians a trustworthy source of information when making a clinical judgement, the WHO has classified the disease lesions into a variety of forms solely based on imaging data obtained in the US [18]. The effectiveness of these imaging data as a screening and follow-up aid is gaining significant attention in centres of both Asia and Europe [19, 20]. Lesions from an abscess or tumour can now be differentiated by these techniques such as Contrast-enhanced ultrasonography (CEUS) [21]. In addition to the above technique, the methodology involved in an imaging technique named FDG-positron emission tomography (FDG-PET) is used to prevent inaccurate tumour interpretations [22].

5.2 Serology

Drawbacks of imaging techniques described above such as the inability to distinguish between an abscess and a neoplasm, difficulty in data interpretation and unreliability with respect to early diagnosis cause a shift in preference toward blood serum analysis known as serology. Furthermore, serology is more accurate as an affirmatory and reliable tool for AE cases. This is largely prevalent in developing nations where these techniques are absent [23]. Apart from these decisive advantages, patient follow up post medical or surgical treatment is also made simpler [24, 25].

5.2.1 Specific serological diagnosis of AE

This section covers the involvement of specific serological markers pertaining to the diagnosis of AE.

Excretory/secretory proteins (ESPs), also termed as parasitic antigens, are responsible for triggering the host’s immune response [26]. A member of the E. multilocularis specific ESPs, Em2, also referred to as Em2a and Em18, allows for precise discrimination between an AE and Cystic echinococcosis patient [27, 28]. Recent findings also render the role of a varied antigen named Em492 in the diagnosis of AE [29]. Similarly, showing high diagnostic performance for confirmation of AE is EM10 and its derivatives (another Echinococcus antigen) [30]. Based on molecular research done on mice, lipoprotein antigen B is the last of the few ESPs that is expressed in the disease condition [31].

5.2.2 Importance of serology both in pre and post therapy of AE

The method of Elisa to detect specific antibodies relating to AE with high sensitivities of up to 95% is employed at various laboratories. Addition of an immunoblotting technique to this ELISA maximised the diagnostic sensitivity [32]. A follow up usually done as relapses can prevail even after surgery of chronic administration of medications. This is where serology reappears back into the confirmation process where the antibody detection can be directly linked to the degree or extent of disease. A challenging situation that arises in this method occurs in the case of an immunosuppressed patient as less information is available to quantify or qualitatively analyse the antibody response. Based on a study to optimise the role of serology both for diagnosis and monitoring of pre or post therapies of AE have brought about the following results

1. Serology can help in distinguishing between an active and inactive lesion. This holds true both in the diagnosis or pretreatment phases thus unnecessary advice for a surgery or medication can be avoided

2. Serological methods as a follow up study post-surgery or therapy can aid in prediction of disease relapse [33].

6. Treatment

6.1 Invasive modus operandi

Profound resection of liver lesions constitutes the basis for the adoption of a treatment decision [34]. Even though hepatic surgery is the best course of action, significant cases of morbidity and mortality cannot be addressed even under expert supervision. This therefore exemplifies the fact as to why only one-third of the patient population develops positive outcomes from the procedure alone. Also note that the majority of geographical regions where this occurs have delayed diagnoses [35]. These drawbacks may also be attributed to the evidence that an intrusive procedure alone is unsafe for disease treatment because of its close association with complications as mentioned above [36].

In light of this, the treatment goals, and regimen for AE have now been tailored as follows.

1. Complete occlusion of the parasitic lesion, followed by 2 years of anti-infective medication (examples discussed later).

2. If the initial strategy fails to diminish disease burden, the period of anti-infective drugs needs an extension (upto 10 years to prevent recurrence).

3. Lingering underlying difficulties can be tackled in aspects of reducing inflammation or obstruction in the bile duct [37]

With respect to the above-laid objectives let us dive deep into some of the pros and cons of the treatment.

An advanced parasite infection is indicated by lesions around the hepatic veins and progress into the inferior Vena cava. Such situations are resolved with the liver transplant procedure. Negative compliance with this strategic approach may be brought on by the lack of an appropriate matching donor and prolonged use of immunosuppressants [17].

As an alternative to a full transplant, the procedure known as Ex vivo liver resection can be used, in which the patient’s liver is physically removed, cleared of lesions post which it is reinserted. In cases of irresectable livers or late stages of the illness, this is favoured and produces favourable results without requiring long-term immunosuppressive treatment [38].

The other types of disease burden are hepatobiliary complications, which signify an unpleasant shift in the disease progression [39]. Ameliorative techniques used up until the turn of the century involved the percutaneous dilatation of the blocked bile ducts [40]. The contribution of such an invasive technique (termed as Perendoscopic bile duct stenting) for treating biliary obstruction is irreplaceable and is at widely being used. The desired result for individuals hospitalised for this procedure is an improvement in the quality of life [41].

6.2 Medication

Breakthroughs in AE have been made possible by faster detection, the introduction of drug therapy, and the gradual abandonment of resective procedures [42]. End-stage diagnoses, a lack of medical resources, and the failure of a specific drug or the severity of their side effects can unnerve nations going through such suffering [43].

7. Negative consequences in the current treatments of AE

Foretelling the outcome of AE is daunting as resection is often accompanied by chemotherapy using benzimidazoles for unquestionable periods of time [44]. Hepatotoxicity of the lot is amongst the major concerns. Along with this distress, although significantly increasing the survival rate of patients; they are capable only in reduction (static effect) but not destruction (cidal effect) of the parasite. In short, recurrence after drug withdrawal cannot be avoided [1].

This presents a clear conundrum regarding the need for additional AE treatment options. Therefore, selectivity, a sizable therapeutic window and a cidal rather than a static effect should be given priority when choosing a conventional drug for treatment of AE.

8. Pharmacological prospects for AE treatment

There is a plethora of preclinical research (both In vitro and In vivo) containing data on potential treatments for AE, such as usage of anti-infectives, anti-cancer drugs etc. However, these could not be completely depended upon due to the absence of thorough and reliable screening methods [45].

With respect to In vitro studies, the development of extensive means for specific species culture of AE larvae have brought about a change in the aforementioned conclusion, thereby opening doors for whole or reliable drug screening assays against the parasite [46, 47].

8.1 Anti-infective agents

These agents find place in AE as this condition is not restrictively a parasitic burden but also infectious in nature.

In vivo data revealed that chemotherapeutic drugs and anthelmintics, in addition to benzimidazoles, all had parasitostatic effects [48]. When used both alone (In vitro) and in conjunction with a benzimidazole (In vivo), nitazoxanide demonstrated promising outcomes against AE [49, 50]. Monotherapy and combination therapies on the contrary failed to treat AE in humans, despite the mentioned claims [51].

Tricloabendazole had the strongest In vitro antiparasitic activity of all the benzimidazole compounds evaluated. When evaluated In vitro and on additional mice models, drugs like fenbendazole, oxfendazole, and febantel were highly efficacious against the disease [52, 53].

8.2 Anti-malarial compounds

The Mefloquine compound used in treating malaria showed promising albendazole-like features when looking at an In vivo activity alone. Higher rates of reduction in the parasite burden were seen with an increase in dose of the said drug candidates. However, the latter’s incomplete pharmacokinetic data and the presence of neurotoxicity following prolonged mefloquine treatment could be a hazard to therapeutic regimens involving them [54].

8.3 Antibiotics

Clarithromycin, an antibiotic macrolide, significantly reduced the proliferation and morphological traits of E. multilocularis in vitro. Similar abnormalities were also translated on to the adult forms of the parasite. However, no suitable in vivo tests were carried out to further investigate these promising findings [55].

8.4 Other methods for assessment of potential targets

Affinity chromatography followed by MS-based sequencing can now be used to validate novel targets or other significant proteins expressed during the host–parasite encounter [56]. When it became necessary to assess the degree of harm brought on by pharmacological therapy, a technique of drug screening based on the release of the enzyme phosphoglucose isomerase was devised. This is now mostly used to anticipate how well different anti-parasitic medications can improve disease burden [57].

8.5 Cancer cell proliferation inhibitors

Reoccurring and indistinguishable characteristics between the parasitic condition and malignancies such as ongoing cell proliferation, ability to alter immune response, production of proteolytic enzymes, angiogenesis stimulation, over-expression of certain proteins, and the capability to create metastases, may find their application in usage of anti-cancer medications as a possible form of treatment [58].

One of the earliest anti-cancer compounds investigated for the potential use against AE was doxorubicin in the form of nanoparticles. Mostly because of the serious side effects that were accompanied to this moiety, this concept of therapy was dropped [59].

Later, genistein, an isoflavonoids-class of anti-tumour drug which demonstrated anti-parasitic properties, was introduced. Although highly effective, its negative impact on long-term treatment deprived it from being implemented or approved for the world scenario [60].

Another occurrence involved the research findings from the endogenous oestrogen metabolite, 2-methoxyestradiol, which caused substantial in vitro harm to the parasite. This however revealed no statistically significant differences from the conventional albendazole medication [61].

At very low concentrations, the mitogen-activated protein kinase and tyrosine-kinase inhibitors pyridinyl imidazoles and imatinib, respectively, caused parasite cell death [62, 63].

A possible therapeutic target that requires careful examination is the role glutathione-S-transferase plays in AE and other malignancies where it promotes cell proliferation. In other words, medications inhibiting cell proliferation could make way into pharmaceutical care for AE [64].

Investigation of other enzyme inhibitors, such as the proteasome inhibitor bortezomib, showed that this enzyme is a viable pharmacological target that should be pursued further [65].

With the help of early findings that require further analyses, cytostatic compounds can also be helpful moieties in AE prevention [66].

9. Recent lab findings

This section emphasises on the recent developments found in the research areas regarding AE.

9.1 Anti-cancer drugs

Alterations to a proto-oncogene (a gene involved in normal cell growth) may lead to the formation of oncogenes, which aids in cancer development. RAF is an example of such a proto-oncogene that regulates a variety of cellular functions, bringing about a gain in malignant properties of a normal cell. The anticancer drug, Sorafenib inhibits tumour cell proliferation and formation of new blood vessels (angiogenesis) by targeting RAF in Raf signalling pathway. The drug in question was found to exhibit strong inhibitions in conditions of multilocular echinococcosis [67].

9.2 Immune checkpoint inhibitor

After invasion the parasite has the capability to escape an encounter with the host immune system [68]. This immunosuppressive setting is highly influential for the viability and proliferation of the parasite [69].

It was found that Programmed Cell Death Ligand 1 abbreviated as PD-L1 plays a negative role in cancers by attenuating immune responses [70]. Studies that focused on this transmembrane protein reached the conclusion that the development of HAE was in close association with high expressions PD-L1. This could be a probable mechanism by which the parasite achieves immune escape [71].

Other supporting research was found to be in agreement with the above inference. Confirmation of this hypothesis was brought about by a control in the infection utilising immunotherapy which acted on PD-L1 pathway blockage [72, 73].

Alongside the above mechanism, an additional blocking activity on TIGIT, an inhibitory receptor led to tumour rejection. This was an indication that TIGIT and PD-1/PD-L1 blockade enhanced or synergised the anti-tumour effects of lymphocytes [74]. When In vivo studies on mice and humans were based on these mechanisms, TIGIT highlighted its potential as an immunomodulatory strategy for the treatment of AE [75, 76].

9.3 Nano drug delivery system

The rate of cure in a conventional anti-infective such as albendazole was found to be low. Poor bioavailability was found to be the reason behind the unfavourable effect. The need to alleviate this drug disadvantage led to the shift in focus for designing new formulations of the drug being discussed.

Liposomes that help in delivering active molecules to the site of action were the answer to this research problem [77, 78]. These treatments significantly reduced parasite burden in patients by increasing the mortality rate against larvae of the parasites when compared with traditional albendazole [79].

Other than liposomes, a valid suggestion for the employment of nanocrystals resulted in an increase in bioavailability of the same medication [80].

The preventive efficacies of these nanotechnology-based preparations were also found to be enhanced [81]. All these findings contribute to the fact that nanomedicinal forms of an anti-infective have developmental potential in improving anti-AE drug therapy.

10. Conclusions

Alveolar Echinococossis, although rare and neglected, is fatal if left untreated. The profound mode of treatment involves the resection of liver. However, we have discussed that this alone wasn’t sufficient and that supportive therapy using medications was a necessity. The severe adverse effects of traditional drugs also caused a decline in quality of life of patients. The above stated reasons brought about the need to seek further advanced treatment options for the disease such as new drug targets, elucidation of novel mechanisms involved in disease progression, various drug delivery technologies etc. The authors hence have highlighted the clinical indications and the need for specific diagnostic approaches of the disease such as imaging techniques and serology. Along with invasive modes of treatment, the additional employment of various medicaments including anthelmintics, anti-malarials, antibiotics, inhibitors of cancer proliferation, immune checkpoint inhibitors and nano drug delivery system that were found to be promising for the treatment of AE without exhibition of the adverse effects of traditional drugs were briefed. This chapter was approached with the sole purpose of exploring the various novel trends and those that are presently in action to tackle this slowly rising, yet worrisome endemic.

Acknowledgments

The authors would like to express their gratitude to People’s University, Bhanpur, Bhopal, for providing the necessary environment for completion of this chapter.

Conflict of interest

We, the authors, would like to declare that there is no conflict of interest based on the information produced.