Where are we going? Translational research in ...

Metab Brain Dis DOI 10.1007/s11011-015-9728-3

ORIGINAL ARTICLE

Where are we going? Translational research in hepatic encephalopathy Piero Amodio 1 & Sara Montagnese 1 & Kevin Mullen 2 & James G. Orr 3 & Hendrik Vilstrup 4

Received: 12 June 2015 / Accepted: 2 September 2015 # Springer Science+Business Media New York 2015

Abstract Translational medicine, rather than being a unidirectional clinical utilization of basic research discoveries, should be a bidirectional process of cross-fertilization between basic science, medical knowledge and clinical utilization. While steps and processes differ across these branches of research, clear language and proper definitions are prerequisites for effective interaction of researchers to facilitate knowledge development. With respect to Hepatic Encephalopathy, at first glance the areas which require development are around prevention, both to reduce the risk of relapse following an episode of overt HE and to reduce the risk of the first episode of HE. In addition, shortening the duration of episodes of overt HE may also be relevant. Comparisons of treatments and combinations of treatments, acting by different but potentially synergistic mechanisms, are reasonable targets for both basic and applied research. Keywords Hepatic encephalopathy . Translational research . Diagnosis . Pharmacoeconomics . Cirrhosis . Delirium The authors equally contributed to the paper and are listed in alphabetical order. The paper has been coordinated by P.A, who wrote the final manuscript, while J.G. O. revised English style. * Piero Amodio piero.amodio@unipd.it 1

Department of Medicine –DIMED, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy

2

Case Western Reserve University School of Medicine, Cleveland, Ohio

3

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

4

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

The following article develops the discussion that was held during the 13th ISHEN in London, in the round table session about the probable future developments in HE research and the requirements to improve translational research in this area. The usual definition of translational medicine is ‘biomedical research that aims to make findings from basic science useful for practical applications that enhance human health and well-being’, although the term itself and its utility is disputed (DeMaria 2013). On closer observation, however, the relationship between basic science and clinical practice can be subdivided into two steps: the first concerning the process of translation from basic science to medical knowledge, the second the process of translation from medical knowledge to clinical practice. The former can be more properly termed ‘translational research’, the latter ‘translational medicine’ sensu stricto. Both these definitions imply the traditional linear view of progress from ‘bench-to-bed’, as if the progress in basic science is at the origin of any improvement in clinical practice. In contrast, contemporary understanding is broader, since it includes the ‘bed-to-bench’ stage and the continuous dynamic interchange and cross-fertilization between the two domains, in a kind of hermeneutic circle (Niessen and Krieg 2014). Notably, in the history of medicine, important steps were derived by the combination and cross fertilization between clinical observation and basic science. Another ground for criticism of the concept and practice of translational medicine derives from the observation that some of the most useful drugs and discoveries arose by chance in laboratories (e.g., penicillin discovery). Further, it may even be questioned which important progress has so far come out of translational medicine. Translational medicine has not been shown to be more cost-effective than funding of laboratories, is not systematically subjected to evidence-based evaluation, and may be accused of irreproducibility.

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Despite these severe critics to the concept and practice of translational medicine per se, a more pragmatic approach to understand the strengths and limitations of translation medicine realizes a characteristic difference between clinical research and basic science. The former is characterized by being driven by humans’ concrete problems and by having a painfully slow execution; however, the potential benefits are incremental progress– and rapid impact on clinical practice. The latter is characterized by often being speculative by nature and sometimes motivated by practicality– but is often rapid to execute. The potentials of basic science are that it may lead to real breakthroughs– but has a delayed impact on clinical practice (Fig. 1). There are a number of challenges and requirements for translational medicine to thrive. The challenges are that a common and defined ‘language’ is needed between different scientists/clinicians. This assumes a true desire and motivation from both sides to ‘translate’, a desire so deeply felt that it can overcome the marked cultural differences. The dominant trend towards scientific reward for individual efforts should be replaced with rewards which acknowledge the contribution of teams. Integration of data of different provenience is difficult, requires organization on a large-scale, and available informatics systems are often inadequate. In the same vein, high rank scientific journals often require tight control of experimental conditions which may be difficult or impossible to obtain in translational medicine. Accordingly, multi-skilled teams that master multidisciplinary collaboration are required to build a knowledge-driven eco system with the capability to generate, contribute, manage, and analyse large data sets. The goal of handling these challenges and requirements and establishing a structure which can execute translational medicine is to create a continuous clinical-basic-clinicalbasic data feed-back loop which accelerates the translation of data into knowledge and increases the rate of making basic and clinical findings useful to humans, as per the definition. So, why apply translational research and medicine to HE? The arguments in favour are that HE remains a challenge, both for basic understanding of its pathophysiology, and clinical practice. Notably, no breakthrough thus far has resulted simultaneously in both areas. In fact, a single-discipline breakthrough is very unlikely. Likewise, there is a lack of innovative interventions for clinical trials, partly because new basic paradigms are missing. What is needed to realize this goal is a more bidirectional information streaming as a driving force for both clinical and basic research. A real effort is needed to translate between the clinical and basic languages, on the linguistic and the conceptual levels. At this aim, programs of extended reciprocal education might be useful as part of scientific ‘tandemprogrammes’ between key clinical and basic researchers, also promoting a higher degree of staff exchange between laboratories and clinical research units.

In summary, the need of clarification of terms, proper definitions and good monitoring techniques is one of the main steps to allow the cross-talk between disciplines that is required to promote research and practice in HE, where poor and confused definitions and diagnostic work-up plague patients’ phenotyping. Of note, this item has been considered by recent EASL and AASLD practice guidelines (Vilstrup et al. 2014). Another important issue that probably requires further development is the one of reliable animal models for episodic HE and minimal HE in addition to those that have been already described in the ISHEN guidelines (Butterworth et al. 2009) that are manly oriented to persistent HE or acute liver failure. The clinical evaluation of patients for HE requires the standardization of criteria to identify the subjects who are at high risk overt HE. In analogy with cardiovascular medicine, where life-long deleterious consequences ensue following the development of cardiovascular events, the identification of clear risk factors (Grundy et al. 1999) have enabled therapy targeted to their control and primary prevention of cardiovascular events. In recent years, the risk of relapsing overt HE for subjects who have suffered from one or more episodes of overt HE in the previous 6 months, has been clearly recognized and broadly quantified. It has become clear that these subjects require prophylaxis and that prophylaxis is possible, even if the risk is only reducible, but not eliminable (Bass et al. 2010). Therefore there is a need for new strategies to further reduce the risk of recurrence and, possibly, strategies for primary prophylaxis to be implemented in patients at high risk of overt HE. Disaccharides and rifaximin, i.e. drugs acting on gut microbiota, have been found to be effective for HE prevention, and their effect might be additive (Agrawal et al. 2012; Bass et al. 2010; Courson et al. 2015; Sharma et al. 2009). However, in acute conditions this possible synergy was not found (Courson et al. 2015). Therefore, treatment mechanisms require further investigation of gut microbiota modulation in cirrhosis. Thus, the modulation of microbiota with foods, prebiotic and probiotic interventions, as well as their interaction, is a field for both basic and clinical research. In addition, other therapies acting on nitrogen metabolism which are independent of gut microbioma modulation have been proved to be effective in HE. Among these treatments, branched chain amino acids and non-ureic nitrogen wasting products have been found to be noteworthy (Rockey et al. 2014; Vilstrup et al. 2014). All these strategies are theoretically synergistic, since they act on different pathophysiological steps in the process leading to encephalopathy. However, a great deal of work is still required to quantify if the reduction of recurrence really occurs in clinical practice with treatment association, and to what extent it might be effective. Further, different individuals might benefit from different strategies depending on the prevailing mechanism leading to encephalopathy and personalized treatment might be hypothesized.

Metab Brain Dis Fig. 1 The bidirectional flux (cross fertilization) between basic research and clinical knowledge. These dynamics suggest the need for clear language and interdisciplinary projects/ conferences/educational programs

Once an overt episode of HE has occurred it is desirable to achieve rapid recovery, both in the interest of the patient and to reduce the burden of managing a confused/comatosed individual. However, research on the speed of recovery has been poorly addressed. Also in this area, clinical and basic research on combinations of treatments is a reasonable target, analogous to what happens in many acute conditions (e.g., acute coronary disease), where combined approaches are effective. To this aim, the development and validation of effective and easily usable techniques for neuro-monitoring in clinical settings would be valuable. However, probably the one of the most relevant target in the future will be the primary prevention of the first episode of HE, since it heralds the triad i) liver function, ii) portalsystemic shunting and iii) brain function has reached decompensation. The detection of patients with a latent phase of brain dysfunction, or metabolic patterns heralding HE, which might be the target for treatments aimed at reducing the risk of overt HE, are obviously relevant targets. In addition, there is evidence suggesting that even minimal cognitive impairment/brain dysfunction ascribable to HE can reduce the ability to drive, the quality of life, the earning ability and increase the burden to caregivers (Bajaj et al. 2011; Kircheis et al. 2009; Montagnese et al. 2012; Prasad et al. 2007; Roman et al. 2011; Schomerus and Hamster 2001) (Table 1). Debate still exists about the procedures to detect and the terminology for the latent and the paucisymptomatic stage of HE. The debate about the terminology is probably mainly nominalistic and academic and, possibly, futile. However, it is a matter of fact that there is need: i) to detect and ii) to quantify this rather broad spectrum of disease ranging from perfect brain function to overt disorientation (a spectrum that the AASL/EASL guidelines suggested to call ‘covert HE’

(Vilstrup et al. 2014), as well as iii) to differentiate it from other kinds of brain dysfunction independent of liver insufficiency or shunting. Unfortunately, limited attention has been paid to differential diagnosis of neuropsychiatric dysfunction in cirrhosis. Cognitive impairment in the patients with cirrhosis who appear adequate on routine clinical assessment has been often immediately qualified as ‘minimal HE’, while it could have been also due to previous alcohol misuse, malnutrition, cerebrovascular disease, electrolyte imbalance, infections, or even the effect of psychoactive or analgesic drugs. This has obviously had negative consequences on the results of studies testing new diagnostic tools and new drugs. Over the last few years, more attention has been devoted to this issue. In addition, the recently published EASL/AASLD guidelines are more specific than the previous ones on the definition of HE (‘caused’ rather than ‘associated’ with liver disease), and more directive on the need for differential diagnosis paths (Vilstrup et al. 2014). In addition, even in recent studies, the reasoning behind the proposition of diagnostic tools for minimal HE has often been the following: i) a test is identified and performed in a number (often small) of healthy volunteers, ii) the same test is then utilised in a group of patients with cirrhosis and no overt HE, iii) the test is found altered in subjects with overt HE, iv) the

Table 1

Conditions associated with ‘covert’ HE

1. Increased falls 2. Impaired driving capacity* 3. Reduced Health Related Quality of Life* 4. Reduced employability 5. Increased risk of Overt HE 6. Increased risk of Liver-related mortality *Reversible with HE Treatment

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patients with cirrhosis without overt HE who perform worse than the healthy volunteers are considered to have minimal HE. It has even been suggested that the higher the number of abnormal results in patients with cirrhosis, the better the test. While these studies may be useful to identify candidate diagnostic tests for minimal HE, such tests can only be considered of value if i) they are correlated to indexes of liver dysfunction and portal-systemic shunting, ii) they are related to other recognised indexes of HE or brain function, and iii) they have the ability to predict the development of overt HE over time. Once a valid objective tool/procedure to detect, quantify and differentiate this condition from other conditions is available, it will be reasonable, in analogy with cardiovascular medicine, to screen patients so that the threshold for treatment might be determined. Interesting, thresholds for treatment may differ from thresholds of normality (Galen and Gambino 1975), as it occurs in cardiovascular medicine where, e.g., the advised level of cholesterol are lower than the level of normality in the general population, and the advised levels of blood pressure and cholesterol depend on the combined risk profile of the patient (Kjeldsen et al. 2014). Of note, if one looks at the literature, it is often observed that patients with cirrhosis, who do not reach the threshold for minimal HE, still tend to perform worse than healthy volunteers of similar age and educational attainment (Montagnese et al. 2007; Schiff et al. 2005; Weissenborn et al. 2005). One could easily imagine that these mild, but detectable neurological-psychiatric abnormalities, may be due to confounders (previous alcohol misuse, hepatitis C infection, cerebrovascular disease in metabolic cirrhosis or diabetes, malnutrition, poor sleep, drugs, fatigue or infection) (Campagna et al. 2015). Alternatively, they may simply reflect a degree of

encephalopathy that is not severe enough to exceed presently accepted threshold of normality, however worthwhile to be considered for treatment. This issue is relevant also in relation to transplantation. Further study of the unimpaired status in cirrhosis, within the model proposed in Fig. 2, may also provide a useful frame for the interpretation of recently published data on HE predisposition (Cordoba et al. 2014), so-called persistence of cognitive impairment after overt HE (Bajaj et al. 2010; Riggio et al. 2011), and post-transplant performance (Campagna et al. 2014; Sotil et al. 2009). Presently, placebo controlled trials will be ethically acceptable in patients without overt HE. Reasonable end point will be the occurrence of episodes of overt HE, health related quality of life of patients and caregivers, ability to perform real life tasks, or even the slowdown of the process of cirrhosis decompensation. The last item is reasonable because many of the procedures to treat or prevent HE modulate gut microbiota and current evidence suggests that gut dysbiosis may be both the consequence of liver failure and a concause of its progression via low grade inflammation, endotoxaemia and increased risk for infections (Goel et al. 2014). Four armed trials comparing disaccharides, rifaximin, selective probiotics and placebo would probably answer a lot of questions currently not yet resolved, even if the possibility to find resources for such studies is doubtful. Another reasonable aim, as previously mentioned, will be the utility of combined treatments, or individually tailored treatments. Clinical trials are usually designed around outcomes which reflect the efficacy of the treatments under investigation. However, health economic evaluation is increasingly required before new therapies are adopted. An understanding of health economic outcome measures is therefore beneficial for the

Fig. 2 Possible interpretations of persistence of cognitive dysfunction after liver transplantation or bouts of overt HE. Top panel: a young individual, with a good level of education and good baseline cognitive performance becomes ill with cirrhosis, he/she is likely to tolerate encephalopathogenic toxins well, developing no HE -or maybe minimal HE-. If this same subject is then transplanted, he/she likely returns to his/ her good baseline performance. Bottom panel: an older patient, with limited education/intellectual stimulation, who has been a heavy drinker

and is also overweight and diabetic, becomes ill with cirrhosis, his/her brain may be frailer, and encephalopathogenic toxins less tolerated, with a higher likelihood of overt HE. If this same patient is then transplanted, the best that can be expected is a return to their own, compromised baseline performance. These frailer individuals may also be more prone to posttransplant neurological/psychiatric dysfunction due to surgery, admission into intensive care, and immunosuppressant drugs.

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design and execution of clinical trials. This is particularly relevant in HE where accurate health economic evaluation can be challenging. There are two key types of health economic evaluation: Cost Effectiveness Analysis and Cost Utility Analysis. Cost Effectiveness Analysis expresses cost in terms of natural outcome units relevant to the condition being studied and is, therefore, useful when different treatments for the same condition are being compared. However, strategic health bodies need to compare treatments for different conditions across the whole health system, therefore a standard outcome measure is required (Drummond et al. 2005). Cost Utility Analysis aims to respond to this later issue. Quality Adjusted Life Years (QALYs) are used as the outcome measure in Cost Utility Analyses. QALYs are calculated from health utilities: a measure of Health Related Quality of Life (HRQOL) expressed on a 0 to 1 scale where 1 represents perfect health and 0 represents death (Briggs et al. 2006). QALYs are calculated as the product of health utilities and time in years such that they will reflect improvements in both HRQOL and longevity (Fig. 3).

Fig. 3 On the top (a): In Cost Utility Analysis, health utilities are used to measure patient health-related quality of life on a 0 to 1 scale. When plotted against time, the area under the curve gives Quality Adjusted Life Years. Comparing two different treatments (1 and 2) allows QALYs gained to be calculated from which Incremental Cost Effectiveness Ratios (ICERs) can be calculated using the costs of treatment in terms of cost per QALY gained (adapted from [1]). On the bottom (b): Clinical course of HE, illustrated in black, shows the quality of life impairment which may be associated with Overt HE. Measurement of health utilities only between episodes of overt HE is likely to lead to an overestimation of quality of life and hence QALYs (grey area)

There are different methods for the derivation of Health Utilities, split into direct and indirect methods. Direct methods can be derived by patients or members of the public while indirect methods tend to be patient-derived from questionnaire-based tools including generic preference (e.g. HUI, EQ-5D and SF6D) and disease-specific instruments(Gray and Clarke, 2011; Morris et al. 2007). The method chosen for derivation of health utilities is vitally important because utility values can vary considerably depending on the method and using an inappropriate method can result in the rejection of the Cost Utility Analysis generated. This is exemplified by the recent appraisal of rifaximin-α for hepatic encephalopathy by the UK’s National Institute for Health Care Excellence (NICE). The initial submission used utilities derived from members of the public, but concern was raised that the estimation of utilities from the general public may be unreliable. Instead, it was recommended that patient-derived HRQOL data collected as part of the pivotal Randomised Controlled Trial (RCT) (Bass et al. 2010) be used in the analysis (NICE 2015). A subsequent submission was made using health utilities derived from the Chronic Liver Disease Questionnaire (CLDQ) data (Berni et al. 2014) collected during the RCT (Sanyal et al. 2011). While the CLDQ is a widely accepted liver disease-specific HRQOL tool (Orr et al. 2014) there is no established method for converting these indices into utility scores. For this reason NICE concluded that Bthe methodology used… to estimate utilities was not appropriate^. Rather, it was suggested that health utilities could have been derived from unpublished SF-36 data which was also collected during the RCT (NICE 2015). SF-36, a widely-used generic HRQOL measure, has the advantage of well-established methodologies for the generation of utility scores (Brazier et al. 2002; Rowen et al. 2009). A final challenge in the design of clinical trials in HE, highlighted by the rifaximin appraisal, is the difficulty recording the HRQOL impacts of an overt episode of HE using patient reported outcome measures. If the HRQOL measures used to derive health utilities are carried out only between overt episodes (as was the case in the RCT of rifaximin-α) it is likely that the HRQOL impacts of the condition will be underestimated (Fig. 3). There is an increasing need to demonstrate not only efficacy, but also cost-effectiveness, before a new therapy can be introduced into clinical practice. Careful consideration should be given to ensure that clinical trials include health economic evaluation. Cost Utility Analyses are widely used by strategic health bodies hence inclusion of a robust method for the derivation of health utilities, such as the patient-derived EQ-5D, should be strongly considered. Issues specific to HE, such as how best to measure the HRQOL impacts of overt HE, require further investigation. In conclusion, more rigorous methodology and terminology, allowing better phenotyping of patients and conditions will be useful both for assembly data across clinical centers and to provide clear concepts for cross fertilization between basic

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and clinical research. Concepts and tools used in neurology, psychiatry and health economics need to be translated into clinical research on HE, as well as more accurate techniques of risk assessment. Therapeutic strategies combining multiple targets of the pathophysiological mechanisms leading to encephalopathy are rational aims both for basic and clinical research.

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