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Redefinition of Fatty Liver Disease from NAFLD to MAFLD through the Lens of Drug Development and Regulatory Science

  • Yasser Fouad1,*,
  • Melissa Palmer2,3,
  • Minjun Chen4,
  • Arie Regev5,
  • Rajarshi Banerjee6,
  • Rob Myers7,
  • Robert Riccio8,
  • Richard Torstenson9,
  • Ramy Younes10,
  • Puneet S. Arora11,
  • Henrik Landgren12,
  • Morten A. Karsdal13,
  • Martin Blake14,
  • David A. Shapiro15,
  • Hans-Juergen Gruss8,
  • Muhammad Y. Sheikh16,
  • Dina Attia17,
  • Steven Bollipo18,19,
  • Alastair D. Smith8,
  • Bradley Freilich20,
  • Robert G. Gish21 and
  • Detlef Schuppan22,23,*
 Author information
Journal of Clinical and Translational Hepatology 2021

DOI: 10.14218/JCTH.2021.00408

Abstract

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) affects a third of the population and is a leading cause of liver-related death. Since no effective treatments exist, novel approaches to drug development are required. Unfortunately, outdated terminology and definitions of the disease are hampering efforts to develop new drugs and treatments. An international consensus panel has put forth an influential proposal for the disease to be renamed from nonalcoholic fatty liver disease (NAFLD) to MAFLD, including a proposal for how the disease should be diagnosed. As allies with the many stakeholders in MAFLD care―including patients, patients’ advocates, clinicians, researchers, nurse and allied health groups, regional societies, and others―we are aware of the negative consequences of the NAFLD term and definition. We share the sense of urgency for change and will act in new ways to achieve our goals. Although there is much work to be done to overcome clinical inertia and reverse worrisome recent trends, the MAFLD initiative provides a firm foundation to build on. It provides a roadmap for moving forward toward more efficient care and affordable, sustainable drug and device innovation in MAFLD care. We hope it will bring promising new opportunities for a brighter future for MAFLD care and improve care and outcomes for patients of one of the globe’s largest and costliest public health burdens. From this viewpoint, we have revisited this initiative through the perspectives of drug development and regulatory science.

Keywords

NAFLD, MAFLD, NASH, Fatty liver disease, Liver, Fibrosis

Introduction

Despite the global shift in the burden of disease from viral hepatitis toward nonalcoholic fatty liver disease (NAFLD), high morbidity and mortality is still experienced by these patients. It is a leading cause of liver transplants and hepatocellular carcinoma, and it is associated with exorbitant healthcare costs. At this time, there are no approved medications for it.1 This is sobering, given the sharp contrast with the great victories that hepatology has witnessed in the treatment of viral hepatitis or as compared to other related metabolic diseases, such as type 2 diabetes and cardiovascular diseases, which have witnessed substantial evolution over the past few decades with the introduction of multiple new drug classes to the treatment landscape.

The rising prevalence of NAFLD and the lack of treatments has prompted many pharmaceutical companies to pursue novel treatments for this disease, with a significant escalation in drug development and randomized controlled trials in NAFLD.2 However, most phase 2b and phase 3 studies have shown no or a modest margin of benefit. This has led many experts to wonder why so many NAFLD clinical trials fail.3,4 In addition, recruiting patients for these clinical trials is difficult, with high screening failure rates. For those trials relying on histology for enrollment, it is even more challenging. This complicated situation has a serious negative impact on the process of drug development for NAFLD.

Using NAFLD as a definition for fatty liver disease has unique limitations. First is the limited awareness of the NAFLD term. Second is that inclusion of patients into clinical trials is based on histologic grading and staging, which affects patient recruitment since NAFLD is a much broader disease when imaging or elevated liver tests may signal this disease. Third, the diagnosis of the disease, which relies solely on “exclusion,” has a negative impact on case definition and target population when alcohol use and alcohol use disorder is a widely prevalent pair of conditions. Lastly, healthcare providers often do not consider the impact of the heterogeneity of the fatty liver disease on diagnostics modalities and therapeutic interventions. The adoption of a one-size-fits-all approach for such a heterogeneous liver disease is likely to be defective. Patient stratifications and examination for overlap of disease states are needed to prevent suboptimal performance of the investigational targets in clinical trials (Fig. 1).

Negative implications of the <italic>NAFLD</italic> term and definition on patients’ recruitment and retention in clinical trials.
Fig. 1  Negative implications of the NAFLD term and definition on patients’ recruitment and retention in clinical trials.

In order for advancement to be achieved in the treatment of this disease, it is crucial to integrate multiple stakeholder efforts that involve the hepatology community, advocacy groups, regulatory agencies, patients, and pharmaceutical companies. Together, they need to find novel solutions to the problems posed above and apply innovative strategies for more effective clinical trial design. Recently, an international consensus panel put forth a novel redefinition for fatty liver disease, including shifting the name of the disease from NAFLD to MAFLD, as a new and more appropriate nomenclature, and providing a positive and inclusive set of diagnostic criteria of the disease to replace the previous exclusion-based set of diagnostic criteria.46 The proposal is generating momentum, with support from numerous liver regional societies, patients’ advocacy groups, and nursing experts.717 In addition, multiple studies have revealed the utility of these criteria in identifying patients with significant hepatic fibrosis, cardiovascular disease, and chronic kidney disease.1820

Here, we intend to provide the readers with a viewpoint on this change through the lens of drug development and regulatory science. We will first discuss the challenges with the definition of the disease, then the failure of nonalcoholic steatohepatitis (NASH) trials, and lastly, we will cover how the new term and definition will improve outcomes for clinical trials and patients.

NAFLD term and definition: How does it impact patient recruitment?

There is universal recognition that patient recruitment is a predeterminate of success for clinical trials. A recent analysis of registered trials showed that 19% of clinical trials were closed or terminated early because they could not accrue enough participants.21 Even if trials do progress, they may experience significant delays due to difficulties in recruiting enough patients. Data suggest that despite the enormous patient population of those with NASH, the average rate of enrollment for NASH studies in the USA and Europe is just 0.1 patients per site, per month.22 This impacts on huge time and cost challenges and has important consequences.

At least four major barriers arising out the previous nomenclature NAFLD/NASH are identified to contribute to this low recruitment rate: (1) patients’ low awareness of NASH and physician underestimation of patient population; (2) necessity of a liver biopsy, which has to show specific histological characteristic to diagnose NASH; (3) impact of the NAFLD-related stigma, which detracts from the expansion of recruitment centers geographically; and (4) impact on building networks with other metabolic diseases with a high risk of NASH. One way to achieve the required trial enrollment numbers is to be strategic, creative, and thorough in effecting a paradigm shift that will change current approaches.

Low awareness of NASH

Of the challenges that pharmaceutical companies face in enrolling patients into NASH studies, the biggest is the lack of awareness of the disease, even among patients most at risk, those with metabolic abnormalities, such as type 2 diabetes, obesity, and hypertension.2326 Patients do not perceive the disease as a health challenge. A recent study showed that more than 80% of patients indicated they would not be concerned if they were diagnosed with NAFLD and would undertake no actions. For comparison, more than 90% of these patients indicated they would be very concerned if they were diagnosed with either hepatitis C or diabetes.27 Worryingly, many physicians are also skeptical about the significance of NAFLD, and they do not perceive it as a priority in primary care,28 which leads to underdiagnosing NAFLD in real-world settings.29,30 This suggests that healthcare providers find the current term for the disease hard to articulate or explain to patients, partly because it has a certain stigma.12 In order to overcome this stigma and uneasiness in discussing the disease, over 30 patient advocacy groups across different disciplines―including liver, renal, diabetes, and obesity―have expressed their support to the MAFLD proposal to overcome these limitations.

NASH and the necessity for biopsy and histology scoring

A major barrier that hinders drug development and effective management of NAFLD is the necessity for liver histology, obtained through liver biopsy, for the diagnosis of NASH and to determine response to different therapeutic agents. This contrasts with type 2 diabetes, for example, where a simple blood test (i.e. HbA1c) is used to establish the diagnosis and assess treatment response.

Beside the technical problems with liver biopsy, including the relatively small tissue size and possibility for sampling error, the procedure is unpleasant for the patient, costly, and carries a risk of rare but potentially life-threatening complications. All of these challenges limit the use of liver biopsy as a tool for mass screening of patients.

Histology scoring of NAFLD involves the quantification of a qualitative assessment of the histology sample. For example, the scoring of balloon cells in the widely used NASH Clinical Research Network (CRN) system uses a 2-point score (as opposed to a 3-point score for steatosis or steatohepatitis) that does not specify the area (e.g., number of high-power fields) that need to be examined for the evaluation.31 Perhaps unsurprisingly, when the utility of NASH histology scoring in practice was recently evaluated in the EMMINENCE trial, both the inter- and intra-expert reader correlations were low. Inter-reader kappa scores ranged from 0.37 to 0.61, and intra-reader-weighted kappa scores ranged from 0.23 to 0.88. In addition, nearly half (46%) of patients whose qualifying histology scores were judged by at least one of three other readers did not meet the study histologic entry criteria as originally determined by a single reader. As the authors note, such inconsistencies in histologic reading diminish the apparent efficacy for a therapeutic drug.32

It has been reported that only a minority (less than 25%) of academic gastroenterologists and hepatologists in the USA routinely perform liver biopsies in patients with presumed NASH.33 A 2020 study in Germany showed that the biopsy rate of patients with NAFLD presenting at outpatient unit was low (13.6%).34 Similarly, two recent studies in Egypt showed that over 95% of patients will decline liver biopsy to assess for NASH if they are asked, as they believe the disease is not serious.27 Over 90% of physicians indicated that the acceptance rate for liver biopsy is substantially lower in patients with NAFLD as compared to that in patients with hepatitis C.35 This indicates that the low acceptance rate for liver biopsy is a widespread phenomenon, regardless of the cultural background of the patient.

Patients enrolled in phase 3 clinical trials for NASH are usually required to have a NAFLD activity score (NAS) of 4 or higher and a fibrosis stage of F2 or higher by liver biopsy according to the NASH CRN. However, approximately half of the screened individuals fail to meet these eligibility criteria.36,37 In the FLINT and REGENERATE trials for individuals with non-cirrhotic NASH histology, this was the most important selection criterion, with 71% of pre-selected study candidates being excluded because they did not have a NAFLD NAS of 4 or higher and 63% of pre-selected study candidates being excluded because they did not have a fibrosis stage of F2 or higher.38,39

In addition, the current histological endpoints of NASH clinical trials require both resolution of NASH without worsening of fibrosis and improvement of fibrosis without worsening of NASH during the treatment phase.40 This implies the need for two liver biopsies within a 48- to 72-week period. Given the exclusion criteria of NAFLD, liver biopsy is also performed to rule out other differential diagnoses just to make the diagnosis of NAFLD.

Histological baseline criteria and the need for two liver biopsies represent the major hurdles for the recruitment of patients in clinical trials and could lead to selection bias, as individuals who make it through the hurdles might be not representative of the total NAFLD patient population. It is, therefore, crucial to identify efficient noninvasive parameters. Although we have many good markers for fibrosis, fat, and inflammation, and imaging modalities for fibrosis, it may take two, three, or four studies to focus on an implied histological diagnosis.4143 We have many noninvasive markers for NASH, yet none are accepted by the USA Food and Drug Administration (FDA) or European Medicines Agency (EMA) for phase 2b and 3 trials, which still require two liver biopsies.43 In addition, it is still a nonvalidated surrogate endpoint that is “likely” to anticipate clinical benefit (i.e. how a patient feels, functions, and survive). The implication being that registrational studies still need to have the phase 3/phase 4 design, which adds further complexity.

Fibrosis is the major determinant of liver-related complications and mortality.44 Fibroblast activity drives fibrosis progression, organ function loss, and comorbidities.45 The fibroblast is the principle promoter of extracellular matrix, which is expanded in all fibrotic disorders.46 The fibrotic extracellular matrix consists mainly of collagens, which are produced by activated fibroblasts. This is important, independent of insults, as there are serological biomarkers that may quantify the overall fibrotic activity, which drives progression, independent of insult, and can objectively quantify the level of activity. All of this may be associated with outcome, response to treatment, and thus the quality of life of patients. For example, type III collagen, either quantified by N-terminal pro-peptide of type III collagen (PIIINP) or type III procollagen (PRO-C3),47 have been directly associated with fibroblast activity, which predicts fibrosis progression,48 response to therapy,49 and relation to fibrosis stage in algorithms such as the ADAPT score (Age, presence of DiAbetes, PRO-C3 [a marker of type III collagen formation], and plateleT count).41 Elevated levels of type III collagen formation is the common denominator in most fibrotic diseases and have been reported in hepatitis B,50 hepatitis C,51 MAFLD,4143 idiopathic pulmonary fibrosis,52 systemic sclerosis,53 and chronic kidney disease.54

Limited geography and site location

To access the required number of patients for developing large clinical trials, recruitment outside of traditional Western markets would be required. Despite its large population and having the highest prevalence of NAFLD worldwide,1,11 the Middle East North Africa (MENA) region has not been considered in most NAFLD clinical trials. The disease remains substantially underdiagnosed in the region, due to the severe social stigma associated with the word alcohol in the NAFLD term.1113

There are many preferential advantages for recruitment in the MENA region. These include the projected higher recruitment rate because of the large general population, and the productivity estimated as aggregated average number of patients per site is approximately 2-fold higher in the MENA region than developed markets in the West.55 The MENA region has shown great capacity for drug development in the era of hepatitis C trials. Additionally, the patients in this region are typically study-naïve and are not recruited in competing clinical trials.56 The costs of conducting a trial are usually considerably lower in the MENA region (including costs for selection of a trial site and patient enrollment compared to Western countries). The unique different ethnicities, the geographic isolation of subpopulations, and the high rate of consanguineous marriages suggest the region can contribute its distinctive gene pool of the MENA region to research.56 Finally, the pharmaceutical market in the Middle East combined with Africa has one of the highest growth rates globally.57 These numbers and reasons reflect that the region has a sizable population and unique opportunity not yet tapped. Overcoming the challenge of the NAFLD term would open new horizons for the market of drug development for fatty liver disease.

No link to other metabolic diseases

One of the major problems with the current NAFLD term is that it implies no link with metabolic diseases. Many stakeholders cite this as a barrier for educating healthcare providers outside of the hepatology community on NAFLD/NASH and for integrating NAFLD/NASH into public health policies and action plans on obesity and other related metabolic conditions.12 The current NAFLD term and definition presents a barrier to diagnosis in primary care and non-hepatology settings, particularly in resource-constrained health systems.

Failure of so many NASH trials: Are current structures designed to fail?

Recent, largely negative, trials beg the question: why do so many NASH trials fail?3,4 (Table 1).

Table 1

Some medications tested in phase 3 clinical trials for NASH

MedicationsConditions for treatmentCurrent status in phase III trials
Obeticholic acidFibrosis due to NASHActive; not recruiting
SelonsertibNASH and fibrosisTerminated
CenicrivirocNASHTerminated
ElafibranorNASH with fibrosisTerminated
RimonabantNASH without diabetesTerminated
PentoxifyllineNASHCompleted
ResmetiromNASH and fibrosisRecruiting

Apart from generic concerns in trial design, various reasons for failure are specific to the definition of the disease.

Relying on outdated case definitions

Prevention of cirrhosis and demonstrating a positive effect on well-defined liver outcomes are key clinical goals when considering a NASH drug development program. Therefore, for trials aiming to support a marketing application, it is important that patients with the greatest risk of progression to cirrhosis be enrolled. Among individual features, liver fibrosis has proven the best independent association with liver-related mortality.44 The MAFLD new definition could identify patients at the highest risk of fibrosis, unlike the current NAFLD definition, which does not help identify the right target population.

Relying on histology rather than disease drivers

One of the main issues with the current definition of the disease is that phase 2b and 3 trial recruitment is based on histologic grading and staging.4 Because many pathways can lead to the same histologic stage, dissection of the predominant pathogenic pathways or the target pathway of the drug (and the stage of the disease at which it is administered) are needed.58,59 Unfortunately, stratifications based on NASH dichotomization do not recognize where an individual patient lies in this pathogenic continuum within liver injury. Due to the differing manifestations of NAFLD, several classes of drugs are required for NAFLD that can be tailored with personalized medicine for patients across the entire continuum of the disease.

Relying on a one-size-fits-all approach

The heterogeneous nature of fatty liver diseases suggest that they cannot be conceptualized as a single entity and managed using a one-size-fits-all strategy.4 Not considering heterogeneity, particularly for metabolic comorbidities may affect treatment response and may interfere with the ability to aptly select patients for clinical trials and evaluate therapeutic drugs. For instance, in the CENTAUR study, cenicriviroc showed a substantial variation in achieving the histologic endpoints in the diabetic groups compared to non-diabetic groups.60 Similarly, in the FLINT trial, the effect of obeticholic acid was negatively affected by baseline hypertriglyceridemia.61

In addition, the disease heterogeneity may also affect the performance of non-invasive fibrosis diagnostic tools such as the NAFLD fibrosis score (NFS), fibrosis 4 index (FIB-4), transient elastography liver stiffness measurement (LSM), and controlled attenuation parameter (CAP), which may vary across the lifespan and between different ethnic populations, and in special subpopulations such as patients with diabetes or those who are obese.62,63

To overcome the challenges described earlier, a stratified randomization approach, may be needed. Such an approach will require new definitions of the disease to be developed that pave the way for patient stratification (Fig. 2).

One-size-fits-all approach of clinical trials in the era of <italic>NAFLD</italic> and proposed personalized trials in the era of MAFLD.
Fig. 2  One-size-fits-all approach of clinical trials in the era of NAFLD and proposed personalized trials in the era of MAFLD.

MAFLD term and definition: New solutions to fatty liver disease’s challenging questions

To change the paradigm in NAFLD/NASH, a novel approach is needed. Embracing real-world evidence and interrogating multiple stakeholders for their views (particularly patients) will allow us to better identify undiagnosed patients, engage primary care providers and non-hepatologists, and create market access and networking strategies that make sense for fatty liver diseases and the patients they affect.

To overcome these challenges, in 2020, an international consortium of 32 experts from 22 countries put forth an influential proposal to update the nomenclature of fatty liver disease associated with metabolic dysfunction from NAFLD to MAFLD. They also formulated a novel set of positive diagnostic criteria to replace the previous negative criteria.4,5 We strongly believe that a transformational change from NAFLD to MAFLD,4,5 with the accompanied new definition of the disease, will be an important initial step in achieving this and may circumvent many challenges faced in the era of NAFLD use.

Improve case detection and identification of target population

Emerging evidence shows that the diagnostic criteria in the MAFLD definition identify patients with significant hepatic fibrosis, cardiovascular disease, or chronic kidney disease,1820,64 and those who would benefit from evaluating genetic risks for fatty liver65 better than the previous NAFLD criteria. The utility of the MAFLD criteria have also been shown in patients with other diseases such as hepatitis B,66 hepatitis C,67,68 human immunodeficiency virus,69 celiac disease,70 Gaucher disease,71 and myotonic dystrophy type 1,72 which need to be excluded to diagnose NAFLD. Not being able to concomitantly diagnose NAFLD and these diseases is another disadvantage to using the NAFLD definition since alcohol and these conditions are excluded, by definition!

Enhance patient recruitment

To overcome the limitation of recruitment, new tools and strategies are needed to more efficiently recruit patients. The correction of terminology may bring MAFLD to the visibility of other metabolic diseases.12 Shifting to the MAFLD term and definition would enable a recruitment strategy to focus on patients with high risk factors and/or diagnosis. This model allows active engagement of diverse stakeholders and the building of an innovation network that would help to identify the large pool of patients with comorbidities such as obesity, type 2 diabetes, or other cardiovascular disease risk factors, who are at a greater risk for NAFLD/NASH. A recent study showed that changing from using NAFLD to MAFLD increased awareness of the disease among primary care providers and physicians in other specialties,35 which can increase trial enrollment rates. Two other studies have demonstrated improved patient awareness with the new term MAFLD.27,73

Use of this new term could lead to efforts to include MAFLD in public health policies and action plans on other related conditions and to launch shared health promotion campaigns. This would allow for establishing new multidisciplinary models of care and teams for MAFLD and foster the development of cross-specialty guidelines to help implement multidisciplinary care in practice.

As recently suggested by the Latin American Association for the Study of the Liver (ALEH), Chinese Society of Hepatology and the Sub-Saharan Africa position statement,9,14,16 simplification of the diagnosis of MAFLD would facilitate the education of primary care providers on MAFLD and develop clear care pathways. This would encourage more effective diagnosis at the community level and the screening of high-risk individuals for MAFLD in primary care and non-hepatology settings, with more efficient and likely cost-effective referral pathways. This would be crucial particularly in resource-constrained health systems.

Such change would enable an expansion of geographic regions for recruiting sites to areas such as MENA and Africa that are not considered at the moment. Based on the conceptualized diagnostic criteria of MAFLD and the reality of the real-world patient landscape, with the high prevalence of MAFLD and alcohol intake worldwide, we may need to consider a more pragmatic approach to target patients with MAFLD with potentially a higher threshold of alcohol intake than used in the past.

Setting definitions for MAFLD based on “positive” criteria and excluding patients with fatty liver unrelated to metabolic dysfunction (with fatty liver but not MAFLD) will render study cohorts more homogeneous, increasing the likelihood of detecting a significant impact on clinical approaches targeting MAFLD.

Improve assessment of drug efficacy

Relying on biopsies makes diagnosing NASH a difficult task for physicians and patients, and it likely complicates the assessment of drug efficacy. Recent studies have raised concerns that the suboptimal reliability of liver biopsy evaluations is having a negative impact on clinical trials.32 This is usually more profound with pathological assessment of NASH compared to fibrosis. There is tremendous plasticity in metabolic liver disease over the life span, and patients can fluctuate from steatosis to NASH and vice versa over short spans of time, with a strong evidence that fibrosis is the major determinant of adverse outcomes.44 To use an analogy, assessment of NASH is like measuring blood glucose in diabetes, while fibrosis is like measuring HbA1c. These factors create serious obstacles for pharmaceutical companies and clinical researchers working to develop treatments for this condition.

Again, redefinition of the disease and considering the disease as a continuum that can be assessed similar to other chronic liver diseases (with some activity and a stage of fibrosis) would help. It would refocus the attention to the need for identification and approval of drugs for the whole spectrum of the disease, as currently exists to treat hypertension or diabetes.

Create novel clinical trial design

The population of patients with MAFLD is diverse and complex.4 The proposed change to using the term MAFLD and its new definition would allow the consideration of alternative and innovative trial designs, such as umbrella, basket, and adaptive designs that could circumvent the aforementioned challenges.

Umbrella trial designs or master protocols allow multiple questions to be assessed and different drugs to be investigated in different conditions (more than one patient subtype or disease), within the same overall trial structure.74 Emerging evidence suggest the presence of subtypes of MAFLD based on the diagnostic criteria; for example, those who meet the overweight/obesity criterion having different characteristics from those who meet the diabetes criterion.20

Basket trials include designs to evaluate a particular drug for multiple diseases that share similar features or pathways (e.g., MAFLD, cardiovascular disease, and type 2 diabetes mellitus), paving the way for clinical trials for shared metabolic diseases.

Adaptive trial designs provide flexibility to adapt one or more aspects of the basic features of the study design based on early findings,75 for example include more patients with diabetes or hyperlipidemia, if early interim analysis shows efficacy in this group (Fig. 3).

Redefinition of fatty liver disease from <italic>NAFLD</italic> to <italic>MAFLD</italic> can guide drug repurposing in fatty liver disease.
Fig. 3  Redefinition of fatty liver disease from NAFLD to MAFLD can guide drug repurposing in fatty liver disease.

MAFLD is a multisystem disease with links to other metabolic disorders, such as diabetes, cardiovascular disease, and chronic kidney disease. MAFLD will bring fatty liver disease closer to other metabolic diseases and enhance understanding of the shared pathways and phenotypes between MAFLD and these related metabolic disorders that are usually investigated in larger cohorts, which can ultimately help in drug repurposing.

The importance of renaming NAFLD to MAFLD for the pediatric population

NAFLD occurs in approximately 40% of obese children and adolescents and in up to 10% of the general pediatric population.7678 The pathophysiology of NAFLD/NASH in children is complex and multifactorial, may begin in utero, and is different from adult disease.7982 But there are similarities to adults with NAFLD; children often have insulin resistance, central or generalized obesity, and dyslipidemia and are at increased risk of cardiovascular disease,83 renal disorders,84 and obstructive sleep apnea. As with NAFLD in adults, treatment is limited to lifestyle modification, which is rarely sustainable.

Despite the increased prevalence, its seriousness, and the unmet medical need of patients with pediatric NAFLD, very few clinical trials have been or are being conducted in this population. This starkly contrasts with the explosion of clinical trials available to adults with NAFLD/NASH. Presently on clinicaltrials.gov, there are no actively recruiting industry-sponsored interventional, multicenter, placebo-controlled clinical trials for pediatric NAFLD.

Thus, the term NAFLD may be an important contributing factor to this discrepancy, as this term is an even greater misnomer in children than in adults. First, excessive alcohol use, especially in younger children, is rarely a contributing factor or a consideration when assessing the etiology of a fatty liver, and second, inherited metabolic disorders often resemble and/or may also occur with NAFLD.85 Using the term nonalcoholic when referring to a pediatric patient with a fatty liver is not only usually inaccurate, it is also likely to be a source of confusion to the family. This may be an important factor contributing to the difficulties in recruiting a pediatric NAFLD/NASH trial. When discussing a child’s diagnosis and potential trial participation, using the term MAFLD would likely be easier for the family to understand and to accept, and it may generate increased interest in clinical trial participation. Recent suggestions from experts encourage the change from NAFLD to MAFLD.85

The prevalence of pediatric obesity is increasing at alarming rates. Using body mass index alone has become a less accurate means for distinguishing NAFLD from an underlying inherited metabolic disorder as the etiology of a fatty liver.85 Notably, recently, a novel set of diagnostic criteria for pediatric MAFLD was released.6

Conclusions

In this work, we revisited the redefinition of fatty liver disease through the perspective of drug development and regulatory science. As allies with the many stakeholders in MAFLD healthcare―including patients, patients’ advocates, clinicians, researchers, nursing and allied health groups, regional societies, and others―we share the sense of urgency for change and will act in new ways to achieve our goals. Although there is much work to be done to overcome clinical inertia and reverse worrisome recent trends,86 we believe that the MAFLD initiative provides a firm foundation to build on. It provides a roadmap for moving forward on more efficient care and affordable, sustainable drug and device innovation in MAFLD care. We hope it will bring promising new opportunities for a brighter future for MAFLD care and improve care and outcomes for patients of one of the globe’s largest and costliest public health burdens.

Abbreviations

ADAPT: 

age, presence of diabetes, PRO-C3, and platelet count

ALEH: 

Latin American Association for the Study of the Liver

CAP: 

controlled attenuation parameter

CRN: 

Clinical Research Network

EMA: 

European Medicines Agency

FDA: 

USA Food and Drug Administration

FIB-4: 

fibrosis 4 index

LSM: 

liver stiffness measurement

MAFLD: 

metabolic associated fatty liver disease

MENA: 

Middle East North Africa

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

NAS: 

NAFLD activity score

PIIINP: 

N-terminal pro-peptide of type III collagen

PRO-C3: 

type III procollagen

Declarations

Acknowledgement

We thank Kelly Schrank, MA, ELS, of Bookworm Editing Services LLC for her editorial services in preparing the manuscript for publication.

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication. The views presented in this article do not necessarily reflect those of the USA Food and Drug Administration. Any mention of commercial products is for clarification and is not intended as an endorsement.

Authors’ contributions

All authors contributed to the study conception and design, data collection, and writing, revision and providing approval of the manuscript. Drafting of the manuscript (YF).

References

  1. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15(1):11-20 View Article
  2. Eslam M, George J. Genetic insights for drug development in NAFLD. Trends Pharmacol Sci 2019;40(7):506-516 View Article
  3. Ratziu V, Friedman SL. Why do so many NASH trials fail?. Gastroenterology 2020:S0016-5085(20)30680-30686 View Article
  4. Eslam M, Sanyal AJ, George J. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158(7):1999-2014.e1 View Article
  5. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020;73(1):202-209 View Article
  6. Eslam M, Alkhouri N, Vajro P, Baumann U, Weiss R, Socha P, et al. Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Lancet Gastroenterol Hepatol 2021;6(10):864-873 View Article
  7. Romero-Gómez M, Ampuero J. Looking for a new name for non-alcoholic fatty liver disease in Spanish: esteatosis hepática metabólica (EHmet). Rev Esp Enferm Dig 2021;113(3):161-163 View Article
  8. Tan SS, Lee YY, Ali RAR, Mustapha F, Chan WK. Endorsing the redefinition of fatty liver disease. Lancet Gastroenterol Hepatol 2021;6(3):163 View Article
  9. Mendez-Sanchez N, Arrese M, Gadano A, Oliveira CP, Fassio E, Arab JP, et al. The Latin American Association for the Study of the Liver (ALEH) position statement on the redefinition of fatty liver disease. Lancet Gastroenterol Hepatol 2021;6(1):65-72 View Article
  10. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 2020;14(6):889-919 View Article
  11. Shiha G, Alswat K, Al Khatry M, Sharara AI, Örmeci N, Waked I, et al. Nomenclature and definition of metabolic-associated fatty liver disease: a consensus from the Middle East and north Africa. Lancet Gastroenterol Hepatol 2021;6(1):57-64 View Article
  12. Shiha G, Korenjak M, Eskridge W, Casanovas T, Velez-Moller P, Högström S, et al. Redefining fatty liver disease: an international patient perspective. Lancet Gastroenterol Hepatol 2021;6(1):73-79 View Article
  13. Fouad Y, Waked I, Bollipo S, Gomaa A, Ajlouni Y, Attia D. What’s in a name? Renaming ‘NAFLD’ to ‘MAFLD’. Liver Int 2020;40(6):1254-1261 View Article
  14. Spearman CW, Desalegn H, Ocama P, Awuku YA, Ojo O, Elsahhar M, et al. The sub-Saharan Africa position statement on the redefinition of fatty liver disease: From NAFLD to MAFLD. J Hepatol 2021;74(5):1256-1258 View Article
  15. Clayton M, Fabrellas N, Luo J, Alghamdi MG, Hafez A, Qadiri TA, et al. From NAFLD to MAFLD: Nurse and allied health perspective. Liver Int 2021;41(4):683-691 View Article
  16. Nan Y, An J, Bao J, Chen H, Chen Y, Ding H, et al. The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease. J Hepatol 2021;75(2):454-461 View Article
  17. Eslam M, Ahmed A, Després JP, Jha V, Halford JCG, Wei Chieh JT, et al. Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases. Lancet Gastroenterol Hepatol 2021;6(9):743-753 View Article
  18. Lee H, Lee YH, Kim SU, Kim HC. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: A nationwide cohort study. Clin Gastroenterol Hepatol 2021;19(10):2138-2147.e10 View Article
  19. Sun DQ, Jin Y, Wang TY, Zheng KI, Rios RS, Zhang HY, et al. MAFLD and risk of CKD. Metabolism 2021;115:154433 View Article
  20. Yamamura S, Eslam M, Kawaguchi T, Tsutsumi T, Nakano D, Yoshinaga S, et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int 2020;40(12):3018-3030 View Article
  21. Carlisle B, Kimmelman J, Ramsay T, MacKinnon N. Unsuccessful trial accrual and human subjects protections: an empirical analysis of recently closed trials. Clin Trials 2015;12(1):77-83 View Article
  22. The liver line. Available from: https://liverline.com/
  23. Cleveland ER, Ning H, Vos MB, Lewis CE, Rinella ME, Carr JJ, et al. Low Awareness of nonalcoholic fatty liver disease in a population-based cohort sample: the CARDIA study. J Gen Intern Med 2019;34(12):2772-2778 View Article
  24. Singh A, Dhaliwal AS, Singh S, Kumar A, Lopez R, Gupta M, et al. Awareness of nonalcoholic fatty liver disease is increasing but remains very low in a representative US cohort. Dig Dis Sci 2020;65(4):978-986 View Article
  25. Zhang W, Chao S, Chen S, Rao H, Huang R, Wei L, et al. Awareness and knowledge of nonalcoholic fatty liver disease among office employees in Beijing, China. Dig Dis Sci 2019;64(3):708-717 View Article
  26. Wieland AC, Mettler P, McDermott MT, Crane LA, Cicutto LC, Bambha KM. Low awareness of nonalcoholic fatty liver disease among patients at high metabolic risk. J Clin Gastroenterol 2015;49(1):e6-e10 View Article
  27. Alem SA, Gaber Y, Abdalla M, Said E, Fouad Y. Capturing patient experience: A qualitative study of change from NAFLD to MAFLD real-time feedback. J Hepatol 2021;74(5):1261-1262 View Article
  28. Wattacheril J, Chalasani N. Nonalcoholic fatty liver disease (NAFLD): is it really a serious condition?. Hepatology 2012;56(4):1580-1584 View Article
  29. Alexander M, Loomis AK, Fairburn-Beech J, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, et al. Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease. BMC Med 2018;16(1):130 View Article
  30. Standing HC, Jarvis H, Orr J, Exley C, Hudson M, Kaner E, et al. GPs’ experiences and perceptions of early detection of liver disease: a qualitative study in primary care. Br J Gen Pract 2018;68(676):e743-e749 View Article
  31. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41(6):1313-1321 View Article
  32. Davison BA, Harrison SA, Cotter G, Alkhouri N, Sanyal A, Edwards C, et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials. J Hepatol 2020;73(6):1322-1332 View Article
  33. Rinella ME, Lominadze Z, Loomba R, Charlton M, Neuschwander-Tetri BA, Caldwell SH, et al. Practice patterns in NAFLD and NASH: real life differs from published guidelines. Therap Adv Gastroenterol 2016;9(1):4-12 View Article
  34. Gerhardt F, Petroff D, Blank V, Böhlig A, van Bömmel F, Wittekind C, et al. Biopsy rate and nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD). Scand J Gastroenterol 2020;55(6):706-711 View Article
  35. Fouad Y, Gomaa A, Semida N, Ghany WA, Attia D. Change from NAFLD to MAFLD increases the awareness of fatty liver disease in primary care physicians and specialists. J Hepatol 2021;74(5):1254-1256 View Article
  36. Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology 2018;67(2):549-559 View Article
  37. Do A, Ilagan-Ying YC, Xu J, Lim JK. Low eligibility for phase 3 clinical trials in a real-life cohort with nonalcoholic steatohepatitis. Hepatology 2018;68(S1):1287A-1288A
  38. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019;394(10215):2184-2196 View Article
  39. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385(9972):956-965 View Article
  40. Omokero S. FDA regulatory considerations for NASH clinical trial endpoints. FDA 2018.
  41. Daniels SJ, Leeming DJ, Eslam M, Hashem AM, Nielsen MJ, Krag A, et al. ADAPT: An algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology 2019;69(3):1075-1086 View Article
  42. Eslam M, Wong GL, Hashem AM, Chan HL, Nielsen MJ, Leeming DJ, et al. A sequential algorithm combining ADAPT and liver stiffness can stage metabolic-associated fatty liver disease in hospital-based and primary care patients. Am J Gastroenterol 2021;116(5):984-993 View Article
  43. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology 2018;68(1):349-360 View Article
  44. Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: A multi-national cohort study. Gastroenterology 2018;155(2):443-457.e17 View Article
  45. Karsdal MA, Manon-Jensen T, Genovese F, Kristensen JH, Nielsen MJ, Sand JM, et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2015;308(10):G807-G830 View Article
  46. Karsdal MA, Nielsen SH, Leeming DJ, Langholm LL, Nielsen MJ, Manon-Jensen T, et al. The good and the bad collagens of fibrosis - Their role in signaling and organ function. Adv Drug Deliv Rev 2017;121:43-56 View Article
  47. Nielsen MJ, Nedergaard AF, Sun S, Veidal SS, Larsen L, Zheng Q, et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am J Transl Res 2013;5(3):303-315
  48. Huber Y, Pfirrmann D, Gebhardt I, Labenz C, Gehrke N, Straub BK, et al. Improvement of non-invasive markers of NAFLD from an individualised, web-based exercise program. Aliment Pharmacol Ther 2019;50(8):930-939 View Article
  49. Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018;391(10126):1174-1185 View Article
  50. Nielsen MJ, Karsdal MA, Kazankov K, Grønbaek H, Krag A, Leeming DJ, et al. Fibrosis is not just fibrosis - basement membrane modelling and collagen metabolism differs between hepatitis B- and C-induced injury. Aliment Pharmacol Ther 2016;44(11-12):1242-1252 View Article
  51. Laursen TL, Villesen IF, Leeming DJ, Karsdal MA, Sølund C, Tarp B, et al. Altered balance between collagen formation and degradation after successful direct-acting antiviral therapy of chronic hepatitis C. J Viral Hepat. 2021;28(2):236-244 View Article
  52. Organ LA, Duggan AR, Oballa E, Taggart SC, Simpson JK, Kang’ombe AR, et al. Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort. Respir Res 2019;20(1):148 View Article
  53. Chun SH, Chun J, Lee KY, Sung TJ. Effects of emergency cerclage on the neonatal outcomes of preterm twin pregnancies compared to preterm singleton pregnancies: A neonatal focus. PLoS One 2018;13(11):e0208136 View Article
  54. Pilemann-Lyberg S, Rasmussen DGK, Hansen TW, Tofte N, Winther SA, Holm Nielsen S, et al. Markers of collagen formation and degradation reflect renal function and predict adverse outcomes in patients with type 1 diabetes. Diabetes Care 2019;42(9):1760-1768 View Article
  55. Graff D. Shifting sands: An interest-relative theory of vagueness. Philosophical topics 2000;28:45-81
  56. Nair SC, Ibrahim H, Celentano DD. Clinical trials in the Middle East and North Africa (MENA) Region: grandstanding or grandeur?. Contemp Clin Trials 2013;36(2):704-710 View Article
  57. IMS Institute global use of medicines: outlook through 2016. Future Prescriber. ;14(1):10-12 View Article
  58. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016;65(8):1038-1048 View Article
  59. Skoien R, Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, et al. Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways. Liver Int 2013;33(4):624-632 View Article
  60. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 2018;67(5):1754-1767 View Article
  61. Loomba R, Sanyal AJ, Kowdley KV, Terrault N, Chalasani NP, Abdelmalek MF, et al. Factors associated with histologic response in adult patients with nonalcoholic steatohepatitis. Gastroenterology 2019;156(1):88-95.e5 View Article
  62. McPherson S, Hardy T, Dufour JF, Petta S, Romero-Gomez M, Allison M, et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol 2017;112(5):740-751 View Article
  63. De Silva S, Li W, Kemos P, Brindley JH, Mecci J, Samsuddin S, et al. Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of South Asian descent. Frontline Gastroenterol 2018;9(2):115-121 View Article
  64. Tsutsumi T, Eslam M, Kawaguchi T, Yamamura S, Kawaguchi A, Nakano D, et al. MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach. Hepatol Res 2021 View Article
  65. Xia M, Zeng H, Wang S, Tang H, Gao X. Insights into contribution of genetic variants towards the susceptibility of MAFLD revealed by the NMR-based lipoprotein profiling. J Hepatol 2021;74(4):974-977 View Article
  66. Mak LY, Yuen MF, Seto WK. Letter regarding “A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement”. J Hepatol 2020;73(6):1573-1574 View Article
  67. Fouad Y, Saad ZM, Moeness HM, Abdel-Raheem EM, Abdelghani Y, Osman NM, et al. Clinical validity of the diagnostic criteria for metabolic-associated fatty liver disease: a real-world experience. medRxiv 2020 View Article
  68. Al Omary A, Byth K, Weltman M, George J, Eslam M. Metabolic-associated fatty liver disease increases fbrosis severity in patients with chronic hepatitis C. J Gastroenterol Hepatol. 2020;35(S1):44-45
  69. Jongraksak T, Sobhonslidsuk A, Jatchavala J, Warodomwichit D, Kaewduang P, Sungkanuparph S. Prevalence and predicting factors of metabolic-associated fatty liver disease diagnosed by transient elastography with controlled attenuation parameters in HIV-positive people. Int J STD AIDS 2021;32(3):266-275 View Article
  70. Rispo A, Imperatore N, Guarino M, Tortora R, Alisi A, Cossiga V, et al. Metabolic-associated fatty liver disease (MAFLD) in coeliac disease. Liver Int 2021;41(4):788-798 View Article
  71. Nascimbeni F, Lugari S, Cassinerio E, Motta I, Cavicchioli A, Dalla Salda A, et al. Liver steatosis is highly prevalent and is associated with metabolic risk factors and liver fibrosis in adult patients with type 1 Gaucher disease. Liver Int 2020;40(12):3061-3070 View Article
  72. Miele L, Perna A, Dajko M, Zocco MA, De Magistris A, Nicoletti TF, et al. Clinical characteristics of metabolic associated fatty liver disease (MAFLD) in subjects with myotonic dystrophy type 1 (DM1). Dig Liver Dis 2021:S1590-8658(20)31092-6 View Article
  73. Méndez-Sánchez N, Díaz-Orozco L, Córdova-Gallardo J. Redefinition of fatty liver disease from NAFLD to MAFLD raised disease awareness: Mexican experience. J Hepatol 2021;75(1):221-222 View Article
  74. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med 2017;377(1):62-70 View Article
  75. Bhatt DL, Mehta C. Adaptive designs for clinical trials. N Engl J Med 2016;375(1):65-74 View Article
  76. Lavine JE, Schwimmer JB. Nonalcoholic fatty liver disease in the pediatric population. Clin Liver Dis 2004;8(3):549-558 View Article
  77. Huang JS, Barlow SE, Quiros-Tejeira RE, Scheimann A, Skelton J, Suskind D, et al. Childhood obesity for pediatric gastroenterologists. J Pediatr Gastroenterol Nutr 2013;56(1):99-109 View Article
  78. Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The prevalence of non-alcoholic fatty liver disease in children and adolescents: A systematic review and meta-analysis. PLoS One 2015;10(10):e0140908 View Article
  79. Wesolowski SR, Kasmi KC, Jonscher KR, Friedman JE. Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol 2017;14(2):81-96 View Article
  80. Eslam M, George J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat Rev Gastroenterol Hepatol 2020;17(1):40-52 View Article
  81. Bayoumi A, Grønbæk H, George J, Eslam M. The epigenetic drug discovery landscape for metabolic-associated fatty liver disease. Trends Genet 2020;36(6):429-441 View Article
  82. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol 2018;68(2):268-279 View Article
  83. Pacifico L, Perla FM, Roggini M, Andreoli G, D’Avanzo M, Chiesa C. A systematic review of NAFLD-associated extrahepatic disorders in youths. J Clin Med 2019;8(6):868 View Article
  84. Yodoshi T, Arce-Clachar AC, Sun Q, Fei L, Bramlage K, Xanthakos SA, et al. Glomerular hyperfiltration is associated with liver disease severity in children with nonalcoholic fatty liver disease. J Pediatr 2020;222:127-133 View Article
  85. Hegarty R, Singh S, Bansal S, Fitzpatrick E, Dhawan A. NAFLD to MAFLD in adults but the saga continues in children: an opportunity to advocate change. J Hepatol 2021;74(4):991-992 View Article
  86. Fouad Y, Elwakil R, Elsahhar M, Said E, Bazeed S, Ali Gomaa A, et al. The NAFLD-MAFLD debate: Eminence vs evidence. Liver Int 2021;41(2):255-260 View Article
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Redefinition of Fatty Liver Disease from NAFLD to MAFLD through the Lens of Drug Development and Regulatory Science

Yasser Fouad, Melissa Palmer, Minjun Chen, Arie Regev, Rajarshi Banerjee, Rob Myers, Robert Riccio, Richard Torstenson, Ramy Younes, Puneet S. Arora, Henrik Landgren, Morten A. Karsdal, Martin Blake, David A. Shapiro, Hans-Juergen Gruss, Muhammad Y. Sheikh, Dina Attia, Steven Bollipo, Alastair D. Smith, Bradley Freilich, Robert G. Gish, Detlef Schuppan
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