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As the NASH pandemic grows in the number and diversity of patient cases, one patient group receiving increased notice includes patients with "lean NASH," those whose BMI levels are "normal." Last month, Gastroenterology published Best Practice recommendations for diagnosing and treating lean NASH. Two of the authors, Drs. Michelle Long and Mazen Noureddin, were good enough to come on the podcast to share the thinking behind this article along with its key observations and recommendations.

This conversation starts with Roger Green asking Michelle and Mazen how they came to write this piece and how the paper came together working with co-author, Dr. Joseph Lim. First, as Michelle notes, "we had to all get on the same page," on the issue of the highest BMI that would be considered lean or, more precisely, not overweight. From there, the team outlined 15 Best Practices based on clinical experience, and set out to refine these based on relevant literature and recommendations from colleagues and reviewers. The co-authors note that while little of what they learned while preparing this paper was surprising, it forced them to focus on creating a fairly simple set of stepwise goals for clinicians to follow.  Louise Campbell joins the conversation to praise the simplicity and clarity of the Best Practices chart the co-authors created. 

After noting that this algorithm is not very different from others,  Mazen goes on to mention "a couple of things...that we're proud of:" identification of high-risk patients based on age (over 40) or presence of Type 2 diabetes. He also notes that they provided greater clarity around more advanced non-invasive tests like ELF, MAST, FAST, MEFIB, MRI, and cT1.

The conversation shifts to focus on the recommendation to retest every 6 or 12 months. Louise notes this approvingly. The group agrees that screening T2D patients annually using FIB-4 is not very different than screening annually for eye, kidney or neurological complications. Roger Green joins the conversation to suggest a 3-5 year follow-up recommendation is not patient-centric, but might calm payers concerned about skyrocketing costs of treating Fatty Liver disease. Mazen shares his expectation that yearly evaluation will be cost-effective and patient-centric. Roger shares an informal belief he has developed that whether due to later stage diagnoses or different disease pathogenesis, lean NASH patients might be more costly because patients progress to cirrhosis more quickly after the original diagnosis. Michelle tends to agree but notes that more research is needed on this.

Next, the conversation shifts toward diagnostic approaches. Roger mentions the possible benefit of the "Fibrosis First" method that Ian Rowe discussed the previous week (S3, E39), particularly appropriate when primary care providers observe danger signs in lean patients. Mazen points to extremely elevated liver enzyme levels (ALT of 80 or 90). Michelle agrees, but notes that most of her lean NASH patients are diagnosed in an ED with complications of cirrhosis. The group then spends time asking what might make primary care providers comfortable testing for fibrosis, even if only to pass the patient on to the appropriate specialist.  

Roger asks what different groups can learn from this paper. Michelle states that this is a clear call for more research. Mazen points to Table 2 in the paper, which lists other diseases that hepatologists should consider when evaluating these patients. He continues to state that the document is helpful for non-hepatologists and hepatologists alike. Finally, he points out that clinical trials are pivotal for these patients. 

The last several moments focus on how to ask patients about alcohol consumption and then the closing question. Michelle notes the importance of using lists and tables in the paper to guide the special issues in treating these patients. 

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This week's "Conversation from the Vault" comes from September 2021, when Anthony Villiotti of NASH kNOWledge joined Louise Campbell and Roger Green to discuss what he considered the "biggest Fatty Liver story of the summer."

In his answer, Tony pointed to two studies published during the summer. The San Antonio Military Medical Center study confirmed work done a decade earlier that suggested overall NAFLD and NASH incidence in a population of asymptomatic middle-aged Texans (37% NAFLD and 14% NASH) might be far higher than the most common publicly quoted numbers (25% and 5,6%, respectively). As we wrote in our conversation synopsis at the time, "Tony and Louise Campbell agree on the importance of educating children starting in their early years of schooling. Tony also comments on his belief in grass-roots education and hopes that as the COVID-19 pandemic abates, he will have more opportunities to do so. Louise talks about the need to educate/motiave primary care practitioners and related specialists to test more frequently and learn about the role the liver plays in non-communicable metabolic diseases they treat more frequently."

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One of the most important challenges facing Fatty Liver stakeholders involves improving early diagnosis for patients with clinically relevant or advanced fibrosis (F2/3). Today, a significant percentage of patients learn they are living with cirrhosis in the Emergency Department during a decompensating event. Four in ten of these patients in the UK do not leave the hospital. Episode 39 reviewed a model that Ian Rowe and Richard Parker developed to determine the most cost-effective strategy for F2/3 diagnosis.

As this conversation starts, Louise Campbell notes that John Dillon reported in Barcelona that slightly over half of patients identified as having Fatt Liver via iLFT never returned for their appointments. Ian Rowe points out that this will reduce the costs in the model due to missed diagnoses but questions whether this cost reduction is truly beneficial since missed patient visits translate into non-treatment. More important, he reminds us that iLFT is under constant improvement so that data collected earlier in its lifecycle might not accurately reflect its costs and benefits today.

Upon Roger Green's invitation for other questions Louise Campbell asks whether "we" (presumably the UK NHS) should do a better job supporting positive diet and exercise activity for healthcare professionals inside the system. On a more serious note, this leads Ian and Louise to focus on the policy issues that can support patients better (particularly those in the workforce). Ian points out that alcohol is issue #1 for many of these patients. He and Louise go on to point out the importance of public policy around things like soda and sweet food advertising in shifting consumers' focus or craving for bad foods. Roger suggests that this is a two-element issue: stopping advertising for soda and sweets will reduce disease over time but we also need to treat patients who already have developed disease. As he puts it, policy can "put your foot on the hose," but even if we stop the in-flow of new Fatty Liver and metabolic patients, we still have "the patients in the hose" and they will need therapy. 

As a final thought before wrap-up, Ian shares his belief (which Louise also holds) that VCTE might be more effective in causing changes in patient behavior than blood tests, even if they point up the exact same patient need. The difference: feedback from VCTE comes in real-time where patients get face-to-face feedback and respond, whereas bloodwork results comeback to the patient several days later and delivered impersonally. 

From here, the group moves to the wrap-up question, which addresses research we should be doing and action steps/changes in behavior we should be promoting. You will have to listen for yourself to hear Surfers' answers.

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One of the most important challenges facing Fatty Liver stakeholders involves improving early diagnosis for patients with clinically relevant or advanced fibrosis (F2/3). Today, a significant percentage of patients learn they are living with cirrhosis in the Emergency Department during a decompensating event. Four in ten of these patients in the UK do not leave the hospital. Episode 39 reviewed a model that Ian Rowe and Richard Parker developed to determine the most cost-effective strategy for F2/3 diagnosis.

This conversation centers around challenges related to early diagnosis and NASH Patient Management. As Roger Green notes, listeners to NASH Tsunami might recall a significant number of conversations in which patients and advocates complain about doctors telling them "not to worry" about their Fatty Livers for years until the condition progresses to cirrhosis. Louise Campbell focuses on a different challenge: that of NASH patient management when patients are dealing with other metabolic diseases that are better known or where approved treatments exist.

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One of the most important challenges facing Fatty Liver stakeholders involves improving early diagnosis for patients with clinically relevant or advanced fibrosis (F2/3). Today, a significant percentage of patients learn they are living with cirrhosis in the Emergency Department during a decompensating event. Four in ten of these patients in the UK do not leave the hospital. Episode 39 reviewed a model that Ian Rowe and Richard Parker developed to determine the most cost-effective strategy for F2/3 diagnosis.

This conversation starts with Louise Campbell agreeing with the vision that led Ian and Richard to build this model. She notes recent data she heard that 85% of all US patients with cirrhosis (and 55% in the UK) learn their diagnoses for the first time in an Emergency Department, which suggests the need to improve earlier diagnosis. She notes that some UK programs are widely cited as examples of good (or best) practice, but, more important, notes that these have been cited as examples for a long time, but also notes that other regions and hospitals have not emulated them. 

She goes on to ask how the efficiency and number of patients captured in the model would increase if the target expanded to include all patients with metabolic disease. Ian notes that these patients were not included in the model and also suggests that the question reflects a larger question about the goal of this kind of screening.

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One of the most important challenges facing Fatty Liver stakeholders involves improving early diagnosis for patients with clinically relevant or advanced fibrosis (F2/3). Today, a significant percentage of patients learn they are living with cirrhosis in the Emergency Department during a decompensating event. Four in ten of these patients in the UK do not leave the hospital. Episode 39 reviewed a model that Ian Rowe and Richard Parker developed to determine the most cost-effective strategy for F2/3 diagnosis.

In this conversation, Ian Rowe describes the factors that motivated him and Richard Parker to build a decision model focusing on early NASH diagnosis. He identifies three data points demonstrating how severely NASH stakeholders need a better early diagnosis paradigm and then describes the five diagnostic strategies his model will test. :

1. the high percentage of people whose liver disease is picked up for the first time when they present in the ED with decompensating disease or hepatic encephalopathy
2. the fact that roughly four in ten of these patients will die during treatment for this initial round of liver disease
3. the inefficiencies around diagnostic current methods, whereby practitioners flag abnormal liver enzyme tests and refer to specialists, where it may take months to get a specialist appointment.

He then describes the five early diagnostic strategies that will be tested and contrasted in this decision curve model.

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One serious challenge in the overall management of Fatty Liver disease involves creating cost-effective methods for "early" diagnosis. The term "early" is relative because, as Ian Rowe puts it, a "substantial proportion" of people admitted to hospital with various symptoms of decompensating cirrhosis or hepatic encephalopathy never received a diagnosis of advanced liver disease before they presented. Simply diagnosing these patients during advanced fibrosis (F2 or F3) can save lives, improve longevity and quality of life for these patients and save money for healthcare systems, all at the same time. 

Ian spends the first ten minutes of this episode describing a model he and Richard Parker developed to evaluate five diagnostic strategies:

• Targeted -- simple non-invasive liver screening 
• Targeted + risk stratification -- targeted assessment plus FIB-4 or VCTE (FibroScan) for patients believed to be at high risk
• iLFT -- automated assessment of abnormal LFTs analyzed with other systemic measures in a medical record system 
• "Comprehensive" -- a "kitchen sink" approach that runs iLFT analysis and conducts FIB-4 +/- VCTE on every patient
• "Fibrosis first" -- an approach that deploys viroserological and iron testing plus FIB-4 +/- VCTE for every patient 

"Fibrosis first" scored best in cost effectiveness (cost per correct diagnosis of treatable liver disease) and "decision curve analysis", which looks at true positive outcomes and false positive outcomes, correctly identifying 85% of treatable liver disease patients (vs. 90% for the comprehensive approach and less than 15% for the current targeted approach.)  Fibrosis first has the added benefit of not progressing treatment for people who may have steatosis without fibrosis. 

The rest of the conversation entails Ian, Louise Campbell and Roger Green sharing questions and observations. Highlights:

• Louise agrees that the current targeted pathway approaches do not work and  identifies lack of access to advanced testing in primary care as a central issue. She asks how many additional patients with Type 2 Diabetes, other metabolic diseases or CVD could be identified through this approach. Ian cannot answer because the question is outside the scope of the research. He points out that to assess different approaches accurately, researchers and policymakers need to settle on whether the goal is to identify steatohepatitis or something broader. 
• Louise asks about the frequency and nature of referrals. Ian notes that one issue with iLFT is a high level of referrals for conditions that might not require treatment, the most common of which is "abnormal LFT without fibrosis."
• Roger notes that iLFT might help patients who complain they never heard about their NASH earlier. He also recalls Quentin Anstee and Stephen Harrison discussing recently that FIB-4 can serve as a prognostic measure not only for liver-related deaths, but also CV deaths and all-cause mortality. 
• Louise suggests that patients will do better if they adopt a  behavior belief model instead of a sick patient approach and that the earlier in disease we intervene, the more success we will have. Roger and Ian note that Louise's focus is broader in scope than his model. Ian further notes that we do not know when non-fibrotic patients should be tested again, although he has some thoughts about this. 
• Louise notes that one element that might make iLFT costly is that only 45% of patients picked up on iLFT are referred into the model. Ian notes that this insight might require changes in the model.

As the conversation winds down, it shifts toward policy issues: should we focus testing on the workforce (Louise) and it the best point of intervention to limit advertising of unhealthy foods (Ian). 

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Our week of "Greatest Hits" episodes from the vault concludes with this conversation from the episode discussing the inaugural Innovations in Clinical Care - Barcelona (or INCBCN) conference that convened this past May. This conversation reviews two controversies about the meaning of patient empowerment that arose at the conference.

One key event that 2022 witnessed was the inception of the Innovations in NAFLD Care series, a global effort to discuss clinical care pathways and patient treatment processes in a systematic way. Surfing the NASH Tsunami is a media partner and advocate for this series. 

This conversation comes from our review of the conference. The discussion itself is triggered by Roger Green's question about controversies at INCBCN 2022 and addresses two issues. The first is the ongoing controversy over what to call the disease itself. The second addresses the concept of biohacking, which either empowers patients by providing them with extensive data for self-management or disempowers them by divorcing the individual patient's interpretation of this data from disease understanding.

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Our week of "Greatest Hits" episodes from the vault continues with this conversation from the episode discussing systematic failures of NAS scoring due to inconsistencies in how different pathologists interpret slides. This conversation explores the reasons for different histopathologists differing consistently in how they interpret liver slides.

One of the primary drivers of reassessing the role of semi-quantitative histopathology in assessing developmental drugs was the paper "Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD," e-published in January 2022 in the Journal of Hepatology. This paper demonstrated strong systematic flaws in the reading of ballooned hepatocytes, which is one of the pivotal factors in assessing drug efficacy. This paper showed that low levels of inter-reader consistency led to an array of interpretive challenges. In this episode, last co-author Quentin Anstee led the Surfers, including co-author Stephen Harrison, through a review of the paper and a discussion of how to resolve this issue. 

This conversation starts with Stephen Harrison noting that the single largest problem facing drugs in development is the inconsistency in efficacy reads (and particularly placebo response rates) at the back end of clinical trials. From here, the group explores how histopathology training leads to variability in the interpretation of slides and inconsistent assessments of drug efficacy.

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Our week of "Greatest Hits" episodes from the vault continues with this conversation from the episode reviewing the NASH Patient-Focused Drug Development meeting sponsored by the Global Liver Institute and held at the FDA on November 4, 2021. This conversation focuses on the perspectives that patient advocates brought to this session.

Late 2021 and early 2022 traced a series of events that sensitized FDA to the need to look "beyond the biopsy" (or at least semi-quantitative reads) to an approach that would more accurately reflect the benefits of NASH drugs in development and the extreme need patients and their advocates felt for new medications. One critical event on this path was the patient-focused drug development (PFDD) meeting the Global Liver Institute organized and held at FDA on November 4, 2021. At this meeting, FDA reportedly acknowledged that if they had understood patients' perspectives better a couple of years earlier, the path of NASH drug development might have been different.

As I wrote at the time: In this conversation, Global Liver Institute Founder, President and CEO Donna Cryer describes the history of the basic Patient-Focussed Drug Development concept and this particular NASH event. Patient and patient advocate Terri Milton discusses the message she hoped regulators would take away from this session and why she believes the group may have succeeded. Finally, the group discusses why regulators and advocates vary so greatly in terms of how they view the efficacy:safety tradeoff for first-in-class drugs.