Surfing the MASH Tsunami

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Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." This conversation centers on papers with similar methods and processes for researching stellate cells.

Scott begins this conversation by describing this process, which is based on another Nobel Prize-winning methodology. In this technique, the researchers start by forcing an adult mature skin cell (or any cell, for that matter) o express a cluster of very well-defined genes and transcription factors, which the researcher then turns into a generalized, Induced Pluripotent Stem (IPS) cell. Researchers have found ways to convert these IPS cells into stellate cells. The developer of this technique posited that it will enable us to explore the proteome. 

To Scott, this process of converting a generalized cell to a stellate cell we can analyze via proteomics to find new targets is more important and noteworthy than the result of this specific study (researchers identified a novel nuclear receptor called RORalpha). To quote Scott, "they're much closer to the action when they find a protein rather than just the mRNA that encodes it." He goes on to discuss a second study from Insitro (a company with which he consults) about their work seeking to optimize the IPS-derived stellate cells to find the one that most closely resembles cells in vivo. 

When Scott finishes, Neil notes that single-cell proteomics is not "coming, but it's not there yet." Neil anticipates we will have this pivotal tool available in a 1-2 year time horizon. Next, Jörn anticipates and asks about the next stage in the process: identifying a protein related to this process we can find in peripheral blood given that, as Neil noted, tissue sampling in the clinical setting will not be possible. Scott discusses a recent paper that seems to provide a solution to this issue in breast cancer. While he notes that the work has to be validated first, it clearly suggests researchers are close to finding proteins we can identify in blood in at least one cancer-related case. 

From there, Scott turns to Rachel for feedback, since this is the area in which her business is building its research. Her answer has several elements to it, but the main point is that proteomic development lags behind some of the other techniques but is making rapid advances as the costs of some key analytical processes come down. She then goes on to provide a description of epigenetics, the area in which she works most intensively.

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Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." This presentation centers around two papers that explore stellate cell dynamics related to the progression and regression of fibrosis, both of which rely on methods pioneered by Neil and his colleague Prakesh Ramachandran to take individual cells from tissue (in this case, the liver), use transcriptomic to interrogate the mRNA and infer how cells interact in different processes.

The first presentation, which takes up the bulk of this conversation, centers around scar formation in mouse livers under injurious assault and then scar healing when the assault ceases. Before discussing the study itself, Scott provides a brief but extremely rich background of the research technique that are driving progress in this area, including Neil's work and other advances that have been recognized with Nobel prizes.

When the focus reverts to the actual papers, Neil notes that this presentation is unusual in that most research devotes far more attention to scar formation than to regression whereas this note looks at both processes (In Season 2, Episode 50, Lars Johansson noted similarly that researchers spend far more time researching "what shouldn't be in the liver" than what should be there.) He continues that we can research these issues far more effectively in mice than in people, in part because we do not biopsy people with healthy or healed livers. This leads to another brief discussion of methods, in this case, spatial transcriptomic. Jörn asks a clinician question: if there are, as this paper suggests, 14 different states of activation, how do we know which are druggable? 

NOTE: The researcher presenting this paper at ILC2022 noted that the research was funded in part by Novo Nordisk.

As the discussion closes, Scott mentions a different paper that touches on the role of peroxidation an antioxidant process, in fibrosis progression. and regression.

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Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022.) On Thursday afternoon, Scott Friedman chaired an abstract session discussing advances in the basic science of researching and understanding mechanisms surrounding fibrosis and stellate cells. Later, he described it as "one of the most exciting groups of presentations I've seen in many years." This presentation centers on the relationship between Circadian rhythms and stellate cells.

It is widely known that we all function under a set of Circadian rhythms tied to day/night changes. Original work in this area focused on physiological changes linked to the central nervous system. In recent years, researchers have learned that other tissues in the body operate on their own Circadian rhythms, presumably tied in some way to the central nervous system. But as Scott exclaims when beginning this discussion, "who would have thought that that included the lowly little hepatic stellate cell, a fibrogenic cell that contains the same mechanisms and the same machinery to regulate circadian rhythm as all those more specialized neuronal tissues." 

Scott goes on to provide greater detail on the mechanisms through which stellate calls control fibrogenic activity in a cyclical manner. When he concludes, the rest of the group shares comments. Neil Henderson notes that Circadian rhythms are strongly tied to fibrogenic processes throughout the body. Jörn Schattenberg, Louise Campbell and Rachel Zayas comment in different ways on the relevance of circadian rhythms to elements of patient care today, and Roger Green asks a question that leads Scott to note that TGF beta, which he described as "the mother of all fibrogenic cytokines," was the signaling mechanisms for this process.

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Last month, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). This episode focuses on an abstract session Scott Friedman chaired on Thursday afternoon discussing advancing in the basic science of researching and understanding mechanisms surrounding fibrosis.

Scott starts by describing the session he co-chaired with Sophie Lotersztajn of INSERM as "one of the most exciting groups of presentations I've seen in many years." During this episode, he leads the rest of the panel through exploration of all six presentations. These include:

--Targeting the liver circadian clock by REV-ERB-alpha activation improves liver fibrosis by circadian gating of TGF-beta signaling, Atish Mukherji, University of Strasbourg. Scott describes this presentation, which demonstrates that stellate cells have a circadian clock, as "one of the most surprising results" in that circadian activity can be linked to the  "lowly stellate cell."  This paper generated significant conversation among the group, ranging from Neil Henderson's observation that circadian regulation is a powerful regulator of fibrotic processes to Jörn Schattenberg's observations about what this might mean for treating patients in the clinic to Roger Green asking whether this concept might be germane to specific drugs in development (Scott had mentioned that signalling occurred through TGFbeta.  Louise Campbell and Rachel Zayas  add comments about the relevance of circadian rhythm to care today and ways this paper might yield exciting new areas for research.

--Stellate cell dynamics in progression and regression of hepatic fibrosis, Laura Almale del Barrio, Denmark. This presentation, funded in part by Novo Nordisk, focused on how mouse livers respond when researchers stop injuring them. It leads Neil to comment on how little attention researchers pay to scar healing relative to how much more they pay to the process of scar creation and injury. In response to a question from Scott, Neil also discusses how advances in spatial transcriptomic will make questions like these easier to research in the not-too-distant future. After this, Jörn goes on to note that the paper discussed 14 different stellate cell states, which he interprets as involves activation and transitioning processes. He asks what this might imply for treating patients in the clinic.

The other four presentations engender a similar level of exploration. They include:
--Peroxidasin deficiency re-programs macrophages toward pro-fibrolysis function and promotes collagen resolution in liver, Mozhdeh Sojoodi, Mass General Hospital and Harvard. 
--Machine learning methods for detailed characterization of TGF-beta-induced signatures in a large iPSC-derived hepatic stellate cell cohort, Kara Marie Liu, Insitro, United States
--The proteomic analysis of hepatic stellate cell differentiation from iPSCs identifies RORalpha as an antifibrogenic target, Raquel A. Martinez Garcia de la Torre, Spain
--Biliary epithelial cell-specific RAGE controls ductular reaction-mediated fibrosis during cholestasis, Macrina Lam, Germany

In each case, Scott starts by discussing the historic of scientific progress that predates the particular paper and topic, places the presentation properly within that context, and invites the others to comment. Each Surfer has unique (and uniquely interesting) comments in their own areas of expertise.

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Last week, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). The first three days of the program focused on a range of issues, with specific emphasis on non-invasive tests (NITs) and their role at different stages in diagnosis and treatment. This conversation touches on two issues: the use of AI to better understand the meaning of liver volume and elements of morphology and, relatedly, how much more sophisticated a view we take of NAFLD and NASH than we did even five years ago.

The issues around AI and liver morphology arise from Jörn Schattenberg's comment that consistent with Stephen Harrison's "KISS" (Keep It Simple, Stupid!) principle, researchers are starting to explore the meaning of changes in liver volume. Ultimately, Jörn notes, pairing these kinds of measures with AI-supported histopathology can yield tremendous benefits. Roger comments on a breakfast he attended that morning that suggested that AI and NITs each provide different, important information on individual liver health: NITs can address collagen burden but not structure, while AI can identify changes in structure but not link them to the impact on the patient. Zobair ends this part of the conversation by noting that companies are starting to use AI in these ways.

The second part of this conversation stems from Roger's observation that we know far more about the disease than we did 3-4 years ago. He goes on to describe how the environment is more collaborative and open-minded than it might have been if, in fact, we saw drug approvals at that time. Zobair takes this observation to a different plane, noting that 5-10 years ago, "some very important experts" believed that we all understood the etiology of Fatty Liver disease, so why spend more time? He goes on, "we could not have been more wrong," observing that what we have learned about progression and regression in placebo arms suggests a far more complex disease than something that progresses linearly, or even constantly in one direction. He goes on to add that the multiple drug trial failures is that targeting drugs to a single solution based on animal models is likely to fail because this is a multiple mode of action disease. His third point: the "source" of the disease is visceral obesity and insulin resistance, which all viable solutions must address. This identifies two targets for treatment, while simultaneously demonstrating that therapy will be chronic, lifelong and with behavioral elements. The rest of the conversation addresses the challenges with shaping this kind of lifelong, multitarget therapy in the US today.

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Last week, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). The first three days of the program focused on a range of issues, with specific emphasis on non-invasive tests (NITs) and their role at different stages in diagnosis and treatment. This conversation touches on the impact that NAFLD has on patient quality-of-life and the importance of integrating quality-of-life issues and metrics into everything from clinical trials to treatment protocols.

This conversation starts with an observation from Jörn Schattenberg about the importance of looking more carefully at quality-of-life metrics, both in terms of patient treatment and clinical trial outcomes. MIchelle Long, making a closing comment, notes how much more collaborative researchers in the meeting are compared to years past. She then makes an announcement about a major, exciting change in her career, and then exits the conversation.

Zobair Younossi identifies "fatigue" as the patient-reported outcome from NAFLD that links most closely to quality-of-life issues He points out that fatigued Fatty Liver patients produce lower quality-of-life scores and also exhibit higher levels of mortality. He goes on to note that fatigue is also linked to unemployment and underemployment, which means that it has clear economic costs. Roger Green asks whether payers will accept economic analysis on this and, as a result, pay for therapy. Zobair suggests that this will depend on whether advocates can make this issue part of the policy, which will drive individual payers' behavior in the US and shape government policy elsewhere. In response to a question from Roger, Louise Campbell comments that the policy environment in the UK is not very different from the US despite differences in how care is actually paid for. She goes on to identify one challenge in this issue, which is that quality-of-life scores decline as soon as a patient becomes aware of their disease, which has the potential to complicate employee analyses when the employee is not yet a patient. She also agrees with Zobair's earlier statement that he would prescribe a slightly more expensive medication if it improves quality-of-life. Zobair closes this conversation by returning to discuss the importance of fatigue and describing himself as "heartened" that fatigue is now measured in most (if not all) clinical trials.

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Last week, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). The first three days of the program focused on a range of issues, with specific emphasis on non-invasive tests (NITs) and their role at different stages in diagnosis and treatment. This conversation touches on two issues: how proper use and explanation of NITs can increase patient motivation and why adding NITs to quality measures can have such an effect on educating providers and increasing treatment.

This conversation starts with Michelle Long and Louise Campbell discussing studies that demonstrated that patients receiving a FibroScan changed behaviors in ways that lasted at least six months, whether or not they learned they had liver fat. From here, Zobair Younossi discusses the importance of front-line, primary care screening with FIB-4 for all patients with diabetes. Zobair suggests that we consider making use of FIB-4 as a test for co-morbidities in diabetes a formal quality measure, in the same way that providers are required to check creatinine to assess possible kidney damage. Michelle and Roger Green added to Zobair's comment to discuss the specific benefits of adding an electronic health record-generated FIB-4 test as a standard assessment for diabetic patients. Zobair goes back to the point that we need primary care to serve as a front line for diabetes testing. In this context, he suggests the importance of FIB-4 and gives reasons he believes FibroScan will never become widely used in primary care. Louise Campbell disagreed, saying that having FibroScan in primary care would educate patients and drive better care. Jörn Schattenberg discusses some sessions where the consensus supported early FIB-4 use. Roger Green wraps up this conversation by talking about the importance of having formal quality measures around FIB-4 use in the US by telling a story from his own medical history.

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Last week, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). On the last full day of the program, several vitally important drug development studies were presented during the late-breaker and dedicated sessions. The conversations in this episode will review some of the most important findings. This particular conversation focuses on the semaglutide cirrhosis late-breaker and, more broadly, what panelists consider the presentation from this Congress most likely to effect change over the next 2-3 years.

Because Stephen Harrison needs to depart, the episode starts with him answering a question about the most consequential paper in the Congress. He focuses on the resmetirom late-breaker, which presages potential drug approval within the next 18 months. Jörn Schattenberg takes a different tack, identifying the semaglutide cirrhosis late-breaker instead. Jörn notes that the study did not achieve its primary endpoint of 1-level fibrosis reduction in 48 weeks, but cites other studies and experiences to suggest this is very, very hard to achieve for any drug. Jörn continued to suggest that semaglutide's safety level combined with the ability to help patients lose weight and reduce their HbA1c levels means this can be a valuable drug for Fatty Liver patients as well as diabetics and people with obesity, the currently indicated patient populations. 

From here, the group provides answers to the "most consequential presentation" question and the conversation comes to an end.

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During last week's #ILC2022 meeting in London, Louise Campbell took the opportunity to sit down with PBC Foundation CEO and Fatty Liver patient Robert Mitchell-Thain to discuss patient engagement from their own perspectives, Louise as a longtime hepatology nurse and Robert as a patient advocate and NAFLD patient.

Robert starts by discussing his own experience with Fatty Liver disease. First, he notes the importance of patients boldly defining themselves as patients and taking ownership of the word "Patient." As he notes, doctors are only involved with patients during brief, infrequent office visits while patients themselves live the part every day when making a range of decisions about their healthy (or not so healthy) lives. 

Louise describes her excitement at seeing the data the British Liver Trust, Echosens and e-Scopics have collected while testing people at the meeting. She goes on to mention data from the MAESTRO NAFLD-1 trial, where patients skipped an average of two months of doses due to logistics related to the COVID-19 pandemic, but still showed clinical benefit. Sharing that kind of data with patients might make them feel more comfortable resuming medication after one (or a few) missed doses. 

Robert goes on to discuss his own "day of diagnosis"...his reaction to the suggestion about losing 10-15% of his body weight and his recognition that the patient's urge at a moment like that is to "fight or flight." He goes on to note that this kind of emotional response is not solution-oriented so that patients and providers alike would do well to consider revisiting how to achieve goals like 10% weight loss at a more rational moment when the patient can focus on solutions. (Robert reminds us that from the moment the patient receives a diagnosis until they leave the physician's office, they fail to retain 40-70% of what they have been told.) 

In the end, Robert would like to see more patient experience and patient involvement presentations next year, while Louise hopes for a successful NASH drug Phase 3 study that might point the way toward approval. They go on to discuss some issues around PBC before wrapping up the conversation.

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During last week's #ILC2022 meeting in London, Louise Campbell took the opportunity to sit down with PBC Foundation CEO and Fatty Liver patient Robert Mitchell-Thain to discuss patient engagement from their own perspectives, Louise as a longtime hepatology nurse (and NAFLD nurse) and Robert as a patient advocate and NAFLD patient.

In this conversation, Louise and Robert start by discussing items that have "rocked their world" from this meeting. Robert starts by commenting on presentations that suggest how many patients get missed with a FIB-4 or ALT and expresses the hope that we will improve screening processes to find more people quickly. From there, the conversation shifts toward the role of stigma in patient communication. Specifically, Robert notes about "internal" stigma, the discomfort that patients have discussing their own issues of weight and appearance or sexual dysfunction. Specifically, he states that patients need to "lead from the front" by bringing the statements out in the open, which will make it more obvious that physicians and nurses need to raise these issues during initial visits. It will also push these issues into clinical trials, where we can learn about frequency. Robert notes that nurses have unique value: physicians care about metrics and medical numbers, patients care about quality-of-life, and nurses has the knowledge and skills to bridge between the two. In closing, both agree that patients need to be bold and up-front about their issues instead of, as Louise notes, surrending all accountability once a person allows herself to be define as a patient.