I recently attended the 2018 meeting of the American Association for the Study of Liver Disease (AASLD). It is the key liver research association in the US. It brings together the top researchers in the field with reports on their work. Since there are no therapies for those of us who have liver disease, this is an important benchmark as we look at the state of research.
I'll discuss this more fully below but the short version is that we will get therapies for liver disease in the next 2 to 5 years.
The message in that, is that it is rational to have hope in the face of a diagnosis of serious disease which currently has no treatment. I'm reminded of a stanza from a favorite poet, Kipling, in a piece called "IF".
If you can force your heart and nerve and sinew
to do their turn long after they are gone,
And so hold on when there is nothing in you
except the will that says to them Hold On.
For so many, holding on is hard to do when faced with the constant strain of chronic illness, but help is on the way. A few observations of the meeting and the state of liver research. This is a little long but it is a big subject, worth your time.
The most obvious feature of the meeting was that it showcased the vast amount of research going into NAFLD/NASH/cirrhosis. The sheer volume of work being done is impressive, but a walk through the poster hall is striking. The number of posters is far too large to take in. Just walking through the hall makes it clear that the amount of effort being deployed toward liver health is really vast. The granularity of the work being done is perhaps the most impressive aspect of the field today.
When we look back just a few years, it is clear that the work being done today was beyond our ability until quite recently. The ability to examine the intricacy of the molecular pathways is very interesting. The black box nature of many of the liver’s functions is giving way to a real understanding of the specific chemical reactions between and within the cells. The consequences of small changes in gene expression, charge transfer, protein folding errors, antigen responses are just glimpses into our society’s effort to understand ourselves. The liver meeting focuses on this centrally critical organ but the effort is but a part of the larger project of learning what makes us tick.
The process of expanding basic knowledge is a tour de force unique in human history. We can think about things like the examination of genes like the PNPLA3 and how it and other genes interact with the serum environment or each other to tip the balance between being well or unwell. It is an example of how one field, DNA analysis broadly, is being applied to a very specific function at the heart of the bio-chemistry of life.
The evolution of new tools and probes coming from the broader arena of basic science point us toward an ever more robust capability in our journey to understand the liver. I was struck by the development of the ability to capture living cell membrane structures, such as ion channels, and to analyze their function at a molecular level. Those membrane processes are critical to fully understanding how we might produce effective medication and until recently we were guessing about the details. We are teasing out the workings of the ER structures within the mitochondria which are so elemental a part of a functional system. As patients we feel profound fatigue but at the root lies ATP production. Our ability to understand and affect such fundamental processes will be a result of the evolution of ever more robust tools.
When we step up a level from how the molecules work we see all the effort going into how the systems of body processes interact. How do living systems respond to varying molecules and which lead toward health or dysfunction or illness. From all of the vast array of molecules at play within the liver what is important and how do they interact really? Our measures of the past have been the best we had but are crude estimates generally. Studies going on today focus on how liver fat, as one example, respond to manipulation of certain thyroid hormones. The nuances of how molecules drive function is life and death and we are opening the books on how all of that really works.
The study of lipids within the liver and body wide is burgeoning as fatty acids are both foundational molecules and dose related substances involved with disease. The study of cellular response such as how stellate cells are affected by different molecules is robust within the complex cellular community that constitute the liver. These are just examples of areas where progress is being made to understand the cellular operation.
Then we step out to the body wide functions where inflammation, wound management, tissue health, immune response, all the other processes that taken as a whole are responsible for the maintenance of a living organism. A lot of work is being done to understand the vast complexity of those processes to learn how and where they might be managed. What functions lead to liver damage and which might be recruited to promote healing.
Here the issue of comorbidity is clearly in focus. While everyone has known of the central nature of the liver for a long time, it was not a real focus because it is so very complex as to have defied most efforts to really understand it until the current array of tools and understanding could be brought to bear. We are seeing those broader relationships with cardiovascular and diabetic disease, as examples, where the dynamic role of the system is coming into better focus in addition to the organ by organ march of much of the effort in the past. The consequences of advancing disease are also being intensively studied. Liver cancer is a particular emphasis of this meeting but the broader role of cancer development is being studied intently.
The profession has had difficulty with the process for triaging patients with active disease, but who present as asymptomatic. A lot of work on non-invasive markers that can be part of a protocol at the primary care level was shown at the meeting. One of the most interesting is the documentation of the role that Fib-4 might play in that process. There is growing evidence that Fib-4, and several other blood based candidates, as filters for FibroScan screening to determine referral to a specialist is effective. Whether that becomes a strategy at the primary level remains to be seen but it is a sign of the evolving diagnostic options. The most important fact is that it is a matter of serious discussion.
Stepping out a bit more, researchers are looking at the role of nutrition and how food and behavior really work. We have very robust population studies which make it clear that we have a health problem and how and what to do are areas of serious study. The role that the various dietary components play in the health of people is being studied in considerable detail. Delivery of that information remains poor but the examination of the liver response to nutrition and not just weight loss as the measure is becoming more common now that the therapeutic value of weight loss has been documented well. The science is far ahead of society in the utilization of this information.
As a patient, being able to see the depth and breadth of the effort whose goal is to save my life and that of the millions of patients like me was both humbling and exhilarating. I seem to lack the skill to adequately express my gratitude to all of the people who are working so very hard to find solutions to liver disease. There is a special pain that comes when the doctor says you have cirrhosis, we have no treatment, and you begin your dance with the angel of death. The knowledge that research will bring solutions offers hope that makes the day to day easier to bear. The dark angel is still there, of course, but now it is a line dance not the Argentine Tango and as patients we find reason to hope.
