So, we have before us the case of a 52-year-old female with type 2 diabetes, a BMI of 38, who undergoes an abdominal ultrasound to evaluate mildly abnormal liver chemistry tests and the ultrasound shows increased echogenicity suggestive of fatty liver. On laboratory evaluation, you note that she has mild elevation in liver chemistry tests. She has normal albumin, bilirubin, platelet count, and INR. And then on further exploration of her history, you note the following relevant things. She has a past medical history of diabetes, but also hypertension and hypothyroidism. From a social perspective, she drinks socially, but it's important to ask how social somebody is. And in her case, it's only four times a month. Family history of relevance is that she is Hispanic and specifically of Mexican ethnicity. Her mother died of liver cancer and also had type 2 diabetes. Current medications include semaglutide, lisinopril, and levothyroxine. So, when you see a patient like this, an increasingly common scenario in hepatology practice, you need to ask yourself a couple of questions. The first is, does this patient have NASH or do they have non-alcoholic fatty liver? Is fibrosis present in this patient? And if so, to what extent? Oops, sorry. And will the patient's liver disease impact their overall or liver-related survival? So we used to think that fatty liver was a little bit more simple than it actually is, whereby if you had NASH, you had a significant risk of a risk of cirrhosis, about 20%, and that was fairly non-movable. And if you had fatty liver, you were actually going to be just fine. But in reality, that's actually not the case. We've learned now from more prospectively collected data and paired biopsy data that fatty liver disease is actually quite fluid, which makes it problematic specifically for the development of biomarkers, whereby NASH and NAFL can move from one to the other with an intermediary of borderline NASH. And then fibrosis, which we used to think was fairly static, is actually quite non-static, whereby 30% progress or remain stable over even a fairly short period of time of one to two years. So this is becoming an increasingly relevant clinical problem because it affects a lot of people. And even though only a small percentage of those people really develop relevant outcomes, it's important to note that when we look at modeling studies, specifically this one by Estes, you can see that in 2030, not just the number overall will increase, but really most relevantly, those that have decompensated disease, those that have liver cancer, and who have liver-related death. So this disease is mediated by many, many things, some of which are modifiable, and Dr. Watt will cover some of these things in the next talk, and others are non-modifiable and also require our attention and understanding. So recent estimates of the human genome suggest that there are about 21,000 protein-encoding genes and there are many important influential factors or polymorphisms that have been found to be relevant. In 2008, Stefano Romeo and Helen Hobbs' group identified PNPLA3 from data from the Dallas Heart Study. This is important because it gave us the first glimpse into why certain ethnic populations have worse disease, namely Hispanics in this case. Other genes have also been discovered that have important relevance not just to disease progression but liver cancer, so on and so forth, and some, namely HSD17B13, may have actually therapeutic target, may be an interesting therapeutic target. So not only is PNPLA3 prevalent in Hispanics, there are also data to suggest that some Asian countries also have a high prevalence of PNPLA3. So again, genetics is starting to really help us understand part of why some people progress over others. So one thing to keep in mind is that while we normally don't think of fat in the liver specifically as impacting outcomes directly, it turns out that at least for the effect of some of these genes, it may be that fibrosis or risk of progression to fibrosis may be linked to the osteotosis content in a given patient, which then I think is an important motivator in a sense to either reduce fat content by lifestyle intervention, of course that has other effects, decreased inflammatory signaling, so on and so forth, but may be I think also a motivator for patients, that they can even do something about their genetic risk. So back to this patient and more relevant to day-to-day practice are the use of clinical prediction rules. And so these are things that we obviously have at our fingertips, either the NAFL fibrosis score, which incorporates age, liver enzymes, and other key laboratory parameters, as well as the presence of diabetes or impaired fasting glucose, and the FIB4, which is even more simple. Now both of these, there are others, but these are the most highly validated in the disease, and the cutoffs are provided there. If we look at this patient, whoops, this patient, they have scores in both of these parameters that leave them right in the intermediate range, which happens in about 30% of patients. So this is not terribly useful, it's really most useful when it's very low, and that's because the negative predictive value of these tests is really where most of their use is. The other thing to note is their performance varies with age, and they can be less accurate in diabetic patients, and they may underestimate disease in leaner patients. So looking at this case from a clinical perspective, I would say this person is high risk, not just they have intermediate clinical risk score, but they also have other factors that can influence disease progression, such as family history of diabetes, family history of cirrhosis, and Mexican ancestry. So the next step would be to assess liver stiffness, and liver stiffness is something that most of us have some access to. The most common point of care technology would be VCTE or FibroScan, and this can be accurate and helpful in helping us risk stratify patients. Other modalities, such as shear wave elastography, using ultrasound-based technology is also present in many centers, and MR elastography, again, can be very useful, and I'll touch on that in a bit. So one of the most important things, I think, to remember about liver stiffness is that we're really talking about just that, liver stiffness. We're not talking about liver fibrosis, so when we do a FibroScan or measure stiffness by other measures, like elastography, you're really not measuring collagen, you're actually measuring the stiffness of the liver, which can be impacted by many things. So when you're doing a VCTE, it's important that it's, of course, a quality study, but also that fasting is present three hours or more, that there's no evidence that there's no hepatic congestion, for example, from heart failure, there's no significant cholestasis that can impact liver stiffness as well, and that there's no significant alcohol. So again, the cutoffs of this test are not uniform across populations, and they're actually not uniform across disease states, so as long as we can contextualize what we see and how we use the information, I think that it's an extremely important tool. So this is a nice study done by Shadab Siddiqui from the NASH CRN, and I think that it illustrates really nicely how you can use VCTE to answer your specific clinical questions. So if you want to know if somebody has F2 fibrosis or higher, and that's clinically relevant because it's associated clearly with worse outcomes down the road, and of course the more fibrosis you have, the more likely you are to have adverse liver-related events. And so if you use a cutoff of 8.6, you'll have reasonable positive and negative predictive value. Now if you're looking for the diagnosis, or much better, the exclusion of cirrhosis, then you can use a different cutoff, and that would be about 13.1 based on this data set. So the thing to take away from this is that look at the negative predictive value. It's .99. The positive predictive value is .39, and that's why it's critical for you not to tell your patient, Mr. Jones or Ms. Smith, you have F2 fibrosis, you have cirrhosis based on a FibroScan measure. So our patient had a liver stiffness score of 9 kilopascals and a CAP score of 300. But what if you can't do, you can't get an accurate measure on FibroScan, which does happen sometimes? There are other options. I tend to go to MRE, but you can also use ultrasound RFI, although MRE is superior from a technical success perspective. It does have a much higher technical success rate overall. And the other thing that's important about MRE is that it does, it is superior statistically to transneliastography and to RFI actually, specifically in the detection of any fibrosis and in the distinction, the identification of cirrhosis specifically. Now whether this is clinically relevant for your day-to-day practice I think really remains in question, but I do think it's an important tool and more and more centers are using it. Now there are multiple emerging biomarkers to identify NASH, so not for fibrosis, but NASH specifically. And those are, run the gamut of lipidomics, metabolomics, transcriptomics, and imaging modalities as well. And I'm not going to spend too much time on this, largely because none of them are really ready for prime time. I think the major reason for this is because the histologic lesion of NASH is really dynamic as I mentioned at first and it's very hard to match a non-invasive biomarker to a moving target. So these are interesting data from Alina Allen and Dick Ehman whereby using different parameters of multi-parametric 3D MRE they were able to correlate these findings with histologic features of NASH. So this was derived from about 155 patients split between a prospective and a retrospective data set. And they were able to identify NASH fairly accurately using a combination of PDFF, which I haven't mentioned, but it is the gold standard for the identification and quantification of hepatic fat done by MRI. So again this is promising and however somewhat preliminary and definitely requires validation. Even more preliminary but kind of interesting is the use of dynamic 18F FDG PET to diagnose NASH. In this particular study, very small study, 22 patients who underwent liver biopsy within six months, you can see that there is a correlation between K1, which is the rate of the FDG transport from the blood to the liver, and either high or low hepatic inflammation. And then also correlated with the NAFLD activity score. But this is very preliminary, just conceptually kind of interesting. So what do we have as far as biomarkers to predict outcomes? So we have the old clinical prediction rules and others at APRI and Forne's index as well that were shown in NHANES to predict all-cause mortality, particularly when they're in their high range. In addition they did appear to have some usefulness also in predicting liver-related mortality, which is a little bit... which was a little bit more robust, although there are multiple caveats within NHANES and probably most important of which in this particular setting would be a judicious account of the alcohol intake of patients, which I think is a major confounder in NASH and an influencer of disease progression that we do not account for enough. So these are data from the Symtuzumab trials that were found to be inefficacious and were stopped early. However, they did give us really important information about the natural history of NASH. This is actually the first prospective data set, a two-year follow-up looking at decompensation rates and conversion to cirrhosis. What we can see here is ELF, which is a proprietary biomarker which is comprised of hyaluronic acid, P3NP, and TMP1, was able to discriminate based on a baseline value of 9.76 on the left to predict progression to cirrhosis. On the right-hand side you can see that an ELF of 11.7 was actually able to predict at baseline future decompensation. So this is really interesting and important. However, I think the most important caveat to this is that the background population were all patients with F3 and F4 fibrosis, and it remains to be seen whether this level of predictability will be able to be applied to people who have populations of a lower prevalence. Liver stiffness can also, to some extent, present mortality. This is a nice meta-analysis of 17 studies looking at liver stiffness and its predictability to mortality and other things as well. Again, this is a mixed population of patients. This is not fatty liver disease. In fact, most of the patients here were alcohol and viral hepatitis. MRE also is promising in that regard. These are also data from a mixed chronic liver disease population, and you can see here that with total decompensation in months dichotomized by a KPA of less than 5.8 or more than 5.8 accounting for other, for example, death and transplantation. You can see that there is definitely a clear separation in those who have elevated liver stiffness who have increased incidence of decompensation. On the right, you can see the addition of a liver stiffness measure of 5.2 KPA to what we already know is an important predictor of mortality and decompensation in cirrhosis, which is a MELD score of 10. But interestingly, adding liver stiffness to this actually further enhanced our ability to diagnose such patients. So back to our case, does this patient need a liver biopsy or can you get away with no liver biopsy? I would argue that you do need a liver biopsy right now in this patient. That may not be the case in the future. So liver biopsy will change your management in the following ways. You need to remember the patient on hypothyroidism. This is actually an important and common lesion in NASH, however, it also suggests that the person's at risk for autoimmune hepatitis and you can't forget about that. So it will rule out autoimmune hepatitis. It'll give you the extent of fibrosis and henceforth, the prognosis and urgency for intervention in this patient. If it diagnoses non-alcoholic fatty liver disease, so no ballooning and inflammation consistent with NASH, then you could recommend lifestyle intervention, bariatric surgery if indicated, et cetera. If the patient has NASH with some fibrosis, you could consider the use of off-label medications that could improve liver histology. The patient's actually already on one that may have some benefits, somaglutide, or bariatric surgery, intensive lifestyle, or potentially a clinical trial. With respect to the diagnosis of NASH cirrhosis, I think we all know what the relevance of that is. It allows us to determine prognosis and, of course, to initiate important screening in this population. So in summary, patients with metabolic comorbidities in the setting of hepatic steatosis require additional workup. Clinical prediction rules can help risk stratify and possibly predict outcomes, but you have at your fingertips in most places liver stiffness assessment, which can further help you in this regard and most importantly, can help you avoid liver biopsy in some patients. NASH, liver fibrosis, or ELF, is predictive of decompensation and this is very exciting. However, it may be less so in lower prevalence populations and we need to wait future data to know that, the answer to that question. The non-basis diagnosis of NASH remains elusive and there are promising approaches emerging as well as differences in the way we analyze liver biopsy that perhaps will take away some of the ambiguity. So we look forward to those changes and with that, I thank you for your attention.

type 2 diabetes

fatty liver

NAFL fibrosis score

NASH diagnosis

liver biopsy