All right, well thank you to the organizers as well for this invitation, wow that's bright. And I've been tasked to talk more about managing some comorbidities and risk stratifying our patients that we're seeing with NAFLD and NASH. I do have a few disclosures, did they go away? All right, okay, we're good. So this is a case-based discussion as you've figured out, and we've been assigned a few topics that we need to cover. So we've got a 52-year-old female with type 2 diabetes, BMI of 38. She's had an MR elastography that's consistent with fatty liver with some fibrosis and some mild splenomegaly. So the questions that we've been tasked to apply to this are what predicts cardiovascular complications, cancer, liver disease in these patients? What's the risk factor for developing hepatocellular carcinoma and non-liver related mortality? And what treatments can reduce future morbidity and mortality? And we're going to include some discussion on alternative medicines because I think we're all seeing these patients come in with a lot of questions about a lot of things they're reading on the internet. So we're going to start off with just identifying these high-risk patients, and this is actually a really great study if you get a chance to read Paul Angulo, the late Paul Angulo, multinational study of untreated histologically proven NAFLD and NASH patients dating all the way back to 1975. But they do have 30 years of follow-up in these patients. And just looking at the multivariable hazard predictors of who's going to develop trouble, it really is based on fibrosis score. That is one of the most predictive values that we have in our patients. So any fibrosis that you're seeing is associated with an increased risk of mortality and liver transplantation. This is demonstrated in the graph here where your red line is the F4 fibrosis, and I don't think that's too much of a surprise, but you can see the grades of increased risk for mortality and liver transplantation based on the fibrosis score. What's also important is that age, diabetes, current smoking were predictive as well, and that statin use was actually protective in this study. Another multinational histologically confirmed NAFLD study. These are all patients with advanced fibrosis, so at least bridging fibrosis and cirrhosis. And you can see that the development of hepatic decompensation really drastically increases even with one additional child score, which is really quite impressive. The development of HCC is obviously higher in patients with cirrhosis than in bridging fibrosis. But again, the risk factor and the risk analysis showing age, male sex, and current smoking to be predictors for decompensation as well as HCC. Type 2 diabetes fits into this one as well now as actually the biggest predictor of both decompensation and HCC. They also went ahead and looked at other major vascular events as well as non-hepatic malignancies, so looking at non-hepatic outcomes. And actually, bridging fibrosis is associated with more of these, which is probably not too surprising since we know that cirrhosis and end-stage liver disease is one of the best cures for hypertension and hyperlipidemia, although it's not recommended. Non-hepatic malignancies are also much higher in the bridging fibrosis group, with 50% of all those malignancies being colorectal cancer. Again, the risk factors and the risk analysis, we're seeing the same things coming up. So cirrhosis, age, BMI in this group, type 2 diabetes again, apparently diabetes is bad, and LDL cholesterol is getting in there as well. So another under-recognized, although I think we're starting to recognize it more, is sarcopenia. This has also been independently associated with not just developing NASH, but also with increasing fibrosis. There's been meta-analyses now showing that NAFLD-related significant fibrosis is more prevalent in patients with sarcopenia. So this is most definitely an increased risk and something that we need to be looking for, although it can be frequently quite cleverly hidden. And alluded to by Dr. Rinella as well, so alcohol impact. So we do tend to forget sometimes maybe to take that alcohol history when somebody who is showing up that's obese, diabetic, hyperlipidemic, and everyone's getting tagged with the term NAFLD at least, or NASH. And so we do need to remember to look for all those other underlying potential liver diseases as NAFLD or NASH might be on top of that. So if you think of alcohol as potentially pouring fuel on a fire, you would be correct. And this is that same multinational study that showed any amount, or sorry, moderate consumption of alcohol was associated with more death, more HCC, and more hepatic decompensation. And this is on top of quite a bit of data out there as well that has shown to be with alcohol, any amount of alcohol being a significant risk factor for HCC. So obesity and diabetes, there's been many studies now. These are all meta-analyses looking at obesity and diabetes as far as increasing risk for HCC. There's no question that they're a risk factor as well. And then another risk factor that we're not completely aware of is people discontinuing statins might actually increase the patient's likelihood of having decompensation or death. And this was presented at a poster two years ago, and I haven't been able to find the publication on it yet, so maybe it's a grain of salt. But it at least was a huge study of VA patients where the statin was stopped within 90 days of their diagnosis of cirrhosis, and they had a much lower survival than patients that continued on their statin. Another VA study, the same group that was working in multicenter, 75,000 patients. This is not specific to NASH, but it's specific to looking at statins and looking at patients that are on statins that are existing users compared to non-users. And then they have people that, once they were diagnosed with cirrhosis, they initiated a statin. And if you initiate the statin, you actually get the same benefits of having been on it. But those that have never been on it actually had worse outcomes. And overall, each year that the statin exposure was 11% decrease in mortality. So statins are likely of benefit and at least don't stop them. And if they've been stopped, restart them. So how do we reduce morbidity and mortality in all these patients? And all these things seem pretty obvious, and we're all doing some of this stuff where you're recommending weight loss and exercise, manage the diabetes, avoid alcohol, stop smoking. I think we forget to do that sometimes. Some of the outcomes we're trying to avoid are HCC. And screening for HCC is an imperfect science, so it's recommended. And if you actually look at the studies, it's not all that frequently done in patients, particularly in patients with NASH. So patients with NAFLD had less frequent surveillance, 43%, compared to viral or alcohol-related disease. Alpha-fetoprotein might actually be of more benefit in our NAFLD patients. It has better sensitivity and specificity than other chronic liver disease patients. The trouble with screening these patients is probably the obesity. And this is actually a very interesting study that looked at ultrasound images and image quality in screening for these patients. And it's been looked at according to definitely adequate, definitely inadequate, and probably quite inadequate. So about 20% of patients have a definitely inadequate or very likely inadequate study. Only about two-thirds of patients have an adequate ultrasound image. If you look at who are those patients with the inadequate images, it's the larger BMIs. So 35% of class 2 obese patients and almost 40% of our class 3 obese patients are getting inadequate images. And certainly more common with NASH-related disease because of that association. So it is a challenging prospect because the whole idea of screening is based on cost benefit. If you're going to have to use MRIs and CT scans, then that kind of takes that out of the picture. So we do need a lot more data and a lot more information on how we're best to screen these patients. And so if you've ever wondered why hair dryers have huge airplane engines, it's because we're actually trying to use these to melt away our fat. Weight loss is the key in NASH, and I think we've seen these studies and we've seen these talks and we all know that weight loss is the key. This is a really great randomized controlled biopsy study that does show if you're able to lose the weight, although very few people did, 10% of the population that they were studying lost the weight, you can have significant histologic benefits, including fibrosis regression. It's a huge challenge to get people to lose the weight. There's studies that show you can get some benefits from the exercise, and it doesn't have to be aerobic exercise, it can be resistance exercise as well. And this study particularly shows that a lower intensity 3.5 METS type of resistance exercise had similar metabolic benefits and similar histologic benefits as the aerobic exercise. So at least getting patients that have all their OA and they can't do the cardio exercises, at least get them doing some resistance exercises. Exercise can also dramatically reduce the potential for liver cancer, at least if you're a mouse. So there's this really cute mouse study that did put these little guys on a treadmill and they actually had a significant dramatic reduction in spontaneous liver disease, inflammation, tumor development, and this is all by reduction in chemokines and various different mediators. So there can be some exercise benefits outside of just improving the steatosis for these patients. Bariatric surgery, you're going to get another whole discussion on bariatric surgery, so just very quickly, looking at the benefits to NASH histologic improvement with the weight loss that comes with bariatric surgery is not subtle. It's definitely there. You definitely get histologic benefits. Fibrosis benefits are also seen with patients that are successfully losing the weight with bariatric surgery. So if they're unable to lose weight, that's certainly a very good option. A lot of patients want to take that magic pill to lose the weight rather than getting on the exercise and diet regimen. So we're going to ask you these questions. Is there any benefit to any of these drugs? And Orlistat's been studied at least twice as far as the benefits for weight loss, or sorry, for NAFLD and NASH. A very early small study did show some steatosis benefits. Steve Harrison looked at this a couple of years ago and actually randomized patients that were given vitamin E as well as calorie reduction to Orlistat or placebo. And there was no difference in the weight loss between the Orlistat groups. But there was a histologic benefit that was seen with at least a 9% loss in weight. So the histologic benefit is shown again with weight loss, not specifically benefited by the Orlistat. So again, weight loss is the key. The other drugs that are used now commonly for weight loss, Qsimia, Belvique, Contrave. Not a lot of data out there that's specific to the liver. There's going to be some dose adjustments you're going to need for some of these based on their renal function. There's no data for sure in child's PUC patients in any of these. And there's some small groups of patients when you do the sub-analyses in some of their obesity studies that have shown some improvement in steatosis with some of these medications. Liraglutide, a GLP1, we're going to discuss in a few more minutes. The one thing to note about these is looking it up in liver talks that you've been referred to by Dr. Fontana this morning, there's no major flags to any of these drugs as far as liver toxicity goes. What about all these herbal products that everyone's coming in and asking you about? A little bit tougher because a lot of them do have liver toxicity. And so you do need to be aware of some of these drugs and at least recognize certain ones. And if you don't know, you're going to need to look them up and some of these are readily available in liver toxicity. But these have definitely been associated with liver toxicity and this is the green tea extract. This is the pill version, not the actual green tea that Lipton puts in their little teabags. So what can we do to our patients right now to try and help treat these problems that they have? They're all comorbid problems with NASH. Maybe some of them can benefit the NASH itself and we're going to be still waiting quite a number of years before we have the combination drugs that we're likely going to need to make a difference. So we've sort of talked a little bit about statins and there's going to be more discussion on the malignancy benefits to statins that we won't discuss here. But there's certainly reduction in portal pressure with statins. So if you have advanced liver disease or their patient has advanced liver disease, you can have a decrease in hepatic venous pressure gradient whether they're on a beta blocker or they've had previous decompensation. And so this is something that could be of benefit for multiple reasons in all of our NASH patients. What's sort of interesting about statins is they're not actually all created equal. And this is an interesting study that was actually done in viral hepatitis, but there may still be some applicable benefits to the NAFLD population. If you look at the lipophilic statins, which are atorvastatin and simvastatin versus the hydrophilic pravastatin and resuvastatin, and if you're looking at benefits for hepatocellular carcinoma, you see a difference in patients that are given the lipophilic version as opposed to the hydrophilic version in HCC prevention. Same with all-cause mortality. There's some benefits to both, but a little bit more benefit in the lipophilic version of statins. So if you're given a choice or you can recommend a choice, you may want to choose the lipophilic version. What about antihypertensive? So we've seen data all through the years, particularly in the viral hepatitis realm, looking at angiotensin receptor blockers and the potential benefit for fibrosis. There's also some additional benefits for fat mobilization and for fatty acid synthesis if you look between some of these sartins. So if you're comparing losartan, it's a very small study, but they compared losartan to telmosartan and actually found that you get improvement in hepatic steatosis with telmosartan. There's some PPAR activity in the telmosartan that the other angiotensin receptor blockers don't have. So there was some benefit to fatty liver. There was a decrease in free fatty acids in the use of telmosartan. So all the antihypertensives may be a little bit of a different choice as well. Histologic drugs. I think you could ask your team that are looking after your patient's diabetes to pretty much use any of these types of drugs that there may be some benefit. So we know the benefits. You've seen them all for the PPARs. The disadvantages is the weight gain. There are advantages to metformin. It may not be specific to NASH, but there's advantages to metformin in the prevention or reduction in malignancies. The GLP1 agonists, there's some histologic benefits. One small randomized controlled trial, DPP4 agents and the SGL2 agents are also starting to get into the studies looking at NASH. I don't think any of these have any overwhelming results to say you absolutely should prescribe these, but you can certainly suggest if you're going to treat the diabetes, why don't you choose one of these types of agents. Not to specifically look at this study for the PPAR agonists, but to look at it for vitamin E, because everyone asks you about vitamin E, undoubtedly. This is one of the bigger studies that showed the histologic benefits to vitamin E. There's now, as of today, there's a new meta-analysis that looked at nine studies for vitamin E. It was just published this month. And five of these studies in adults and the rest in children. And there's benefits to the inflammation cascade, at least, on histology for adults, but not so much for the pediatric population. So there can be some benefits to the vitamin E, but you also have to weigh these now with the risks that have been published. And whether they're true causative risks, nobody knows. But association studies with prostate cancer all cause mortality. There was, I didn't get to update these slides because we're not supposed to, but there is now another more recent study on diabetics using vitamin E, and it was similarly potentially beneficial in some patients. Pyoglitazone does have its disadvantages and risks as well, particularly with the weight gain. What about prebiotics? They're everywhere. Probiotics. Everyone's on probiotics now because we know the microbiome is involved in all diseases and at all times. And there's studies, these are all, this is meta-analysis looking at all the studies specific to obesity and BMI with prebiotics, so basically fiber being an advantage, probiotics not quite so much. ALTs, ASTs, improvement as well on the prebiotic side, not as much on the probiotic side. Inflammatory markers, again the prebiotics being an advantage, and some of the cholesterol studies as well, the prebiotics showing some advantage. So if fiber is going to potentially be an advantage for all these metabolic issues, I don't see as huge downside to fiber. So coffee, everyone's excited about the benefits of coffee, and of course that's the one thing we can give back to our patients as we take away alcohol, we take away food, and we can give them back their coffee. So the benefits now, there's three studies enough to warrant a meta-analysis, if you can believe, but there is an advantage to coffee. There's also some data to suggest that the real advantage starts at about three cups a day, so more is better in this particular circumstance. And this is something that most patients would be very delighted to know about. A lot of people are starting to read about green tea, and so there is actually a study that just came out from Pakistan that looked specifically at green tea, and this was basically a very specific way that they made these capsules with the tea extract, and it's not the formulated tea extract that has actually been associated with some toxicity. They had 80 overweight, non-diabetic, dyslipidemic patients randomized to this capsule that they made in the pharmacy to placebo, and they actually showed benefits in all of the metabolic parameters, including adiponectins, inflammatory markers, et cetera. It basically covers the same polyphenols and antioxidants that coffee does. But we do need to be very wary about the issues with the green tea extracts that we've actually been seeing patients with hepatotoxicity. Other supplements that people keep coming in asking about, curcumin, turmeric, cardamom, there's a little bit of data out there. There's randomized controlled trial in the green cardamom. It does show some potential benefits to liver enzymes, fairly small studies, no BMI or really liver AST benefits, not really quite clear how much help it's going to be. There's enough data out there in turmeric that there's been a systematic review of the four to six randomized controlled trials with 228 patients, and there was an improvement in liver enzymes, we can say, not really much else as far as improvement in NASH. There's a meta-analysis of these studies looking specifically at weight loss, and there was no change in body weight or waist circumference. Carnitine, there's one randomized controlled trial that's looking at liver enzymes and histology benefits, and they did not necessarily find those benefits. Vitamin D, there's actually been seven randomized controlled trials, no real effect on pretty much anything that was measurable, and so you can take it for all the other reasons but maybe not for their NAPL or their NASH. And the other thing to caution your patients about, because we are kind of trying to give them dietary suggestions, is to really avoid these artificial sweeteners. So there's a lot of different effects these artificial sweeteners have, none of which are good as far as NASH, obesity, diabetes, and all of our metabolic issues. So artificial sweeteners are affecting the microbiome, they really interact with your neuro-humoral hormonal access, and that's basically shutting off your, you eat the food, your food's supposed to trigger satiety, and it's just shutting all of that off. It alters the energy balance, it alters glucose homeostasis, and they've actually even shown that calorie consumption increases if you're eating these artificial sweeteners. And they've done swap-out studies where someone thought they were taking, you know, a regular Coke or a regular drink, and then they gave them an artificial sweetener, and they didn't increase their calorie intake. So if you actively know you're eating something without calories, you'll ultimately eat more calories. And so there's actually definite weight gain that happens in these patients. So the takeaway points from all of this is, the risk for bad outcomes, this is not a huge surprise, advanced fibrosis, diabetes, age. If you're trying to help manage these metabolic syndrome patients, suggesting that they be on the statin, at least don't stop the statins, give them coffee, give them prebiotics such as fiber, and I'm definitely not Bob Fontana, so, and give them their coffee. So the best thing that we can do is to actually allow our referring providers to know how to treat the metabolic syndrome stuff. So you're basically empowering them to start the statins, tell them which oral hypoglycemics may be of benefit. I'm already done, so we don't need to bring it up. Anyways, thank you very much.

NAFLD

NASH

comorbidities

risk stratification

fibrosis score

liver transplantation