Good morning, I would like to thank the organizers of the Hepatology Associates course and ASLD for the opportunity to give this talk on controversies and cirrhosis. I have nothing to disclose, I have a lot to disclose but not for this talk. This morning I've been given a big task in 20 minutes so here's the four main objectives that I'd like to cover with you. We're going to discuss the use of beta blockers in portal hypertension management, we'll be evaluating the use of prophylactic antibiotics in spontaneous bacterial peritonitis, we'll describe some herbal medication use and cirrhosis, and finally briefly discuss the recent warnings from the FDA in hepatitis C treatment and the cirrhotic individual. As previously mentioned in Angela's talk, ascites and portal hypertension are two consequences of cirrhosis that often lead to mortality in these patients. Therefore treatment strategies and interventions are important to prevent late decompensation episodes and death. Acute on chronic liver failure is a syndrome that develops in patients with acute decompensation of cirrhosis and is associated with high mortality. It is present in 25 to 40% of hospitalized patients with cirrhosis and is associated with systemic inflammation as evidenced by elevated C reactive proteins and elevated white blood cell counts. Infection and alcohol are the major triggers, however in 40 to 50% of cases often there is no identified trigger. The European canonic study identified three types of patients. These three groups of acute on chronic liver failure are characterized by higher mortality with the type of organ failure a risk factor for this mortality. The kidney was the most often affected organ, therefore we always have the mantra of protect that kidney. Mortality rates are directly proportional to the number of organ failures and you can see here with higher mortality rates in those with two to three organ failures. Portal hypertension is a main consequence of cirrhosis and is responsible for many of its complications. ASLD guidelines provide recommendations based on risk stratification and the need for individualized patient care. You can see here that those with compensated cirrhosis may or may not have varices while those in decompensated stages almost always present with varices. Mild portal hypertension is hepatic venous pressure gradient greater than five but less than 10 millimeters of mercury and in these patients there's no indication for treatment with beta blockers and you want to focus on treating the underlying cause. Clinically significant portal hypertension is hepatic venous pressure gradient greater than 10 and is present in 50 to 60 percent of compensated patients without varices. It increases the risk for the development of varices as well as clinical decompensation including ascites, GI bleeds, and hepatic encephalopathy and as well as increases the risk for the development of hepatocellular carcinoma. In these patients non-selective beta blockers to prevent bleeding and reduce mortality are indicated. Non-selective beta blockers lower portal pressure as well as reducing the bacterial translocation and we know our major side effects of these are hypotension, fatigue, and weakness often leading to some patients not being able to tolerate these medications. Cirrhosis is characterized by diffuse fibrosis causing severe disruption of the intrahepatic arterial and venous flow leading to increased portal hypertension with a hyperdynamic circulatory picture. Beta blockers most important effect is the decrease in cardiac output via beta 1 and beta 2 receptors which reduce portal inflow. Carvedilol also has the additional intrinsic anti-alpha-1 adrenergic activity which also helps with the vasodilation. So let's briefly talk about compensated cirrhotic patients without varices with the goal of therapy in these being to prevent clinical decompensation. In 2005 a beta blocker trial showed no difference between placebo group and the beta blocker group in the prevention of varices. And so here's a study that was recently published in the Lancet this year aiming to evaluate patients in preventing decompensation episodes in these patients. So the study enrolled 201 patients with compensated cirrhosis and clinically significant portal hypertension without high-risk varices. 101 patients received placebo and 100 patients received either propanolol or carvedilol. The primary endpoint was the incidence of cirrhosis decompensation as defined by the researchers as the development of ascites, bleeding, or encephalopathy. The results of this study show that decompensation occurred in 27% of the patients in the placebo group compared to 16% of those in the beta blocker group. And the researchers felt the difference was due to the decreased incidence of ascites in the beta blocker group. The overall incidence of adverse events was similar in both groups. So what about compensated patients with varices? And the goal in these patients is to prevent a bleed or variceal hemorrhage. With the reduction of portal pressures greater than 12 or greater than 20 percent, less than 12 sorry, or greater than 20 percent from baseline portal pressure shown to be protective and considered response to beta blocker therapy. How about our patients where we want to present a re-bleed in those individuals previously having a GI bleed? This is high risk of re-bleeding occurs in the first year and is often associated with increased mortality. Therefore the first line of therapy is to use beta blockers with endoscopic variceal ligation or banding. If an individual has had a placement of a successful TIPS, then beta blocker therapy is no longer indicated. These are very important special considerations and this deals with the information around when do we stop our beta blockers. Certainly doses should be reduced or discontinued in any patient with refractory ascites, especially with signs of severe circulatory dysfunction such as hypotension, hypernatremia, and deterioration in renal function. Remember protect those kidneys. And then finally individuals that are bleeding while on beta blocker therapy, you want to continue the beta blockers as well as treatments with endoscopic banding and possibly considering TIPS in these patients. All right, let's move on to the topic of ascites and spontaneal bacterial peritonitis. The guidelines for ascites management both from easel as well as ASLD show us in the first line ascites management we certainly want to stop alcohol use, restrict sodium, dual diuretics are used, discontinue the NSAIDs and in these patients make sure you refer for transplantation evaluation. For patients that continue to struggle with ascites you want to discontinue the beta blockers as I previously mentioned as well as any nephrotoxic drugs. This is patients you consider octreotide and metadrine as well as therapeutic paracentesis and TIPS and always remembering to refer for transplantation. Spontaneous bacterial peritonitis is an infection most often caused by gram negative bacteria migrated from the intestinal lumen to the acidic fluid via the systemic circulation. It accounts for mortality in about 40% of our patients and is the most common infection in severe alcoholic hepatitis patients. Those at risk of developing SPP include our cirrhotic patients, those with low protein status in their ascites fluid and patients with elevated total serum bilirubin greater than 2.5 as well as individuals that have had a previous episode of SPP or variceal hemorrhage. There was a systematic review published this year which aimed to evaluate the benefit and harm of different antibiotics used in SPP treatment and decompensated cirrhotics. The review included 12 intervention trials with over 1,200 patients included with follow-up periods of one week to three months in these patients. The majority of patients were giving third-generation cephalosporins or ciprofloxacin with 75% recovering from their SPP. There was a 25% mortality within three months in these patients. However, compared to the different types of antibiotic use there was no difference in mortality, adverse events, resolution of SPP or decompensation which led the researchers to conclude there's significant uncertainty which exists about which antibiotic is better. So can we influence or prevent episodes of SPP with use of antibiotics? So this is certainly a controversial subject. Primary prophylaxis of SPP is the long-term use of antibiotics in those at high risk for developing SPP with ascites. The drugs that are typically used include the fluoroquinolones with a sulfa antibiotic as another option. Secondary prophylaxis includes long-term use of antibiotics for those individuals who have had an episode of SPP and you're trying to prevent another episode of SPP. In this study that was presented at ESL last year and published this year looked at outcomes in patients with in cirrhosis between primary compared to secondary prophylaxis for SPP. The database from the North American Consortium for the Study of End-Stage Liver Disease was used and included hospitalized patients with cirrhosis from June of 2013 to January of 2017 from 14 tertiary hepatology care centers here in the U.S. SPP was defined as greater than 250 PMNs in the acidic fluid and admission in 90-day follow-up periods were assessed. The study enrolled a total of 2,731 patients with 2,239 not on SPP prophylaxis therefore it left the research with after propensity matching for MELD scores and serum albumin on admission a group of 154 patients in each group 154 receiving primary prophylaxis and 154 receiving secondary prophylaxis. 75% of these patients were on fluoroquinolones at the time of their admission and the average length of prophylaxis prior to admission was anywhere from six to eight months. So here's some outcomes in the inpatient and I don't have time to go through these individually so let me give you some of the highlights. Those individuals on primary prophylaxis were found to have a greater incidence of systemic inflammatory reactive syndrome leading to more in ICU admissions. The secondary prophylaxis group had a greater number of infections upon admission as well as episodes of HE and decompensation and requiring rifaximin use. 25% of these patients were admitted with SPP. Looking at the 90-day outcomes in these patients you'll notice that in the primary prophylactic group there was a higher incidence significantly difference in the two groups between acute kidney injury and mortality. Therefore the conclusions from this study is that patients on primary prophylaxis had a higher rate of ICU admissions, acute kidney injury, and mortality compared to the secondary prophylactic group despite similar lengths of stays and development of acute on chronic liver failure. Liver transplantation rates between these two groups were similar and even with our primary and secondary prophylaxis of antibiotic use 10 to 25% of these serotics still developed SPP. Now switching gears to our third topic here I have a case study. This is a 58 year old Hispanic female referred to your office for hepatitis C evaluation. She has a history of diabetes type 2 and is controlled on metformin and takes some vitamin D with calcium. She was screened by her primary care and found to have hepatitis C antibody positivity. As part of your evaluation you notice that she has a BMI of 33.9. Her physical exam shows no ascites however pulmonary erythema. Her labs tell you that she's a genotype 3 with a viral load and platelets of 110. On EGD she shows no varices and her CAT scan shows no liver lesions and no ascites. You perform transient elastography by fiber scan which shows a CAP score of 290 indicating fat in the liver and a kilopascal of 12.4 which would put her in a grade 4 or stage 4 cirrhosis picture. So you diagnose her with chronic hepatitis C infection possibly NASH and stage her as a compensated serotic and here's the million-dollar question. You're discussing hepatitis C treatment and she wants to know if she can do herbal products or a liver cure lens right? How many times in our office do we see patients bring these bottles? This is a big business with lots of patients out there wanting to use herbal products. However we really have a lack of information and data to tell these patients especially in human studies. So does it help or does it harm? This is a great reference to investigate if we have data and where is the data on liver injury from herbal and dietary supplements. So this is information from the DILI network and in this case you would call it HILI, the herbal induced liver injury and so this it's amazing what you can find on this site. There's a lot of great data. I just pulled two for you that I think are probably our most frequently asked question. You know the question of can I take what milk thistle? Does milk thistle help me? We know milk thistles are herbal product. Silymarin and animal models show prevention or amelioration of acute liver injury. However human studies are really inconclusive. A recent meta-analysis showed that reduction in AST and ALT but without clinical significance. Turmeric or curcumin is another plant root that's very popular due to its anti-inflammatory and antioxidant effects. It's generally considered safe however there have been reported cases of idiosyncratic liver injury and transient elevations of liver enzymes. And finally let's briefly discuss the FDA safety concerns that were raised at the end of August for use of PI containing DAA regimens in hepatitis C patients. The package inserts state that these drugs are used to treat chronic hepatitis C patients with moderate. The use of these drugs in moderate to severe liver impairment has resulted in cases of worsening liver function or liver failure and therefore the PI does not have an indication for use in your decompensated patients. The FDA received reports of 63 cases of worsening liver function, including liver failure and eight deaths in patients that were receiving PI-containing DAA regimens, and yet the graph shows you the breakdown of which regimens these 63 cases were receiving. However, upon further investigation of these cases, many of the cases were either classified as not having cirrhosis or having compensated cirrhotic. However, there was evidence in these cases of more advanced liver disease with risk factors of decompensation, such as low platelets or portal hypertension, raising the issue that many of these patients were probably misclassified by being put on their hepatitis C treatment. So in closing, non-selective beta blockers are an important intervention for many cirrhotic patients with portal hypertension. SBP is a significant factor in mortality of cirrhotic individuals, and treatment with broad-spectrum antibiotics as prevention may need reconsideration. Herbal and dietary supplements are commonly used by patients with liver disease. However, there is a need for more human studies to show benefit versus risk. And finally, monitoring of hepatitis C cirrhotic patients while on HCV therapy remains critical. ASLD has recently updated their guidelines to help us around this area of who needs more close, careful monitoring in which patients can be monitored with unique intervention, innovative intervention, such as what the data presented from the SMART-C study at ESL. Thank you very much for your attention. Thank you both for two amazing talks to get us started this morning. At this time, we're going to have a panel discussion. We'll open the floor to some questions that you all may have from the audience that you're curious about and using their expertise to answer those questions. So microphones are in the aisle there on each aisle, so I invite anybody who has questions to go ahead and come up to there. And in the meantime, while we're waiting on a couple people to come up, Janan and I have come up with a couple questions that we were kind of thinking about as we were sitting down listening to these great talks. So I'll start with Angela. Do you have specific recommendations that you would have as far as treating for osteopenia or osteoporosis as far as calcium and vitamin D supplementation? Any particular choice that you would normally use? No, I think it's because of the formularies, because of what the insurance recommends. It's really just a standard dosing of calcium, maybe like 1,000 milligrams. The vitamin D can just be over the counter. As far as the prescription strength, I think that would be based on the DEXA scans. And then individual ones, of course, based on what the insurances would recommend. Do you recommend daily or twice a day? Twice daily. Twice daily. Right. Good. For Dr. Posa, do you have any sort of sway one way or the other for a non-selective beta blocker? Which one do you primarily choose? And do you have a preference of why? Well, I think with the carbidolol, you have the additional benefit of the vasodilation in addition to the portal inflow issues. And so you possibly have an agent that as well doesn't seem to have the heart rate sensitivities like the propanolol and nalol do. So I think that would be my drug of choice. Don't be shy, guys. For Angela, what do you recommend as far as imaging if you don't have readily available an MRI or a very specific type of CT scanner? Thinking more of a rural area, what and how would we be able to get imaging for that type of patient? Yeah. I think in that situation, then you would have to rely on the ultrasound. And somebody who ideally has less abdominal fat than an ultrasound imaging could actually show you what you need to see. And over time, it would not be based on one simple image. It would be based on CRL images. And if there's a trend towards an increase in the size and there's no dynamic imaging, if there is an increase in the size and an increase in your concern clinically, then it may warrant a diagnosis, I mean, a biopsy. Okay. Good. We have a question. Oh, I'm sorry. Go ahead. Hi. My name is Professor Amir from Pakistan. Could I just ask you about your banding program? We found out for various reasons because of cost and things that once you ablilitate, we don't band them very frequently. So instead of two weeks or four weeks, I mean, what is the protocol you guys are following now? Do you want me to say? So I can speak to what the program does at Yale New Haven Hospital. And so for primary prophylaxis, as Renee had said, we really rely heavily on non-selective beta blocker. We found that with, and it could just be a geographical thing, but we tend to use propanolol or natolol a little bit more just because carvatalol actually is a little too good sometimes and can lower the blood pressure and the renal perfusion in a more further decompensated. So when it comes to the point of thinking about, and you're thinking elective banding as opposed to emergent. Is that right? Yeah. So if it looks like maybe there are some red whale signs or a suggestion that there's some high risk stigmata and maybe they need to be banded, they would be banded and then about four weeks later go in again. If it looks like there's still sizable varices that require banding, it's every four to six weeks after that until obliteration combined with a non-selective beta blocker. We would have a similar protocol banding at about going back in and looking six weeks later to make sure you don't need to do further banding. Thank you. Good morning. Nice presentation guys. Thanks very much for sharing with us. I was intrigued by one of the early comments. It's not exactly a controversy that was elucidated in the larger amount of slides, but one of the comments early on about early liver transplant consideration. Could you expand a little bit about that and what you mean in terms of as soon as you see them, no matter what the state of presentation is and the significance or not of when to consider liver transplantation? Yeah. So for sure. So I'm sure I'm not unique in that I've had people come in who literally just did heroin like an hour before or maybe they come in inebriated. And those I think are the obvious no's, but for the people who are not the obvious no's, then in your mind, if you're not thinking about it, then it won't be thought about. So I go through all these decompensations in my mind and even as I'm doing my notes, I make notes to myself that improvement from last visit, they now have shown better insight. So there's really a spectrum of you can actually see them becoming a little bit more of a candidate. And then once you feel that they have reached a point where they show good insight and they have really great social support and they've been abstinent, then it's time for referral. But if you don't bring this up with the patient, they may actually not even know that transplant is an option for them. But if you have that conversation very early, it may change their mind about maybe some behaviors. It may not. But the best you can do is try. Thank you. We have another question over here. Good morning. Thank you. Excellent information. For patients with severe osteoporosis who have esophageal varices, how are you handling those patients? Yeah. That's a really tricky group. Thank you for bringing that up. So that group, you really want to move away from the alendronate. That's a tough one to say. The bisphosphonates, just because of the increase in the gastric acidity and irritation. So in that situation, we would incorporate the use of either the primary care physician or an endocrinologist, just because that's a very specialized group that needs individualized attention. As far as the varices, we would just manage them as we normally would with non-selective beta blocker. Or if it looks like there's stigmata, then potentially with Band-Aid. In that same vein, if they presented with larger varices and they were better controlled on a beta blocker after banding on repeat endoscopy, would you consider allowing them to use bisphosphonate? Because this is a question I've gotten from primary care providers in my area. Yeah. In that situation where they're better controlled, it would be okay to do. But then we usually do still take the recommendation of the endocrinologist and make it a multidisciplinary approach. Thank you very much. Yeah. Thank you. Go ahead. Hi. I'm a little bit confused. I thought I was told the management of varices has changed, so we're doing EGD now, like every six months with banding as needed and then we're stopping the nonspecific beta blocker? Do you know that? So for screening for varices, if patients don't have varices, the recommendations is every few years in your compensated serotics, you know, more frequently and certainly anyone who's had episodes of decompensation and the use of the beta blockers is there to prevent further, for prevent decompensation, especially with the evidence. Now remember that you want to protect the kidneys and so certainly looking at renal function and patients with decompensation, those are the patients you definitely want to consider not using the beta blockers in. But still I would say that the majority of patients that are looking at managing your varices, beta blockers are recommended. Yeah. There's very specific in the ASFD guidelines when to EGD, what MELD score, and you can't do both unless you really need to. Whatever is in the guideline is still active, right? We haven't transitioned to just doing EGD because... There's been no changes recently in the guidelines, but I think what you might be referring to is just a couple years ago there was a very real scare about using beta blockers in the further decompensated serotic and maybe precipitating HRS-2 physiology so that you're actually worsening the renin-angiotensin-aldosterone physiology and actually increasing ascites and increasing portal pressures. And what happened was that that whole physiology was evaluated and while that's true and you do want to be careful with using beta blockers when the mean blood pressure is less than 90 or so, what we do know from the studies since that time is that the overall mortality and morbidity is lessened with ongoing use of beta blockade. And this is where you would probably just use a non-long acting one, so maybe propanolol and titrate the dose a little bit so that you're not experiencing such tremendous reductions in the blood pressure and renal perfusion pressures. Thank you. Sure. Thank you. Good morning. My question is for Renee. Thank you guys this morning for such a great presentation. So Renee, my question, I'm a little confused. So primary prophylaxis for SBP, your data was very intriguing that it may be not helpful to treat primary prophylaxis. What is your practice? Yeah, so I think this is really making us reevaluate both the impact of bacterial resistance. Many of these patients in many of these studies have been on fluoroclonolones and we all know what kind of resistance patterns we're seeing in these patients as well as the patients that were coming in with SBP were coming in with ground positive SBP, reasons for their SBP, right? So I think we can't underestimate the bacterial resistance and the use then of trying to prevent something with antibiotics and what are we doing to patients. As well as in that primary prophylaxis group, the incidence of almost acute on chronic liver failure or inflammatory markers in kidney, you know, that's concerning. So I think it does raise in that group of patients, are we benefiting them or are we potentially causing harm? So I think it is something for us to reconsider and I think both, we were talking about this last night, that those are a group of patients that probably, certainly you can make a case of putting in secondary prophylaxis for those with SBP episodes, but those that have never had one, reconsidering your use of antibiotics in those patients. Thank you. Thank you. Do you want to ask yours? Yeah. Okay, I have a question, more for Angela here. So sometimes, you know, you presented a case where somebody who's fairly well compensated, decompensated. And that can sometimes be a very traumatic event that can really precipitate some significant psychological distress, can be very overwhelming. How do you see a good way to incorporate psychological support into your hepatology practice? So some clinics are very well suited, such as our transplant clinic at Yale where they have social workers, psychologists. Unfortunately, Christine and I really didn't. So we became the therapist for these individuals. And that's a great point because in general, we look at what's really objective in front of us. They have ascites. They have a variceal bleed. And the non-objective part of this is definitely going to play a role. So I think in addition to taking care of all the clinical aspects, you also have to make sure that from a mental health perspective, they're doing well. I rely very heavily on the primary care physician and I recommend the patient seeing a therapist as well. Thank you. Sure, thank you. Hi. My question is that a lot of times we get patients that have been hospitalized for SBP and the beta blockers are withdrawn. And most of these patients are secondary on beta blockers for previous history of bleeds. So my question is, how long do you wait to put them back on the beta blockers and if you do so? Well, I think it's looking at the picture of the patient, certainly looking at that kidney function as well as your screening or evaluating with endoscopy, the varices and looking at what they're doing. If they fall back into those categories where you feel comfortable reinitiating, I would start on a low dose of a propanolol for a beta blocker. But I think it's going to be individualized to the patient. Okay. Thank you very much. We're going to move on to our next speaker. So I want to thank Renee and Angela for giving us an excellent talk on these first two topics.

hepatic controversies

cirrhosis management

beta blockers

portal hypertension

spontaneous bacterial peritonitis

FDA warnings

liver transplantation