Good morning, everybody. I'd like to thank the chairs for having me here and the education committee for asking me to be here today. I'd like to use this opportunity more as a to open up what an amazing opportunity this is for the associates course. It's going to be an introduction to a lot of the talks that you're going to hear a little later on. And I'll make references to who's going to give you those talks. So I have nothing to disclose. No, I think we're all familiar with the progression to cirrhosis, but this is going to be an area that we're going to need to keep in mind when we're thinking about the various decompensations and what's happening intrinsically within the liver. The natural history of progression to cirrhosis is usually between 10 and 20 years to a state of compensated cirrhosis. And then after that, you tend to experience your first episode of decompensation. So the first line is the years to this area. The second line here speaks to cirrhosis, decompensated cirrhosis, and then the further decompensated cirrhosis, where you have a lot of your refractory symptoms. And then the next line relates to the hepatic venous pressure gradient, or the pressures within the sinusoids. The decompensations usually occur when there's decompensated cirrhosis where pressure gradient's greater than 10. But you'll notice that non-bleeding varices actually crosses that border. So non-bleeding varices are not specifically a decompensation, only when they do bleed. So I'm going to start off with a case presentation. We have a 56-year-old gentleman who has a known history of alcohol abuse, alcohol-related cirrhosis that thus far has been compensated, and he's obese with a BMI of 33. He presents to your post-hospital clinic after a hospitalization for volume overload, which manifested primarily as ascites, which is new for him, and lower extremity edema. His ascites was characterized in the hospital, meaning that they did a diagnostic paracentesis, they did the protein, found it to be low, and a serum albumin, comparing that to the fluid albumin gradient, and it was found to be high. He was seen by a dietician to review the need for a low-sodium diet, and was started on the standard dose of ratio of the Lasix and L-dactone of 40 and 100. So what next? You're seeing him now, he's never been seen before. So the knowns are that he's 56, he has long-standing history of compensated cirrhosis, he has a new ascites, which tells you that there's some decompensation, whether it's an acute or chronic event, or natural progression, and he was started on diuretics. So you wanna think about what his volume management is, what his variceal status is, what his nutritional status is, his bone density status, does he have any hepatic encephalopathy, or is he at risk? How about HCC screening, has that been done? Or is he a transplant candidate? And this is enough to make anyone crazy, especially in a 20-minute visit. So you wanna think about all this in a very systematic approach, and if you do it in a systematic approach, you'll tend not to miss anything. You wanna think about things in terms of why the management needs to be done, as well as what needs to be done. So with regards to ascites, the why for ascites is we know that the development of ascites suggests increased portal pressures, and that often correlates with a decline in the hepatic synthetic function. The presence of the ascites suggests to you as a clinician, you know that without transplant, this person has probably, at most, three years without transplant to live. So when you see the presence of ascites, automatically you also wanna think about, is this person eligible for a liver transplant? In characterizing the ascites, you wanna do this in terms of protein. If there's a high protein versus low protein, that can actually tell you a little bit about where it's coming from, along with the albumin. You wanna know the current diuretic dose. You want to know the patient's dry weight, where they were before they developed the ascites, because that will be essentially your goal to get down to. And then you also wanna know if they've ever had a history of bacterial peritonitis. In this person, probably not, because he's never had ascites. But it's important to know their status, and if they need to have primary versus secondary treatment. Excuse me, you'll hear more about this in one of the controversies from Renee. The nutritional status plays a huge role in liver disease. And what we are understanding more and more is that the nutritional status directly correlates with morbidity and mortality outcomes. The presence of sarcopenia or lipopenia actually portends a worse outcome. And there's been consideration to include sarcopenia in the MELD score for this reason. What you wanna do is really focus on your physical exam. You wanna look at the axial skeleton and look for muscle loss and fat loss. You wanna measure hand grip, how easily or how not so easily they rise from their chair, and also their unassisted ambulatory speed. There's also programs that can be incorporated into your radiology department that looks very specifically for measurement of sarcolipopenia through MRI or CAT scans. And this is a standard patient who we see with gross ascites as well as axial sarcolipopenia. Now the variceal status, we're all very acutely aware of this. The why is of course to assess for the risk of variceal bleed. And how we wanna go about doing this is through upper endoscopy as the gold standard. Capsule endoscopy has also been used. I'm not in a position to comment on that fully during this venue. Once we know that varices are present, the use of non-selective beta blockers versus banding or a combination of both is generally incorporated with focus on the heart rate and aside from the use of Corgar, I mean Carveda Law. If there's no varices at the time of the initial screening, then keep in mind that that's not gonna be just the only time that they're screened. They will need to be screened frequently, so every one to two years following that. So the picture on the left shows you esophageal varices that are pretty large. I'm kind of old school, so I do the grade one, two, three, and four, but the newer ones are large and small. So I think we could agree that these would probably be grade three or large. The picture on the right is a gastric varix that looks pretty angry. And this one is dropping down from the gastric cardia. Now bone density is something, it's sort of, it should be in the forefront of your mind with any liver disease. I think we think about bone density and bone mineral demineralization more so in the setting of the cholestatic liver diseases. But the reality is that this bone mineral demineralization actually occurs in all of end stage liver disease on the basis of a lot of different, it's multifactorial. So you have the presence of hepatic osteodystrophy leading to osteoporosis or osteomalacia. This occurs in general up to about 30 to 40% of people in those with chronic liver disease. Again, more so in those with the cholestatic liver disease because of the altered regulation of vitamin K. Chronic liver disease, in chronic liver disease you have altered regulation of interleukin-6 and tumor necrosis factor alpha. These cytokines, these are pro-inflammatory cytokines. They increase the effect of osteoclasts which lead to a breakdown in the bone. So the adipose derived cytokines such as adipokines, such as leptin, they tend to inhibit this process but actually by doing so they stimulate other pro-inflammatory cytokines that then lead to a reduction of bone resorption. It's estimated that in the course of somebody's lifetime, 40% of people will be either at risk or have a fracture secondary to reductions in bone density either on the basis of dysfunction and resorption or breakdown. Additional factors that lead to bone density dysfunction and demineralization include a previous fragility fracture, post-menopausal women, premature menopause before age 45, secondary amenorrhea, male hypogonadism. This occurs oftentimes with the HFE mutation or hemochromatosis, low BMI less than 19 and in our sarco-lipopenic patients this is oftentimes where we would see people and glucocorticoid therapy and it doesn't take much. Maybe it's actually less than physiologic which is seven. So as little as three months of five milligrams daily it can affect your bony demineralization. So what do you want to do to evaluate this? And the easiest thing to do, you want to check their calcium and vitamin D but you also want to check a DEXA scan as a baseline. And pre-transplant you may also want to consider additional measures such as if there's a family history of osteoporosis, you want to get their thoracolumbar spine x-rays or serum calcium levels. In men you want to get free testosterone levels. And then you do want to be aggressive in repleting the calcium and vitamin D. Other agents such as estrogens, bisphosphonates, testosterone, calcitonin, those all have risks associated with them and that one you just need to weigh the benefits with the risk and their use. Now this is a DEXA and there's a lot of areas that you want to, that are displayed as far as numbers. The most important one is the T. So you want to get the T value. The T value is a value that looks at the density of somebody who's about age 30 and the reason for that is because that's when your bones are the most tense. And a normal T value actually ranges between negative one and one. So our example here within .77 is actually normal. I wouldn't mind having this bone mineral density scan. And then when you're looking at the presence of osteomalacia, it's a presence between negative one to 2.5 and then less than negative 2.5 is osteoporosis. The Z-matched zone is looking at it based on age-matched individuals. If you're gonna look at the one thing that tells you the most information about your individual patient, you would want to look at the T zone. The next one that you, the next to compensation that you want to be aware of is hepatocellular carcinoma and do hepatocellular screening. The reason is that it's really the, one of the most common primary liver cancers and it's actually the sixth most common malignancy worldwide. There's variable risk factors associated with chronic liver disease and there's variability within hepatitis B where you don't actually have to have cirrhosis. It incorporates into the host DNA along with hepatitis C, alcohol, and then some of the metabolic processes such as NASH and alpha-1 antitrypsin where again you don't also have to have cirrhosis. Now hepatocellular carcinoma screening as it relates to coffee, I think we all know that coffee has some really good effects and we may actually hear a little bit more about this later on from Caitlin and Dr. Harnoy. What I'm just gonna encourage you to do is just keep drinking your coffee for now. So how do we want to do screening? We want to initially do this with an ultrasound with or without an alpha-fetoprotein. We know that about 60% of the tumors that develop don't secrete alpha-fetoprotein but it's still currently within the guidelines. As far as dynamic imaging, you can also choose triple-phase CT which looks at the various phases of arterial enhancement, washout, and then the presence for a pseudocapsule along with an MRI that looks at the same thing. Now in an MRI, this is what you would typically see with the presence of a hepatocellular carcinoma. In A, you're seeing arterial enhancement and it's very bright. In B, you're seeing the portal venous washout so it's very dark and you're also seeing a very nice pseudocapsule around the lesion. Any patient that comes through your door, even if they're actively drinking, even if they're inebriated in your clinic, you still want to think about if they're a transplant candidate. And the reason for that is because if you don't think about it, it's not gonna be thought about when the need comes. So this is a conversation that needs to be held very frequently and very early. And this should be considered for all liver disease carriers who have experienced any sort of index complication, meaning if there was a decompensation of a variceal hemorrhage or a CITES. How you wanna do this is by determining their MELD score and their CHILD scores and we'll hear a little bit more about that from Carolyn later on. You want to assess for any absolute contraindications and again, I'll leave the details to Carolyn. Optimize their eligibility. So if you find that maybe they're not the best candidate right now, it's nicer for you as a clinician to state how you're gonna optimize their deficiencies rather than saying you're not a candidate at this point. So again, just hold the discussions early and very often. Now, putting this all together for our patient, our 56-year-old gentleman who came in with liver disease with the new ASCITES, and when you're trying to organize the information, you can do it as follows. So the ASCITES was characterized as low protein, high SAG. He's stable on his current regimen. His current weight is 180 pounds at discharge and his weight today is 176. So knowing that he was recently discharged, you're thinking is that too fast, is it too slow? It sounds like it's just about right. You know that his dry weight is about 170, so that's where you're gonna be aiming towards. You're gonna continue the current dose of the diuretics of 40 milligrams and 100 milligrams and then you wanna have him weigh himself on a regular basis. I usually tell my patients to weigh themselves daily and if they have more than a three pound weight gain or loss over a one week period to give a call because you don't want anything more aggressive than that in the outpatient setting. You wanna reinforce the low sodium diet and then order scans to observe for vascular patency. Now his ASCITES appeared to be intra-sinusoidal, but if it was a post-sinusoidal process, then you may want to look outside of the liver or outside of the sinusoids for a reason for having high proteins. Variceal screening, he's not undergone that in the past, so you order that during that visit and then you make sure that it is ordered. If it can't be ordered, why? And when you plan to do it next. His nutritional status, you wanna comment on the degree of sarco-lipopenia. If he needs any increased recommendations for protein. At Yale we usually do pretty aggressive protein restrictions so usually about 1.7 grams or more of protein per kilogram per day based on a pre-morbid weight and that's the important part. And so it gives you X amount of protein to really shoot for, but it's a marathon. It's not a sprint. So even if they increase their protein intake by 10% following your visit and then increase from there, it's still gonna benefit them. Bone density, you wanna know which type of chronic liver disease they have. If you've ordered a DEXA, what the prior DEXA has showed. If they've ever had any kind of fracture or steroid use or any other risk factors for bony demineralization. And also comment on what their replacement is. For hepatocellular screening, you want to know if there's ever been any sort of dynamic imaging, what it showed, and then what you plan to do in follow-up. For a transplant candidacy, you wanna know, even right now if they're not a candidate, you want to still note what their MELD score is, what their child score is, what their positive aspects are as far as social support, how long sober they've been, what their long-term sobriety plan is. And then continue to follow them and encourage them on a daily basis. I like to also include a general area, looking at their vaccine status and looking at hepatitis A, B, C, and HIV. And if they have immunity from either vaccine or innate. And if they don't, if you plan to vaccinate. The last one is a very etiology-specific treatment. And it just relates to anything that's not previously said. So for example, if there's any kind of phlebotomy necessary for HIV, or for alcohol, ongoing abstinence, or anything other very treatment-specific. The key takeaway points that I would like for you to go home with is that management of patients with chronic liver disease is absolutely complex. It requires a multi-system, and you almost have to predict what's gonna happen in order to manage the common decompensations. And this is where the first screen comes in with the HVPG and the decompensations. Performance of screening and surveillance tools will definitely help you to identify where on that spectrum your patient lies. And then this will allow you to have a timely intervention or referral for possible liver transplant and early interventions. And that's it for today. Thank you.

cirrhosis

decompensated cirrhosis

liver disease complications

alcohol-related cirrhosis

patient management