Good morning to everybody. This morning I'm going to be talking about the management of variceal bleeding and cirrhosis. I have no disclosures. So first I want to just define cirrhosis and portal hypertension before we get into the development of varices and how we treat them. So cirrhosis is defined as the fibrotic replacement of liver tissue for any chronic liver disease, including hemochromatosis, as mentioned by Dr. Bakari in the previous talk. As characterized by the development of these regenerative nodules that are surrounded by areas of dense fibrosis, on the left-hand side you can see a cirrhotic explant. You can see the nodular surface and scarred surface of the liver, and on the right-hand side in a histologic view, the red areas are the regenerative nodules that develop, and the purple or darker areas are the bands of fibrosis that separate these nodules. There are multiple etiologies of chronic liver disease. The most common that we find in the U.S. are alcohol, non-alcoholic fatty liver disease, which is currently being rebranded as metabolic-associated steatotic liver disease, and viral hepatitis C. But as you can see, there's multiple other etiologies we need to keep in mind when we're evaluating somebody for their underlying disease process. Portal hypertension is defined as elevated portal pressure, and it results from a combination of factors, including increased outflow resistance through distorted hepatic sinusoids, so increased hepatic resistance on the top left, as well as increased or enhanced portal flow through spiky arteriole or vasodilation, as you see in the bottom half of the diagram here. And this combination of factors can lead to the development of complications of portal hypertension, including varices. Portal hypertension is measured by the hepatic venous pressure gradient. This is the pressure gradient between the hepatic vein and the portal vein. Normal is less than or up to 5 millimeters of mercury. Portal hypertension is defined as anything greater than that, but clinically significant portal hypertension really occurs when that gradient is up above 10 millimeters of mercury, and that's where varices can develop. The risk of variceal bleeding increases as that gradient increases, and we see that most commonly up above 12 millimeters of mercury. So esophageal varices are veins that lie deep within the submucosa of the esophagus, and they become progressively more superficial in the distal esophagus. They can develop at a rate of 5 to 15 percent per year. Patients without varices, we see that new varices develop at approximately 5 percent by year one and 28 percent by year three. And those patients with small varices at the time of diagnosis, they do progress at a rate of 12 percent, or we see an increase at 12 percent at year one and 31 percent at year three. The risk of progression is, or the risk of progression, ways to understand the risk of progression, there's multiple factors that we look at to understand that risk. The child score, or child putercard score, is a measurement of the severity of the underlying liver disease. It's a good marker for chronic liver disease, understanding long-term prognosis, and the higher the score indicates an increased progression in varices. The presence of red whale signs at the time of diagnosis, and we'll see some pictures of what that indicates, and underlying alcohol etiology for the cirrhosis. The risk of progression is greatest in the first one to two years from the time of the initial identification. And the risk of bleeding increases as the size of the varices increases. This goes to basic physics, Laplace's law, small increases in the size of the radius of a vessel result in larger increases in wall tension and an increased risk of bleeding and rupture. The D-junction tends to be the most common location where the varices are likely to rupture and subsequently bleed. One-third of patients with cirrhosis will develop variceal bleeding, and that two-year risk in patients with small varices is at 12 percent. Most patients without variceal bleeding who have a small risk of developing variceal bleeding within the first two years. So here are some pictures. So on the left-hand side, this is what we would grade as grade one varices. These are varices that flatten. The flat varices, basically when we're doing an endoscopy, we're insufflating air into the esophagus. These varices flatten out, so you can see a pretty much open lumen. In the middle picture, you see what we call grade two varices. So these varices are separating from each other, but they don't completely flatten. And then grade three varices on the right-hand side in panel C, these are varices that really don't separate from each other. And all of these, you can see these red lines that are what we call red whale marks. You'll see another picture of that in a few. Okay, so this slide actually shows you better pictures of what red whale signs are on the right-hand side. Red whale signs are these monotonal red streaks on the right-hand side. They're on the surface of the varices, and they kind of look like corduroy type appearance. On the left-hand side in the middle screen, you see cherry red spots and hematocystic spots. These three red spots that overlie the varices, all of these would be indicators of a higher risk of bleeding and a higher risk of progression of varices. So why is this important? I've highlighted a number of things from this talk on the prevalence of this incidence of mortality of various complications of sclerosis to highlight varices of bleeding specifically. So varices overall form at a rate of about 9% per year in patients with sclerosis, and bleeding occurs in 1% to 4% of patients within three years of diagnosis. Variceal bleeding carries a very high mortality rate of nearly 20% within the first six weeks after initial variceal bleeding, and it accounts for nearly 10% of hospitalizations of sclerosis in the U.S. So I'm going to talk a little bit about screening, some more on the outpatient setting, and then we'll talk about hemorrhage as well. So how do we do a screening for esophageal varices? We start with a screening endoscopy. In a patient with newly diagnosed sclerosis, we want to assess for the presence of portal hypertension, and so we do a screening endoscopy to assess for the presence of esophageal varices. We can also assess for other indicators of portal hypertension, like gastric varices and portal hypertensive gastropathy. In patients who have well-compensated liver disease and no evidence of varices at the time of the initial endoscopy, we may screen them again every two to three years, and most commonly we'll screen them every two years in those patients where the underlying liver disease is not, or is inadequately controlled. Those patients who drink actively, those patients who have underlying disease process, fatty liver disease, or hemochromatosis is not adequately controlled, you'll want to screen them more frequently. If they have evidence of decompensated liver disease, for instance, ascites or vitiated hepatic encephalopathy, you'll want to screen those patients on an annual basis. Once you've identified varices on an endoscopy, if they're small, they don't require endoscopic treatment, you'll want to survey them on an annual basis, and those patients who do have large varices without bleeding, you'll want to be treating those patients to try to reduce the risk of bleeding, and we have a couple of options we'll get into. So primary prophylaxis, primary prophylaxis is treating the patient for their varices before they have an onset of bleeding, you want to make sure that you're treating the underlying liver disease, and then you have two options, non-selective beta blockers and non-selective beta blockers work by reducing that splenctin blood flow, so they reduce some of the pressure that leads to exacerbation of portal hypertension, we have a few options here in the U.S., carvatalol, propranolol, and betalol, and regardless of which you choose, the goal is to drive the heart rate down to about 55 beats per minute. And that may be limited by side effects and blood pressure response to the medication, but non-selective beta blockers have been shown to significantly reduce the mortality risk in patients compared with no intervention. There are significant side effects we have to pay attention to, to beta blockers, including hypotension, shortness of breath, T, bronchoconstriction, and certain contraindications as well, particularly that low blood pressure and kidney injury. The other option is variceal band ligation. This will be performed during the endoscopy, so during your screening endoscopy, if you identify large varices, band ligation can be performed, patients are expected for that initially. Once you embark upon band ligation as your choice for primary prophylaxis, you usually want to repeat the endoscopy every two to four weeks to confirm that the varices have been adequately eradicated, and usually that entails approximately three or four sessions of endoscopy. Once the varices are eradicated, during the first year, we'll typically survey the esophagus every three to six months to confirm that they do, in fact, stay well controlled, and then continue on an annual basis thereafter. If varices do recur, you can proceed with repeat band ligation as needed. There are risks involved with band ligation, of course, the most common being symptoms of dysphagia and chest pain after the procedure, but other complications can include ulceration and subsequent bleeding, either immediately during the band placement or bleeding from esophageal ulcers. Usually that's about one to two weeks after the banding is performed, and in rare circumstances, development of strictures. This is a diagram portraying what variceal band ligation involves, so band ligation is achieved by placing a banding device on the tip of the endoscope, and as you can see on the left-hand side, you have a clear cap, several bands on the cap on the outside, depending on the device manufacturer, that may be four, six, seven bands. Once the cap is attached to the scope, the scope is reinserted into the esophagus, we target the distal esophagus as close to the esophagus as possible. The target varice has been suctioned into the cap. Once you get a red out on your screen, you can deploy a band, and the band basically strangulates the base of the varice, thereby reducing the blood flow into the varice, leading to localized inflammation, osteoporosis, and scarring. The band will typically fall off, leaving a scar that limits the blood flow into the varice. Anywhere from one to three bands can be applied to the varice, and usually this will result in requiring fewer treatment sessions compared to other options that we'll talk about later. We mentioned some of the adverse effects, but in panel C here, you can see the endoscopic view after a band has been deployed. Severity of bleeding is a GI emergency, and it's considered a decompensating event for patients with sclerosis. Severity of bleeding can be severe and life-threatening. I mentioned the annual rate of first bleeding at this point is about 12%, and each episode is associated with up to 20% mortality at six weeks. In the cases where bleeding stops spontaneously and can occur up to 50%, they do have a high risk of early re-bleeding and a very high overall re-bleeding rate of 70% long-term. That's if no intervention is performed. So the pillars of variceal bleeding, the pillars of management for variceal bleeding are resuscitation and stabilization, controlling the bleeding with pharmacologic therapy and endoscopic management, and then prevention of complications, going through each of these. So first and foremost, resuscitation and stabilization. You want to make sure that the patient has adequate IV access. That usually entails at least two to three large, more peripheral IVs or a central venous line. IV fluid resuscitation and supplemental oxygen to maintain adequate oxygenation and perfusion to end organs. You may want to consider whether that patient should be intubated, whether that's due to hemodynamic instability, hepatic encephalopathy, and altered mental status or ongoing episode of hematemesis. And you also want to consider administration of a prokinetic agent such as erythromycin or amethoclopramide prior to endoscopy to improve the endoscopic visualization. When it comes to transfusion, you want to use judicious transfusion. Target hemoglobin should be between seven and nine. Higher transfusion pressure should be considered for those patients who do have unstable coronary artery disease or those that are considered to be at increased risk of adverse events from hypoperfusion. But you want to be careful to avoid volume overload. This is why it's judicious because there is a risk of rebound portal hypertension with overtransfusion and that can lead to re-bleeding. Massive transfusion protocol is considered after patients have received five or six units of transfusion and in that setting, you want to consider whether or not they may benefit also from administration of plasma or platelets. Again, keep in mind, you want to avoid volume overload and worsening portal hypertension from the rebound. You also may want to consider giving vitamin K for those patients who may have coagulopathy, not just as a result of hepatic dysfunction, but those patients also may have nutrition component for elevated INR. Then getting into pharmacologic therapy, we have two options in the US. Turlopressin is a synthetic analog of vasopressin. This is not yet widely available. It certainly should be available or is available in many academic centers across the country, but it's not widely available in the community. It acts by decreasing portal blood flow with every four hours administration and you'll want to continue that for eight or five days after controlling the bleeding. It has been shown to reduce all-cause mortality, but is limited by side effects that can include hyponatremia, ischemia, volume overload, and pulmonary edema. What is much more widely available and what we use typically is octreotide. Octreotide is an analog of the subatostatin. This has shown a decreased blood flow through the spiking phase of the constriction and this is given as an initial bolus followed by a continuous infusion, again, for a period of two to five days. Octreotide has been shown to increase the ability to treat hemostasis to prevent re-bleeding, but has not been shown to have any effect on mortality. It's also limited by similar side effects as triglyceride. Antibiotics play a major role in pharmacologic therapy in the setting of GI bleeding and cirrhotics. You want to use broad-spectrum antibiotic prophylaxis and this has been shown to reduce mortality, infection, anti-bleeding rates. Infection, most prominently, reducing the risk of STD and urinary tract infection. This is preferably given upfront and the most commonly used agent is ceftriaxone or third-generation cephalosporin. You will usually give this for seven days. If the patient is transitioning to oral medications or discharged prior to seven days, you can take ceftriaxone with the oral form of cirrhotoxis twice a day to complete the course. Moving on to endoscopic management. Variceal band ligation, as we talked about in primary prophylaxis, is also the endoscopic method of choice for management of variceal bleeding. You can see, again, on the right-hand side, the endoscopic view after the band has been deployed in the setting of, in the management of varices. It decreases the risk of re-bleeding across 30%, decreases the mortality rate to 25%. An alternative option is endoscopic sclerotherapy. I don't really know how much this is being done or the world, but it is an endoscopic option. It involves the injection of a sclerosis directly into the varices, the most commonly used sclerosis, mortuary and epithelial mean. The risks of this procedure are similar to some of those that we see with endoscopic, with variceal band ligation, including ulceration, bleeding, and stricter formation. Because you're injecting the sclerosin directly into the varices, there's also a risk of mediastinitis and perforation. Early tips is also an important consideration for patients that have variceal bleeding. Early tips is considered specifically for secondary prophylaxis. It's shown to lower all-cause mortality and lower failure rates related to bleeding. So it reduces the risk of re-bleeding, reduces mortality, improves transplant-free survival. And early, meaning within the first 72 hours after controlled bleeding. There are important contraindications to consider when you're evaluating somebody for tips, including heart failure, pulmonary hypertension, polycystic liver disease, sepsis, portal vein thrombosis, and the important complications to understand of tips. There are risks involved, including development of hepatic encephalopathy or worsening of hepatic encephalopathy. And then there's also a risk of stenosis, which can lead to rebound portal hypertension and bleeding in the future. This is an example, this is a diagram of how a tips is performed. It's done by our interventional radiology colleagues. They access the ventricular vein, go down through the IVC and hepatic vein, and basically make a fistula from a hepatic vein within the parenchyma of the liver directly to one of the large portal veins. And they place this fully covered metal stent across, shunt from the portal vein directly to the hepatic vein, thereby bypassing the portal hypertension. What happens when endoscopic methods fail and we need to reach for those, or we have ongoing emergency, ongoing bleeding? You may have heard of Blakemore tubes or Minnesota tubes, which are an example of that. These really provide only short term hemostasis, temporary hemostasis, but can be considered in those emergency situations where either band ligation is unsuccessful or inadequate. There is an alternative that's evolving with the idea of the esophageal step placement. This of course requires endoscopists to have training in esophageal step placement, access to fluoroscopy in an emergency situation. And there are risks associated with balloon deployment, including re-bleeding and esophageal rupture. This is an example of what the tubes look like on the blood vessel. This is an example of what the tubes look like towards the bottom is the gastric area. So you have a gastric balloon that is inflated and used to apply pressure to the gastroesophageal junction tamponade at that area. There's an esophageal balloon that may or may not be inflated. If it is inflated, you have to be very careful with that because that's for the risk of esophageal rupture or future severe esophagitis that can develop if it's inflated and there's too much pressure or prolonged pressure. And at the top, you see the access balloon. So we have a gastric balloon port and an esophageal balloon port for each of the balloons specifically, as well as aspiration ports to assess for the presence or absence of ongoing bleeding. And other options in the setting of refractory situations or emergency situations, hemospray is an off-label indication for emergency bleeding. Emergency tips should be considered. Again, this depends on your local expertise and your access to tips and interventional radiologists for the use of this. It could occur in the middle of the night or on weekends and access may not be as readily available. And emergency sunt surgeries, this requires, again, surgeons that have expertise in dealing with patients with portal hypertension and performing emergency surgeries. These can be extremely effective in preventing bleeding and preventing re-bleeding, but there's a very, very high risk of mortality associated with these surgeries because these patients are subsequent to begin with. Additional considerations, you want to be careful with the ongoing use of PPIs in patients who don't have a strong indication for them. Once you've confirmed that varices are truly the etiology of the GI bleeding, you want to consider discontinuation of PPIs once GI bleeding has been controlled. There is association with increased sympathetic encephalopathy and liver decompensation in patients with prolonged uses of PPI. Consider thiamine for those with an underlying alcohol use disorder. You want to make sure you're repleting electrolytes. You also want to be careful when you resume your enteral nutrition. There's a concern that very early resumption of enteral nutrition may increase spleen and blood flow and increase portal pressure. So many times we'll use clear liquids for a day or so before advancing the diet. And in patients who've presented with variceal bleeding, you want to consider abdominal ultrasound to assess for oral vein thrombosis as the reason for the acute onset bleeding. What is that re-bleeding risk? So initial, if the initial bleed is untreated, as I mentioned before, the risk of re-bleeding is very high, 60 to 70% within the first year. We break down re-bleeding risk as early, meaning within six weeks versus delayed. And risk factors for early re-bleeding include age, renal failure, and the presence of ascites. 50% of early re-bleeding will occur within the first two days. You also want to, again, focus on, make sure you're treating the underlying cause of the liver disease to reduce the long-standing portal hypertension to reduce the re-bleeding risk. Secondary prophylaxis, so for those patients who've had bleeding and now we've managed the bleeding, how do we go to reduce the risk of re-bleeding? Usually we can use a combination of variceal band ligation in combination with non-selective beta blockers. Non-selective beta blockers are typically started on day five or so after the octreotide or turbulent presence has stopped after achieving hemostasis. Variceal band ligation, again, every two to four weeks until we confirm that the varicea has been eradicated and then followed by surveillance every three to six months during the first year and annually thereafter. You want to think about evaluating the patient's tips, make sure you're managing their underlying chronic liver disease and control for liver transplant. Monitor for complications as well. So once we've controlled the bleeding or other complications that can develop as a consequence of variceal bleeding are hepatic encephalopathy and renal failure. Hepatic encephalopathy can be managed with lactulose and rifaxin and correction of any electrolyte abnormalities. Again, using antibiotic prophylaxis to reduce the risk of infection. A brief word about other varices. So we've talked at length about esophageal varices, but there are other forms of varices that we have to be cognizant of. Gastric varices can occur basically anywhere in the stomach here you see. This is the sarin classification for gastric varices. Then you have GOV1, which are esophageal varices, sorry, gastric varices that are in continuity with the esophageal varices along the lesser curvature of the stomach. GOV2 are similar, but on the greater curvature of the stomach. And IGV1 meaning isolated gastric varices. IGV1 are typically in the fundus of the stomach, IGV2 are elsewhere. Actually in the diagram for IGV2, you can see a red area down in the dupium that would be considered ectopic varice. So how do we manage gastric and ectopic varices? Again, non-selective beta blockers play a major role in reducing portal hypertension. There can't be a role for variceal band ligations for those GOV1 types where the esophageal, sorry, where the gastric varice is a continuity with the esophageal varice on the lesser curvature. Other endoscopic options may include endoscopic cyanoacrylate injection or using EUS guided placement of coils in addition to cyanoacrylate. And then in terms of considering non-endoscopic options, these are done by our colleagues. Again, tips for shunt within the liver, which we showed earlier, and an alternative of balloon occluded retrograde transvenous obliteration or BRTO. Here you can see tips on the left-hand side, which we already talked about in comparison to BRTO. In BRTO, which is the right side, you have the IR docs are able to access a gastrorenal shunt and they occlude both sides of the shunt and then they inject a sclerosant into the area where the gastric varices are to reduce the risk of bleeding from those gastric varices. So in summary or pearls for this talk specifically with relation to variceal bleeding, resuscitation is first and foremost for management. Pharmacologic therapy options include IV octreotide or Trilopress where it's available. You want to remember the importance of using antibiotics to reduce the risk of infection and infectious complications related to variceal bleeding and urgent to be within the first 24 hours presentation. After variceal bleeding has occurred in terms of secondary prophylaxis, we use combination variceal band ligation and non-selective beta blockers. Beta blockers can be used to reduce heart rate or pulse to 55. Obviously that's limited by hypotension, but your goal is to try to reach that endpoint. Balloon tamponade is an option for temporary hemispasis in an emergency situation where you cannot control variceal bleeding. Emergency tips is also an important consideration if you have access to IR quickly. Surgical shunting is rarely done nowadays because of the high risk of mortality and decompensation afterwards. And then consider early tips for those that you have been able to achieve hemostasis on for secondary prophylaxis. Thank you.

variceal bleeding

cirrhosis management

portal hypertension

esophageal varices

band ligation

hepatic encephalopathy