On for our second session, hepatic failure. Again, we'll acknowledge Dr. Nanchal for the pre-session material that he has provided. First case is a 36-year-old male, two days history of severe malaise, abdominal pain, nausea, vomiting, no known medical history, does have history of occasional alcohol use, non-smoker, just returned from a two-week camping trip with his boyfriend from Haiti. On exam, hypotensive, tachycardic, alert-oriented, diffused achiness, but no guarding rigidity or rebound tenderness is reported. Patient is ictric. On exam, blood counts are normal. Basic profile is normal. LFTs are elevated, with ALT of 1,400, AST of 1,600, bilirubin is 3, INR is normal. Patient is admitted to ICU the following day because he starts developing worsening mentation, has a GCS of 7, E2M4M1, sorry, V1. Viral workup is positive for acute hepatitis A. Day two labs are done. Transaminases are now in the 2,000 range. Ammonia level has gone up to 210. Worsening renal failure, hypoglycemia, oliguric at 250 mils over the last 18 hours of hospitalization. Patient is now intubated, started on volume resuscitation with 30 mils per kg of balanced fluids. Norepinephrine and vasopressin are initiated. Day three in ICU, patient continues to be altered, follow-up labs show worsening transaminases and ammonia levels. What is your diagnosis and treatment approach? So how many feel that this qualifies as acute fulminant viral hepatitis and want to use N-acetylcysteine and conservative treatment? Any owners for this one? Second is acute fulminant viral hepatitis and just conservative therapy. Next, acute viral hepatitis and conservative therapy. And last one is acute viral hepatitis along with N-acetylcysteine and conservative therapy. So the answer here is acute fulminant viral hepatitis along with N-acetylcysteine and conservative therapy. The reason we add the word fulminant is as soon as you involve encephalopathy, it falls in the definition of fulminant. And within the time frame, this is an acute viral hepatitis. The symptom onset is less than seven days. It would fall within the hyperacute to acute, depending on the duration of travel. But the symptoms do fall within the acute stage. And this time frame is based on the onset of jaundice to development of the hepatic encephalopathy. Now, this question of N-acetylcysteine, we always read about it for acetaminophen toxicity. And occasionally, at some places, they say if the liver is bad, just put everyone on N-acetylcysteine. The story with non-acetaminophen-dependent acute liver failure, this is a review article which looked at the transplant-free survival at one year and the proportion of patients transplanted at one year. It was better with grade 1 and 2 encephalopathy or all grades of hepatic encephalopathy in patients that received N-acetylcysteine versus patients who did not receive N-acetylcysteine. When we talk about only survival, there was not a difference. But if you talk about transplant-free survival or proportion of patients transplanted, there is a benefit. It is a low-cost medication. I don't think there will be much of a randomized control trial looking at viral hepatitis, isolated N-acetylcysteine versus not. So recommendation is if you're in the acute fulminant liver failure or acute liver failure, go ahead and put these patients on N-acetylcysteine and continue with conservative treatment. So acute liver failure organ dysfunctions. We know in the brain it causes encephalopathy, primarily secondary to cerebral edema. It happens secondary to the ammonia along with a bunch of other vasodilatory receptors. So the other is heart, high output state. It can cause subclinical myocardial injury and cardiomyocyte suppression. Lungs can cause lung injury, ARDS. In liver, definitely causes hypoglycemia, lactic acidosis, hyperammonemia, and coagulopathy. Pancreatitis, inadequate glucocorticoid production contributing to hypotension, so relative adrenal insufficiency. Acute kidney injury, and then bone marrow suppression, risk for sepsis, and definitely a more flawed systemic inflammatory response. So what is your next step in this patient? So I'll give you a quick recap. Young patient, acute viral hepatitis, acute fulminant viral hepatitis. Is developing worsening mentation. Ammonia levels are elevated. Transaminases are elevated. So what would be your next step? Watchful waiting and continue supportive care. CT head to rule out bleeding. Because of concern for encephalopathy and cerebral edema, we would perform an invasive ICP monitoring, initiate renal replacement therapy, or liver transplant. So how many of you want to continue with one? No one wants to continue with one? How about two? Rule out bleeding. Three. Four. Few people want to go down that route. And five, call the liver transplant team. OK. OK. Well, liver transplant, calling the liver transplant team is always the right answer, but that is not the next step. The next step in this situation will be the renal replacement therapy. And why do we go down that route? Depending on the nephrologist you talk to, and I'm married to one, I can tell you that they have strong feelings about using renal replacement therapy for ammonia clearance. But acute fulminant liver failure is one indication that they don't feel that there is any loss of putting someone on CVVH. They are happy to do that, primarily because, as you can see here, ammonia levels, they are associated with high risk for encephalopathy and definitely cause significantly high intracranial hypertension in acute liver failure patients. AKI, renal replacement therapy in acute liver failure, AKI is present in 50% of these patients. Mostly it's pre-renal. Renal replacement therapy is indicated primarily for downstream volume overload, because these patients, they keep getting volume for hypotension, tibialactic acidosis, or hyperammonemia. The recommendation is always to use CVVH and not use HD. And that is based off of, there was only one study that has been done, and this is from 1980s. The CRRT is not associated with increased ICP, but intermittent hemodialysis is associated with increased intracranial pressures, even in non-liver failure patients. So CRRT, as you can see here, the ammonia levels come down much better with CRRT compared to intermittent renal replacement therapy or patients without renal replacement therapy. So as I said, transplant is always the right answer, just not the next step. Transplant referral should be made anytime there is an onset of hepatic encephalopathy with acute liver failure. INR is going up. Patient is developing refractory metabolic acidosis, progressively worsening, and if there is no contraindications to a transplant. Our next case is a 60-year-old patient with history of advanced non-alcohol associated liver disease. Patient reports weakness, dyspnea, and fatigue over several months. Reports adequate intake at one bowel movement and reduced urine output in the last 24 hours. Mucus membranes are moist. Abdominal exam is benign. Blood pressure is 110 over 60, heart rate of 90. Afebrile. Patient is on room air, has severe fetal edema. Blood counts are normal, BUNs 20, creatinines 1.9. Known baseline creatinine from a month ago was 0.8. Which of the following is not considered a treatment of choice in this condition? So how many of you would give octreotide in this situation? So this is a patient who's otherwise fine, just feeling fatigue, comes in, has his blood drawn, has AKI, and has severe fetal edema and hemodynamically stable. So we would give octreotide. How many of you would give midodrine? Not epinephrine. Tristaloids? Would anyone give tristaloids? No. And consult transplant team. So in this situation, we're trying to look at hepatorenal syndrome. Our approach for hepatorenal syndrome is you try octreotide, midodrine, not epinephrine. You would not give tristaloids. So AKI in cirrhosis, there was an old definition. The new definition at this point in time is you have a serum creatinine, which is more than 1.5 milligrams per deciliter. And you rule out all other etiologies. If a patient is on pressers, rest assured, you can rule out hepatorenal syndrome. If a patient has had history of any form of nephrotoxic drugs, you can rule out hepatorenal syndrome. You treat according to the etiologies. If patient has any form of hematuria or proteinuria, hepatorenal syndrome is ruled out. You treat based on what you find. And if there is a parenchymal disease present on the renal ultrasound, that rules out hepatorenal syndrome. Once you've gone through that initial workup and you've identified hepatorenal syndrome, then we approach it with the treatment. And the treatment initiates with splanchnic vasoconstrictors. You can use octreotide, terliprasin, along with albumin. Albumin is given one gram per kg daily for approximately 72 hours. Then you can do a combination treatment with octreotide and midodrine. You can use norepinephrine. Renal replacement therapy is recommended. You could use it for a short duration or if a patient is being bridged towards liver transplant. Liver transplant is considered as a treatment if the dialysis has been ongoing for more than six weeks with no improvement in the renal function. Then you could also attach a kidney transplant along with the liver transplant if it's been ongoing for six weeks. Prognosis for hepatorenal is uniformly fatal if a patient is not a transplant candidate and there is no improvement in the renal function. And creatinine now is used in defining the severity for the liver disease to prioritize liver transplant recipients. So the same patient, while transferring from the bed along with physical therapy, patient develops an acute worsening of dyspnea and hypoxia along with hypotension. On sequential oximetry checks, patient is noted to have desaturation with sitting and standing up. Orthodeoxia and platypnea is noted. Echo with a bubble study shows elevated right ventricular systolic pressure along with a delayed occurrence of bubbles in four to six beats. Right heart catheterization shows a mean pulmonary artery pressure of 45. Treatment is initiated and a mean pulmonary artery pressure follow-up in four weeks is 35. During pre-transplant evaluation, family asks whether the symptoms of dyspnea and edema will reverse and if the patient will need to continue to take IV epiprostanol continuously. So we had brief discussion about this during our earlier Q&A session. So this patient essentially has both the things. Has portopulmonary hypertension and also has hepatopulmonary syndrome. We figured that out based on the echo with bubble study showing delayed occurrence of the bubbles in four to six weeks. So there is a right to left shunt that is also consistent with the symptoms of orthodeoxia and platypnea. And based on the right heart cath, we know the patient has hypertension, pulmonary hypertension. So after a transplant, the patient's dyspnea will completely recover and IV epiprostanol will stop. These two complications do not reverse completely after transplant. Patient's symptoms and disease needing the IV epiprostanol is not related to the need for liver transplant. That is incorrect because they are both related to patient's underlying advanced liver disease. Symptoms of dyspnea and need for oxygen will improve over weeks but may not completely resolve. IV epiprostanol is likely to continue. That is the answer. Pulmonary hypertension does not completely reverse, but patient's hepato-pulmonary syndrome does reverse following transplant. So they are able to come off the oxygen. Symptoms of dyspnea improve, but most often they do need to continue on the pulmonary hypertension treatments. Dyspnea and need for oxygen will continue, but the need for IV epiprostanol will likely not continue. So that's the opposite. Hepato-pulmonary syndrome, chest CTs should be done to rule out underlying parenchymal or pleural lung diseases. PFTs will show an isolated low diffusion capacity. That's primarily because of the right to left shunt. And late bubbles on TTE are suggestive of this diagnosis in the right clinical setting. Treatment is supplemental oxygen can be given. It helps in particular positions, and then it does not help in the other positions based on the AV malformations. Coil embolization in rare cases of radiologically visible pulmonary AVMs can be used. Liver transplant typically reverses the hypoxemia in weeks to months, irrespective of the pre-transplant severity. The port-pulmonary hypertension diagnosis, the initial study is TTE. Estimated RVSP of more than 50 based on the echocardiogram triggers the right heart cath. Right heart cath is generally positive in these situations with a mean PAP of more than 25. And the pulmonary vascular resistance of more than 240. Target mean PAP for liver transplant candidacy is less than 35. So this is a similar evaluation that should be done even prior to a TIPS intervention. Going back to our Q&A question earlier today, this was related to the liver transplant. This was related to that, that if a patient has pulmonary hypertension, you're listing them for liver transplant. Treating their pulmonary hypertension is of utmost importance to minimize the risk of bleeding or rejection. Treatment is monitoring of the RV function with TTE and right heart cath. Therapy with dobutamine and milrinone for inotropy and IV epiprostanol for pulmonary vasodilation is recommended to acutely bring down the pressures. Chronic IV epiprostanol with a goal to decrease mean PAP less than 35 for liver transplant candidacy. And then there is emerging role for co-therapies with the other medications. Liver transplant, varying degrees of reversal of portopulmonary hypertension after transplant is noted. OK. I have three questions. One is, why do patients get adrenal syndrome? Why do patients get it? Why does that happen? So it happens. The definitive pathophysiology isn't known. There are all hypotheses. One of those is the presence of pulmonary vasodilation, presence of a lot of biochemical and nitric oxide stimulants that are present that cause vasodilation, causes reduced blood flow. And there is also a secondary renal vasoconstriction that happens. For when that happens, the renal parenchyma considers that as a low blood flow stage, tends to reabsorb sodium, and essentially causing a pre-renal stage for the kidneys. That is why when you look at the FINA or you look at any of the other renal labs, they always are suggestive of a pre-renal state, pre-renal vasoconstriction being one of the most common physiological presence. And just to follow up on that, you mentioned norepinephrine as therapy. What blood pressure would you use that at? The goal is to maintain a higher MAP of 65 to 70. And it's considered more as a vasoconstrictor to increase the forward flow. In the same way that you would use the midodrine and the octreotide, you're trying to shunt the blood away, causing more of peripheral vasoconstriction because your body is in a vasodilatory state. The recommendation is not to be in a volume deficit stage. So in the question, that's why all the physiological or the hemodynamic criterias essentially had patient being in clinical uvulemia. There is not a guideline-based recommendation that you use levophed or norepinephrine to maintain a particular MAP. The recommendation is you maintain it between 65 and 70. A MAP of more than 70 is sometimes recommended as renal protective. There's no evidence-based guidelines for that. And the last question is, you mentioned both portopulmonary hypertension and hepatopulmonary syndrome. Are there differences between the two? How do you differentiate? So hepatopulmonary syndrome is more related to the changes in the pulmonary vasculature. You have pulmonary capillaries and pulmonary arterioles and venules that get dilated, increasing the right to left shunt that happens. And that is why a lot of these patients present with orthodoxy because whenever they get up, the blood goes to the dependent portion, which is where the AV malformations are more dilated. And that's why there's a right to left shunt and these patients develop hypoxia, versus when they're laying down and not doing much, these vessels are mostly closed. So that's a right to left shunt that happens, that's hepatopulmonary syndrome, versus the portopulmonary hypertension, which is essentially changes in the pulmonary artery thickness and pulmonary artery pathophysiology, which causes the pulmonary hypertension. So hepatopulmonary syndrome in itself would not cause your RVSPs to go up. Do you change in the guidelines for pulmonary hypertension? Have they changed it to 20 and then for the liver transplant to 30 or is it? No, it's still the same. It's still the same, 25. And they have used this where they acutely just bring the pressures down for a day or two from a listing standpoint. Because what is important is what is the pressure at that particular time when they're doing the transplant. It's independent of what was going on prior to that. Excellent. Any other questions for Dr. Do you struggle with the pulmonary artery thickness, the K squared CR? There's not an absolute level more than 200 or the rate of change. If you were 50 today and 180 tomorrow and you know that there is clinical worsening, then you would approach it. If terlipresin is showing like what kind of panic when these cases, so is there a specific reason that it's not available in the United States? I think it's still in the works. I don't think it's an absolute no. Terlipresin has also been associated with the reversal of hepatorenal syndrome. Not being shown in larger studies, but there are some incidental studies. Five days of terlipresin can actually reverse hepatorenal syndrome. Excellent. So it's 3.01. Why don't we come back at 3.15 sharp? Thank you, Dr. Board.

hepatic failure

acute fulminant viral hepatitis

N-acetylcysteine

renal replacement therapy

hepatorenal syndrome

liver transplant