During this 20-25 minute pre-recorded lecture, Dr. James F. Crismale discusses the topic of acute liver failure. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards.
Hi everyone. Thanks for joining us. My name is Jim Chris Molly and for the next 20 minutes or so I'll be presenting on acute liver failure First. Let's start by defining acute liver failure, which is the development of new liver injury. Typically represented by elevated liver enzymes and jaundice without prior liver disease. Plus the rapid onset of parasite dysfunction, which is represented by the development of Caligula apathy with an iron ore of at least 1.5 and have had a encephalopathy. The presence of hepatic encephalopathy is critical to the definition of acute liver failure. Such that without it, the patient, by definition cannot have acute liver failure. If the paddock encephalopathy is not present, then the syndrome is acute liver injury rather than acute liver failure. And this is important because these two syndromes have very different outcomes. Finally, to meet criteria for acute liver failure. The onset of encephalopathy has to occur within 26 weeks of the onset of liver injury. Acute liver failure is a rare disease. There are less than 2000 cases in the U. S. Per year and fewer than 10 cases per million patients per year within developed countries worldwide As such, it only accounts for around 1-2% of patients on the liver transplant waiting list. In terms of ideology by far and away, the most common cause of liver failure in the U. S. Is acetaminophen overdose. This is followed by non acetaminophen induced drug induced liver injury. Other causes like autoimmune. Hepatitis and viral hepatitis are less common, Although it should be mentioned that up to 12% of cases are of undetermined ideology. Clinically, patients with acute liver failure will generally present with non specific symptoms like fatigue, malaise, right upper quadrant pain and nausea and vomiting, along with the presence of elevated um you know, trance phrases. Well, then go on to develop overt evidence of hepatic synthetic dysfunction like jaundice and curricula apathy. And this is eventually followed by the development of hepatic encephalopathy, which we grade on the West Haven criteria, which we'll discuss in more detail Later in the talk, once the syndrome of acute liver failure sets in patients can then go on to develop multi system organ failure, the most concerning component of which is neurological failure caused by cerebral oedema and brainstem herniation, which is the most common cause of death in acute liver failure. Okay, so let's pause here for our first question. In this case, we have a 19 year old college student who was brought in by her roommate After she told her she took a bunch of acetaminophen 24 hours ago in a suicide attempt. According to her roommate. The patient is coherent, but her speech and personality seem a little bit off. She has no past medical history and takes no medications on a regular basis. Her vital signs show a blood pressure of 90/60 for heart rate of 1 10 respiratory rate of eight and an 02 sat of 98% on room air on exam she's joined us with hysterics clearing. She has no asides and there's no evidence of spider and Yamada or muscle wasting. In terms of her labs she has a white blood cell count of 13 a hemoglobin of 11 platelet count at 2:40. Her chemistry is normal except for a low phosphorus of 0.9 a. ph of 7.19 lactate of four lt of 6500 S. T. Of 82 35. And a billy Rubin of three point before Her iron ore is 1.7. Her viral hepatitis serology is show a positive hepatitis B surface antibody negative other viral serology ease. In terms of auto immune studies she has a positive in a negative with muscle antibody a serial a plasma of 63 10 of 1000 and an alpha feta protein of 1 20. She also has an undetectable acetaminophen level. So which of the following is the next best step in management to be a start ponsolle Sistine and give activated charcoal. Be start ivy and cecile Sistine and monitor with syria lab checks on the regular medical ward. See start ivy and little Sistine and transferred to the ICU at a liver transplant center or D monitor with syria lab checks on the regular medical board so the answer is c start ivy and acetyl Sistine and transferred to the ICU at a liver transplant center. So this is acetaminophen induced acute liver failure which began accounts for around 40% of cases of acute liver failure in the US so it's important to recall that only a minority of patients who overdose honestly the many thin will develop acute liver failure. The toxicity is dose related, requiring around 7.5-10 g per day, which is equivalent to around 20 extra strength tablets. It takes about 24-72 hours for the liver enzymes to increase after ingestion. And this is one of the conditions that can cause liver enzymes to exceed 10,000. Although typically we'll see elevations in the 3-4,000 range. We do measure the acetaminophen level. But if the liver enzymes are already elevated and the patient has a good story for it, acetaminophen overdose then treatment isn't going to be based upon the acetaminophen level. So the treatment for acetaminophen induced liver failure is NSAID assisting or neck, which is an antioxidant which acts to replete hepatic glutathione which can scavenge the toxic metabolite of acetaminophen. It's most effective when it's given within 48 hours of the acetaminophen overdose and in the setting of acute liver failure we utilize ivy and cecile Sistine rather than p. o. As there are fewer data for ponsolle Sistine in this setting. Again, we'll give this regardless of you see the minimum level. If the liver enzymes are elevated and the story is a good one for acetaminophen overdose and rather than give it for a predetermined period of time will continue the Sistine infusion until the patient improves or they go to liver transplant. We can also utilize activated charcoal in the setting of acetaminophen overdose. But this is typically only useful if it's given within four hours of ingestion. So just to say a word about the use of neck and non honestly the benefit of the use, acute liver failure. There are data from an older randomized controlled trial that showed the use of neck in this setting led to an improvement in transplant free survival. Although the survival benefit was seen predominantly among patients with grade 1 to 2, a static encephalopathy because acute liver failure is a true emergency. The initial care of these patients is centered around stabilizing them and performing a rapid assessment of the possible ideologies as a there are some ideologies of acute liver failure that can be potentially stabilised medically and resolved without the need for transplantation and be there are some ideologies of acute liver failure for which transplant is not indicated, which will discuss. As with most things in medicine, we want to start with the history and here this is centered around possible exposures, especially medications, both prescription and nonprescription, including herbal and dietary supplements. Many of these patients will be encephalopathies. So obtaining collateral from family members and friends is essential of note if patients have any degree of encephalopathy during the initial evaluation, it's important to get them to an icy where there can be monitored closely because these patients can progress very rapidly. Lab testing should include a panel like the one illustrated on the right which includes your basic chemistries as well as viral and autoimmune psychologies. It's important to remember also to check the PCR tests for HIPPA trophic viruses like hepatitis B as well as non HEPA tropic viruses like HSV to assess for acute forms of these conditions which can present with acute liver failure. It's also important to obtain serology is necessary for listing the patient for transplant, including HIV and RPR. All patients should have imaging of some kind to rule out vascular ideologies of acute liver failure such as Budd chiari syndrome, ideally this should be done with contrast enhanced cross sectional imaging like CT or MRI. But if this isn't available or if the patient has renal failure, a Doppler ultrasound of the abdomen is also acceptable, liver biopsy is generally not necessary. As the data suggests that it does not improve management or prognosis. With the exceptions being cases where there is a high suspicion for autoimmune hepatitis but with negative serological testing or in the setting of suspected infiltrated malignancy, which would be a contra indication to transplant. This table illustrates several ideologies of acute liver failure and their treatments. All of these should be noted with the caveat that in many cases these treatments only act to stabilize ongoing hepatic injury and may not prevent progression of acute liver failure and the necessity of transplant. Especially in cases like Wilson disease. Where there is a near 100% mortality without transplant. It's important to determine the ideology of acute liver failure not only to initiate management but also to determine whether transplant is even an appropriate intervention. Generally speaking transplants as appropriate if the liver failure is due to a primary hepatic process like drug induced liver injury, viral or autoimmune hepatitis. On the other hand it's generally not appropriate when it occurs as a secondary result of a systemic process like sepsis or a malignancy. Okay so for our 2nd board style question the patient from Question one is transferred to the she received supportive care and I. V. Neck is initiated. Despite that supportive care. However, her encephalopathy worsens and she requires intubation for airway protection. She remains responsive to noxious stimuli and her head cT shows some evidence of decreased cycle markings. Her serum osmolarity is 300 And her arterial ammonia level is to 20 million mph. In addition to consulting neurosurgery and considering placement of an intracranial pressure monitor, the next most appropriate step is a give half normal saline to maintain the serum sodium between 1 31 35 million equivalents for leader big of mannitol 0.5 to one g per kilo and assess response. See increased the patient's minute ventilation or D. Start lacks. Hello Spy N. G. Tube. Mhm. Okay so the answer is to give Mannitol 0.5-1 g per kilo times one and assess response. So this patient has grade four hepatic encephalopathy which is graded by the West Haven criteria which you may be familiar with. Grade one includes subtle changes in effect, including difficulty concentrating and impairment of performance on mental status exams. Grade two is when we start to see things like asterix and more overt disorientation. Grade three encephalopathy include somnolence and market confusion with the caveat that in a liver failure this is sometimes replaced by agitation and finally in grade four patients will enter into hepatic coma. Encephalopathy is much more ominous in the setting of acute liver failure than it is in chronic liver disease because of its connection to cerebral oedema. So one of the ideologies of encephalopathy is entry of ammonia and other toxins into astrocytes and other glial cells leading to an increase in intracellular Oz mel's like glutamine. These inter cellular Oz mel's can lead to an increase of water influx into the cell, leading to swelling of that cell in cirrhosis. This happens very slowly. Such that astrocytes and other glial cells can kick out other organic Osma lights like my own hospital and creating and compensate for this such that the osmolarity of the cell becomes equivalent with that of the plasma in acute liver failure. However, there is no time for the brain cells to adapt, leading to cell swelling and site of toxic cerebral oedema. Edema can occur and actually 75% of patients who progress to stage four encephalopathy And it can cause irreversible brain injury in two ways. 1st V. A cerebral herniation due to increased intracranial pressure and second due to global hypoxic injury, from a decrease in the cerebral blood flow, which occurs, which is reflected in a decrease in the cerebral profusion pressure, which is the mean arterial pressure minus the intracranial pressure. And between these two, this serves as the most common identifiable cause of death in acute liver failure. So in order to prevent this we want to maintain cerebral profusion pressure greater than 50 to prevent global cerebral hypoxic injury and to keep intracranial pressure less than 20-30 to prevent brainstem herniation. There's a couple different ways that we try to do this number one we want to manage these patients in the room where the patient can be very closely monitored. We want to elevate the head of the bed to reduce the effects of gravity on inter cranial pressure. We want to place these patients in a quiet room where we minimize stimuli and this includes suctioning for intubated patients. We want to limit pain and agitation for patients and this includes intubating and sedating patients if they're severely agitated and finally, if patients have evidence of elevated intracranial pressure, they should receive treatment aimed at reducing this intracranial pressure like mannitol or hyper tonic sailing at some programs and intracranial pressure monitor. also known as a bolt, is placed. Although there is no good data that shows that this alters outcomes. Although there are data that suggests that it increases the number of interventions that are performed to treat cerebral oedema. Intracranial pressure monitors can be useful in some cases for prognostication in the sense that they persistently reduced cerebral profusion pressure may be a sign of irreversible brain injury and some centers use this to preclude patients from transplant. In terms of specific therapies, mannitol can be given um in 0.5 to one g per kilo bolus is to reduce established cerebral oedema and this can be repeated one or two times as long as the sierra Moslems are less than 3 20 although caution should be utilized in renal failure because this can lead to volume overload. Hypersonic saline can be utilized to maintain mild hypercholesterolemia, which can help to prevent inter cranial hypertension. And this was shown in one small randomized controlled trial hyperventilation to maintain a ph CO two of 25 to 30 has been shown previously to improve auto regulation of the cerebral profusion pressure, although the effect is transient so it can be used to forestall herniation. For example, in patients with severe intracranial hypertension. Although in one randomized controlled trial, there was no benefit to prophylactic hyperventilation aside from hepatic encephalopathy. Another feature that defines the presence of acute liver failure is the development of co angle apathy, although it should be stated that this is somewhat of a misnomer as a deficiency of both pro and anti coagulant factors in acute liver failure leads to a rebalanced coagulation cascade. Where although the I. N. R. Is elevated, the risk of bleeding may not be significantly different than baseline. This has been demonstrated in a number of studies using thrown but we last biography that have shown preserved clotting in many of these patients that said the iron ore is followed as a critical marker of prognosis such that if it's increasing this is a sign that delivers synthetic function overall is worsening because it's such an important prognostic marker, we generally don't correct. The iron are with F. F. P. Or other products unless necessary for invasive procedures or in the setting of overt bleeding. We do sometimes give a short course of vitamin K. If there is concern that the I. N. R. Is elevated due to nutritional deficiency if it's elevated purely due to the acute liver failure, the iron ore won't improve with vitamin K. Finally, while spontaneous bleeding is rare and acute liver failure, it is recommended to give ulcer bleeding prophylaxis with a P. P. I. In these critically ill patients. Aside from neurologic catastrophe, the next most common cause of death in acute liver failure is infection. This is because acute liver failure leads to immune dis regulation with the fact of T cell and antigen presenting cells response organisms that are most commonly cultured from liver failure patients are those most commonly seen in the which includes gram positive organisms as well as gram negatives. Although gram positives are cultured a little more commonly. Fungal infections may also be seen in these patients, especially if they have concomitant renal failure, prior immuno suppression or prolonged stays in the because of this. And because signs of infection in these patients can be very subtle, surveillance cultures are recommended. That being said there is no clear benefit for the use of prophylactic broad spectrum antibiotics, although we have a very low threshold for the initiation of antibiotics in the setting of any clinical deterioration, including worsening, encephalopathy, renal failure or worsening called the stasis. As these may be subtle signs of impending or actual infection. Renal failure is another common complication of acute liver failure, affecting up to 70% of patients. Usually this is multifactorial and can include a hippodrome renal syndrome like picture that results from acute liver failure induced circulatory dysfunction which can coexist with acute tubular necrosis. If patients do require renal replacement therapy, continuous forms of RT like CVV HR preferred as this may lead to fewer fluid shifts which can worsen inter cranial pressure. Okay, so for our third board type question, we have a 23 year old graduate student who's brought in with a change in mood. He was noted to have some increased agitation irritability and difficulty concentrating on his work. In addition, over the last two weeks he developed nighttime awakening and excessive sleepiness during the day he denies recent drugs or alcohol or other new medications. His physical exam is notable for mildly at Terex clary besides and pale jaundiced skin. He has no hepatitis plan omega lee and no other stigmata of chronic liver disease. In terms of his lab testing, He has a white blood cell count to 14 hemoglobin of seven platelets of 350 sodium is 1 32. Got a mild acai with a creatinine of 1.34 is LT and str. 59 and 84 With an alpha's of 32. This total Billy Rubin is 21.7 with a direct fraction of 9.8 and his uric acid is too. His i. n. r. is 1.8. His viral hepatitis serology Czar notable for a positive hepatitis B Surface antibody. His and a. And smooth muscle antibody are negative. His cereal a plasma in is 22 and his 14 is 1345 is acetaminophen level is undetectable. The patient underwent a liver biopsy, the results of which are shown here. So the next most appropriate step for him is a initiate treatment with lobotomy and monitor for clinical improvement. B initiate treatment with Tridentine and monitor for clinical improvement. See begin transplant work up and list the status one a. Or D begin transplant work up and list the patient at his melt of 29. So the answer is C begin transplant work up and list the patient as status one a. So this patient most likely has acute liver failure due to culminate Wilson's disease. With biopsy proven wilson's disease along with new onset of hepatic encephalopathy and decides other features of fulminate wilson's disease can include a low to normal alphas with an alcohol stably Ruben ratio of less than four. The abrupt onset of vacuums, negative hemolytic anemia renal impairment due to direct tubular damage from copper, low uric acid secondary to Fanconi syndrome. Kaiser Fleischer rings and about 50% of patients high serum and urine copper levels as well as a low Cirillo plasma. Although caution should be exercised in interpreting Cirillo plasma in in the setting of fulminate Wilson's disease, where it can be mildly elevated into the normal range because it is an acute phase reactant. Full minute Wilson's disease has a 100% mortality without transplant, someone's decompensation develops treatment with zinc or copper key leaders like triamterene or penicillin mean is generally ineffective. Called one of the most difficult jobs we have in transplantation is determining whether a patient with acute liver failure is going to recover on their own or if they will really benefit from transplant. This is because acute liver failure is a battle between the opposing forces of necrosis. On the one hand, which will lead to death without transplant and about 60% of cases And Hipolito cellular regeneration on the other, which can lead to spontaneous recovery and 40% of cases. It's important that we make this distinction because we don't want to transplant patients who will recover spontaneously, committing them to a lifetime of immuno suppression unnecessarily. But on the other hand, we also don't want to allow a patient who will die without transplant to become too or sick ultimately, to receive one. So one of the ways that we can help to differentiate which of these opposing forces will win out is via established scoring systems. The best known is the King's College criteria, which includes the criteria listed above. And these differ depending on whether the patient has acetaminophen induced to keep liver failure or non acetaminophen induced to keep liver failure In acetaminophen induced acute liver failure. If the patient has an arterial ph of less than 7.3, that's all. They need to meet criteria. If not, then they need all three of the following and I and our of greater than 6.5, grade 3-4 encephalopathy and a serum creatinine of greater than 3.4 In non acetaminophen induced acute liver failure. If a patient has an iron are of greater than 6.5, then they meet criteria. If not, then they need to have three of the following criteria. They have to Have aged less than 10 or greater than 40. They have to have an unfavorable ideology of liver disease, like idiopathic ALF, Drug induced liver injury or Wilson's disease, and iron are of greater than 3.85 A Syrian Billy Rubin of Greater than 17 Or a period of time. From the development of jaundice to the development of hepatic encephalopathy of greater than seven days. These criteria have been looked at in a number of studies where they've been found to have A 59% sensitivity and a 79% specificity for death without liver transplant. So that means that if patients meet any of those criteria, they have an 80% chance of dying without liver transplant. More modern criteria include the acute liver failure study group score rather than look at mortality. Here, this actually looks at the likelihood of a transplant free survival and it appears to have better discriminatory capacity than other scoring systems. Like the King's College criteria. Just a note, this is available as a smartphone app that can be downloaded and used on rounds when we're determining who might need transplant and who will survive without a transplant. If we do decide that a patient requires transplant, then they can be listed as status one a within you knows which is the highest listing status of patient can have. It means that they can receive transplant offers prior to other patients within a 500 nautical mile radius. In order for patients to meet criteria. In addition to having documented acute liver failure, they need to have at least one of the following An iron are of greater than two ventilator dependence or dependence upon renal replacement therapy. There are a few other indications for Status one A listing. And these include things like acute compensated wilson's disease and hepatic patients, or those with early complications after liver transplant, including primary graft, non function or hepatic artery thrombosis. Following transplant. For acute liver failure, patients generally do well with 80% of patients surviving at one year, which is a bit lower than patients transplanted for other causes. This is mainly due to unrecognized irreversible brain injury or infection that is acquired in the pre transplant. So that being said, those that survived the initial post transplant period tend to do very well with a two-year survival of around 92%. This is a final diagram summarizing much of what we just discussed all included here. For your reference. I think the most important intervention that can be performed in the management of these patients is early referral to a transplant center where patients can be rapidly assessed and, if appropriate listed early in their course because time is of the essence when it comes to these patients. Thank you very much for your attention
