I'm Rahul Ghanjal. I'm an intensivist at the Medical College of Wisconsin. And today I will be talking about hepatic failure. I have no disclosures. Today, we will talk about acute liver failure, the causes and complications, and some treatment strategies. We will also talk about acute and chronic liver failure and some of the unique complications and challenges that patients with acute and chronic liver failure or chronic liver failure experience. We will also touch on indications and contraindications for liver transplant, coagulation in liver disease, and finally, extracorporeal liver spore. The syndrome of acute liver injury is heterogeneous. Acute liver failure is a rare disease which occurs in patients without any prior history of liver disease and is characterized by intense hepatocyte necrosis. Portal hypertension is absent and the most common complications include cerebral edema and multisystem artery failure. In contrast, acute and chronic liver failure is much more common and occurs in patients with underlying chronic liver disease. It is characterized by organ failure and the most common complications include hepatic encephalopathy, hepatorenal syndrome, bleeding, infection, and acute kidney injury. Here is the first question for the audience. The question is, which of the following are necessary for the diagnosis of acute, in brackets, fulminant liver failure? And the choices are hepatic encephalopathy, jaundice, coagulopathy, and hepatitis, with the correct answer being hepatic encephalopathy. Acute or fulminant liver failure is defined as severe acute liver injury which leads to encephalopathy and impaired synthetic function in a patient without cirrhosis of preexisting liver disease. Acute liver failure can be divided into hyperacute, acute, or subacute, depending on the timing of encephalopathy in relation to the incident insult to the liver. Hyperacute, the encephalopathy occurs less than seven days after the incident insult. In acute, seven to 28 days. And in subacute, more than four weeks. This slide describes the different phenotypes of acute liver failure, namely hyperacute, acute, and subacute. The hyperacute and acute phenotypes are characterized by greater coagulopathy and more intracranial hypertension, while the subacute phenotype has greater severity of jaundice. However, spontaneous recovery occurs more commonly in the hyperacute and acute forms while survival without liver transplantation is dismal for the subacute phenotype. Some typical causes of the hyperacute phenotype are Tylenol, acute phenotype, hepatitis B, and the subacute phenotype is drug-induced liver injury, which is not Tylenol-mediated. Acute liver failure commonly leads to multiple system organ failure, which can affect virtually any organ of the body. Hepatocyte necrosis leads to a systemic inflammatory response syndrome and a sepsis-like state. Unique complications include the occurrence of cerebral edema and the loss of metabolic function of the liver, which results in hyperglycemia, hyperammonemia, severe coagulopathy, and impaired lactate clearance causing severe lactic acidosis. Other manifestations include a high output state, adrenal insufficiency, acute kidney injury, bone marrow suppression, and the occurrence of acute respiratory distress syndrome. Here is the second question for the audience. The question is, which of the following is not a cause of acute liver failure? And the choices are one, cetaminophen, two, autoimmune hepatitis, three, alcoholic hepatitis, four, hepatitis B, and five, fatty liver of pregnancy, with the correct answer being three, alcoholic hepatitis. This slide demonstrates data from the U.S. Acute Liver Failure Study Group on the etiologies of acute liver failure for over a decade, from 1998 to 2008. In this study, the most common cause of acute liver failure was Tylenol. Other common causes included hepatitis B infection and drug reactions. Rarer causes included acute fatty liver of pregnancy, Burkhiari syndrome, and Wilson's disease. We all know the utility of N-acetylcysteine for Tylenol-mediated acute liver failure. The Acute Liver Failure Study Group also studied the effectiveness of N-acetylcysteine in acute liver failure that was not Tylenol-mediated. They found that the use of N-acetylcysteine was associated with both an improved transplant-free survival at one year, as well as the proportion of patients transplanted at one year. The benefit was seen across grades of hepatic encephalopathy, but was particularly striking for early-grade hepatic encephalopathy. Based on these results, the take-home message is that all patients with acute liver failure should likely receive N-acetylcysteine. Cerebral edema is a well-known and probably the most feared complication of acute liver failure. There are a variety of mechanisms which encompass both cytotoxic edema and vasogenic edema. Cytotoxic edema is caused by overwhelming accumulation of glutamine that is partly driven by hyperammonia and expulsion of organic osmolite from pesticides. Vasogenic edema is the result of destruction of the blood-brain barrier and loss of autoregulation that is partly driven by the systemic inflammatory response syndrome. In a single-center study of over 3,300 patients over 35 years, the King's College in London demonstrated major improvements in survival, as well as a fall in the prevalence of cerebral edema and intracranial hypertension, which was likely a consequence of earlier illness recognition, improved ICU care, and greater use of emergency liver transplantation. What are some of the risk factors for hepatic encephalopathy and the subsequent development of intracranial hypertension in acute liver failure? In another study from the King's College in London, arterial ammonia level of over 150 micromoles per meter, a hyperacute cause of liver failure, such as Tylenol, the need for vasopressor agents, the need for renal replacement therapy, high-grade hepatic encephalopathy, and the presence of the systemic inflammatory response syndrome predicted the development of intracranial hypertension. The management of severe hepatic encephalopathy is based on simple physiological principles and good supportive care. Head of bed elevation to enhance cerebral venous drainage, reducing cerebral metabolic rate by controlling fever, and avoiding intravascular volume overload are essential steps. Patients with high-grade encephalopathy should be electively intubated. Ventilator synchrony should be ensured. Often, this may require deep sedation and paralysis. Hyper or hypocapnia should be avoided, and fever should be actively treated. The jury is still out on whether therapeutic or prophylactic hypothermia should be performed. Consideration should be given to early renal replacement therapy and hyperosmolarity by maintaining the serum sodium levels between 145 and 150 millimoles per liter. Is there a role for aggressive intervention, such as ICV monitoring or therapeutic hypothermia in severe hepatic encephalopathy and cerebral edema in patients with acute liver failure? In a retrospective analysis of data from the U.S. Acute Liver Failure Study Group, in 629 patients with high-grade encephalopathy, 140 patients received an ICV monitor, and comprehensive data was available for analysis in 87 of these patients. From the patients whose data was available for analysis, 51% had an ICV greater than 25 millimeters of mercury. Although the patients who received an ICV monitor had more, received more ICV therapies, there were no mortality differences noted between those who received an ICV monitor and between controls. If anything, the patients who had non-tylenol-mediated acute liver failure did worse. Intracranial hemorrhage, although it was very rare, in patients who received an ICV monitor. Similarly, therapeutic hypothermia, or hypothermia between 33 and 34 degrees centigrade, makes intuitive sense, but there is no evidence that it improves outcomes, i.e., there are no differences in rates of transplant, adverse events, or death, as compared to euthernia or 36 degrees centigrade. What is the role of renal replacement therapy in acute liver failure? We know that acute kidney injury occurs in approximately 50% of patients with acute liver failure. The causes of AKI are manyfold, namely a pre-renal component, autoregulation disturbances, and direct nephrotoxicity from drugs such as Tylenol. Renal replacement therapy is extremely useful as it corrects both volume and metabolic disturbances, such as hyperammonemia and acidosis. Continuous renal replacement therapy is the preferred modality of renal replacement therapy. This is because it minimizes solute shifts, hemodynamic changes, and increases an intracranial pressure. We know that hyperammonemia is associated with intracranial hypertension and mortality in patients with acute liver failure. In a study from the US Acute Liver Failure Study Group, continuous renal replacement therapy was demonstrated to enhance ammonia clearance as compared to intermittent renal replacement therapy or no renal replacement therapy. In a multivariate analysis from the same study, continuous renal replacement therapy in acute liver failure was independently associated with a reduction in serum ammonia levels and an improvement in 21-day transplant-free survival. One of the most widely used criteria for eligibility for liver transplantation for acute liver failure are the King's College criteria. They are different depending on whether the cause is Tylenol or non-Tylenol. For Tylenol-mediated acute liver failure, the criteria for transplant are either a pH of less than 7.3 at 24 hours or all of the following, reactinin of more than 3.4 milligrams per deciliter, an INR of greater than 6.5, and grade three or four hepatic encephalopathy. For non-acetaminophen-mediated acute liver failure, one has to have an INR of 6.5 or any three of the following, an INR of 3.5, a bilirubin of greater than 17 milligrams per deciliter, a duration of jaundice before hepatic encephalopathy of greater than seven days, an age less than 10 or greater than 40, or an unfavorable cause. With acute liver failure, reference to a transplant center should occur if there is any hepatic encephalopathy, which means confusion, asterexis, or a Glasgow Coma scale of less than 14. If the INR is greater than two, if there is any metabolic acidosis, if the trajectory of illness is one of deterioration and there are no obvious contraindications to liver transplantation. In another study from the US Acute Liver Failure Study Group amongst 1,028 Tylenol acute liver failure patients in more recent cohort, i.e. that from 2008 to 2018, compared to an earlier cohort from 1998 to 2007, demonstrated marked improvements in transplant-free survival, decreased intracranial hypertension and cerebral anema, which was possibly related to the increased use of renal replacement, continuous renal replacement therapy. Transitioning to acute on chronic liver failure, this is a syndrome which is more common than acute liver failure. A European-American consensus group agreed upon criteria for its definition. These criteria were the presence of preexisting liver disease, hepatic decompensation, and the occurrence of organ failure. Acute on chronic liver failure is a distinct syndrome with predictable outcomes. No ACLF is either no organ failure, the presence of single non-renal organ failure with a serum creatinine of less than 1.5 milligrams per deciliter and no hepatic encephalopathy, or hepatic encephalopathy and a serum creatinine of less than 1.5 milligrams per deciliter. ACLF-1 is either renal failure or any other single organ failure with a serum creatinine that is between 1.5 and two and hepatic encephalopathy of grade one or two. ACLF-2 denotes two organ failures and ACLF-3 denotes three organ failures. And as this graph demonstrates, as the grades of ACLF increase, so does 28-day and 90-day mortality. This is the third question for the audience. And the question is, which cause of acute kidney injury has the worst prognosis in cirrhotic patients in the absence of transplant? And the choices are glomerulonephritis, hepatorenal syndrome, acute tubular necrosis, and pre-renal azothemia, with the correct answer being two, hepatorenal syndrome. Hepatorenal syndrome is an entity distinct to chronic liver disease. The pathophysiology of hepatorenal syndrome is interdependent on four related pathways which are initiated by hepatic decompensation. Hyperdynamic circulation and decreased systemic vascular resistance, stimulation of neurohormonal compensation in the renal circulation, which is the release of ADH, activation of the sympathetic nervous system, and activation of the renin-angiotensin-andosteron system, cardiac dysfunction or cirrhotic cardiomyopathy, which compounds the circulatory derangements and kidney hyperperfusion, and inflammatory and vasoactive mediators that induce direct renal injury and indirect effects on the renal circulation. The older definitions of acute kidney injury in the context of cirrhosis were predicated upon an increase of serum creatinine by over 50% of baseline to a final value of greater than 1.5 mg per deciliter. The diagnosis of hepatorenal syndrome was then established by ruling out other causes of acute kidney injury such as hypovolemia, shock, nephrotoxic agents, and renal parenchymal disease. We know that serum creatinine overestimates renal function in cirrhotic patients because of reduced muscle mass, increased secretion in renal tubules, dilution due to increased volume of distribution, and assay interference by high bilirubin levels. The International Club of Societies in 2015 recommended a consensus definition of acute kidney injury in cirrhosis. According to this definition, acute kidney injury in cirrhosis is defined as an increase in serum creatinine of 0.3 or more within 48 hours of presentation or a 50% increase in serum creatinine from baseline within the past seven days of presentation. Acute kidney injury is then divided into three stages based on the increases in serum creatinine. The consensus definitions also contain criteria for response to treatment. The new criteria for diagnosis of hepatorenal syndrome are based on the definitions of acute kidney injury by the new consensus criteria and ruling out other causes of acute kidney injury such as hypovolemia, shock, nephrotoxic agents, obstruction, and renal parenchymal disease. This allows pharmacological therapy for hepatorenal syndrome to be started much earlier in the acute kidney injury continuum. Although not all acute kidney injury in cirrhosis is hepatorenal syndrome, but when hepatorenal syndrome does occur, it is associated with a very high mortality. In this study by Martin Mahi and his colleagues published in Gastroenterology in 2011, the incidence and 90-day mortality was highest for acute kidney injury if the acute kidney injury was hepatorenal syndrome. Hepatorenal syndrome was independently associated with 90-day mortality after adjusting for the menstrual, sodium, and hepatic encephalopathy. The treatment of hepatorenal syndrome revolves around using splanctic vasoconstrictors and aluminum. Agents such as the combination of octreotide and migravine, norepinephrine, or tell repressin can be used. Please note that tell repressin is not yet available in the United States. If hepatorenal syndrome cannot be reversed, transplant-eligible patients may be placed on renal replacement therapy. Liver transplantation remains the only definitive therapy for hepatorenal syndrome, and if patients have been on dialysis for more than six weeks, consideration should be given to combined liver-kidney transplantation. The prognosis of hepatorenal syndrome in the absence of transplant remains poor. Creatinine is now used in defining the severity of liver disease and prioritizing liver transplant recipients. The fourth question for the audience. Which cause of acute kidney injury has the worst prognosis in cirrhotic patients after liver transplantation? The choices are glomerulonephritis, hepatorenal syndrome, acute tubular necrosis, and pre-renal azothemia, with the correct answer being pre-acute tubular necrosis. In this study on the impact of the etiology of acute kidney injury on outcomes following liver transplantation, Mitra Nadeem and her colleagues demonstrated that if patients had acute tubular necrosis pre-liver transplantation, they were more likely to have chronic kidney disease post-liver transplantation, and in comparison to patients who either had HRS or no acute kidney injury were also less likely to survive. Hepatopulmonary syndrome is a unique manifestation of cirrhosis. It is characterized by hypoxemia, which is from intrapulmonary shunting in the presence of chronic liver disease and portal hypertension. The mechanism is pulmonary vasodilation due to vasodilators such as nitric oxide emanating from hepatic venous drainage. Key findings include hypoxemia with a normal chest x-ray, metipnea, which is dyspnea in the upright position, and orthodeoxia, which is desaturation in the upright position. Orthodeoxia occurs because there is a predominance of vascular dilatation due to vest zone 3 in the basilar regions. The prevalence is about 10 to 32 percent in some retrospective data sets. Hepatopulmonary syndrome is associated with increased mortality when compared to non-hepatopulmonary syndrome, and the survival is significantly worse if the room air partial pressure of oxygen is less than 50 millimeters of mercury. The diagnosis of hepatopulmonary syndrome is usually established using a bubble study on trans-thoracic echocardiogram. The trans-thoracic echocardiogram demonstrates late bubbles within four to six cardiac cycles. Other tests performed include a chest CT, which is used to rule out associated parenchymal or pleural lung disease. Pulmonary function tests, if performed, will demonstrate a low diffusion capacity for carbon monoxide. The therapy of hepatopulmonary syndrome involves supplemental oxygen therapy, which overrides the diffusion limitation. Sometimes coil angulization is performed if pulmonary atriovenous malformations are radiographically visible. Liver transplantation typically reverses hypoxemia in weeks to months, irrespective of the pre-transplant severity. Photopulmonary hypertension is another unique manifestation of cirrhosis. Photopulmonary hypertension is predominantly pulmonary arterial hypertension, and histologically, it is identical to idiopathic pulmonary hypertension. The pathophysiology of photopulmonary hypertension revolves around vascular injury and or inflammation, which is mediated by some serum factors, which abnormally persist in the hepatic outflow, and also shear stress, which is caused by the hyperdynamic circulation of cirrhosis. The prevalence ranges from four to 16 percent in retrospective illnesses. The signs and symptoms of photopulmonary hypertension include dyspnea, angina, exacerbation of ascites, and lower extremity fever. Acute cardiac or pulmonary insults can exacerbate pre-existing photopulmonary hypertension by increasing the RV afterload and increase the risk of acute RV failure. Initially, the presence of photopulmonary hypertension is suggested by an elevated right ventricular systolic pressure on transthoracic echocardiography, which often triggers right heart catheterization. The diagnosis is confirmed on right heart catheterization if the mean pulmonary artery pressure is greater than 25 and the pulmonary vascular resistance is greater than 240. Patients with photopulmonary hypertension may still be candidates for liver transplantation if the mean pulmonary artery pressure can be reduced to below 35 millimeters of mercury. Similar criteria are used for the placement of tips. It should be noted that tips may lead to right ventricular decompensation in patients with uncontrolled photopulmonary hypertension. The therapy of photopulmonary hypertension usually involves monitoring of RV function with serial transthoracic echocardiograms and right heart catheterization. Therapy with duvutamine and milidone for inotropy and IV epiprostanol for pulmonary vasodilation is used. Chronic intravenous epiprostanol therapy is used with the goal to decrease mean pulmonary artery pressure below 35 millimeter of mercury to make patients eligible for liver transplant. There is an emerging role for co-therapy with endothelin receptor antagonist. Unlike hepatopulmonary syndrome, liver transplantation only reverses photopulmonary hypertension to varying degrees. The fifth question for the audience is which of the following is true regarding coagulation in acute liver failure or acute and chronic liver failure? And the choices are one, the most accurate test to predict bleeding risk is the INR. Two, normal thrombin generation is preserved with a platelet count above 50. Three, the use of viscoelastic testing is associated with increased blood product use. And four, patients with acute liver failure or acute and chronic liver failure are auto-anticoagulated and do not require venous prophylaxis with the correct answer being two, normal thrombin generation is preserved with a platelet count above 50. This slide demonstrates the concept of rebalanced hemostasis in patients with liver disease. Patients with liver disease have defects in both their hemostatic and anti-hemostatic pathways. As a result, the bleeding risk in many patients is not increased and in fact some patients may even be hypercoagulated. Thus, routine tests of coagulation such as the INR do not predict bleeding risk. Viscoelastic testing is the method of choice for determining coagulation status in patients with liver disease. Although the INR predicts severity and prognosis in liver disease, it does not predict bleeding and it should not be used to guide transfusion. Viscoelastic testing is becoming standard of care to guide transfusion in patients with liver disease. Thrombin generation is preserved at a platelet count of above 50 and a fibrinogen level of above 150 milligrams per deciliter. Patients with acute liver failure or acute on chronic liver failure are not anticoagulated and consideration should be given to anticoagulation and or prophylaxis to treat or prevent thrombosis. This is an example of viscoelastic testing that can be used for liver disease. Malnutrition and muscle wasting are common in liver disease. Early and aggressive nutrition should be given consideration. Protein should not be restricted. Micronutrients and vitamins should be replaced and monitoring should be performed for refeeding syndrome. The mechanistic rationale for performance of extracorporeal liver support is to remove the toxins that are generated as a result of hepatocyte necrosis, acute liver failure, and acute or chronic liver failure. These are the toxins that lead to multisystem organ failure and impair hepatic regeneration. Extracorporeal liver support consists of either artificial liver support or bioartificial liver support. Artificial liver support has no hepatocytes in the extracorporeal circuit. The mechanism is solely detoxification and examples include albumin dialysis and high volume plasma extrusion. Bioartificial liver support, on the other hand, has hepatocytes in the extracorporeal circuit and the mechanism involves both detoxification and synthesis. Examples include the extracorporeal liver assist device. Albumin dialysis in the form of molecular adsorbent reticular system has not demonstrated survival benefit in randomized controlled trials. Potential benefits of this therapy include clearance of severe hepatic encephalopathy, clearance of hyperbiliruminemia, and decreased vasopressor support. It may be a useful bridge to transplant in acute or chronic liver failure and acute liver failure. On the other hand, high volume plasma exchange in a randomized controlled trial demonstrated a statistically significant increase in transplant-free survival in the acute liver failure cohort. High volume plasma exchange was defined as an exchange of 8 to 12 liters of fresh frozen plasma over 9 hours with a mean number of 2.4 sessions per patient. In conclusion, here are some take-home points. Acute liver failure is characterized by neo-onset encephalopathy and acute hepatic dysfunction. Basic neurocritical care and ICU-supported care are essential. Advanced therapies may or may not be helpful. An early transfer to a transplant center is recommended. Acute or chronic liver failure is characterized by unique manifestations such as photopulmonary hypertension, hepatopulmonary syndrome, and hepatorenal syndrome. Outcomes are predictable. Acute kidney injury is bad. And there is an emerging role for extracorporeal liver support therapies.

hepatic failure

acute liver failure

chronic liver failure

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liver transplant