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• W4280491934 abstract "Robert J. Fontana, MD Jason J. Pan, MD Acute liver failure (ALF) or fulminant hepatic failure is a rare cause of liver disease due to a multitude of etiologies with an estimated annual incidence of only 2000–3000 cases in the United States.[1] ALF is defined as the sudden onset of encephalopathy and coagulopathy (i.e., an international normalized ratio [INR] of >1.5) in an individual without preexisting liver disease in the past 8–24 weeks. The encephalopathy in ALF arises due to rapid increases in ammonia and other neurotoxins that can disrupt the blood–brain barrier with resultant cerebral edema. The likelihood of spontaneous recovery or transplantation-free survival (TFS) is strongly related to the etiology of ALF and maximal degree of encephalopathy.[2, 3] Significant improvements in TFS over the past two decades among patients with ALF are largely attributed to improvements in critical care including greater use of N-acetylcysteine (NAC) and continuous renal replacement therapy (CRRT) and less frequent use of blood products and mechanical intubation.[2] Nonetheless, nearly one-quarter of patients with ALF listed for liver transplantation (LT) will die awaiting an organ. Although LT is done under emergency circumstances in patients with ALF, 1- and 5-year survival rates and neurological outcomes are now excellent and approaching those of patients with cirrhosis undergoing LT.[4-6] All patients with ALF should undergo a rapid and comprehensive diagnostic evaluation at presentation because the etiology of ALF has both therapeutic and prognostic implications (Table 1). IV or oral NAC up to 72 h Ipecac syrup and activated charcoal if single-time-point ingestion within 12 h Stop suspect agent Consider IV or oral NAC up to 72 h Consult LiverTox database Tenofovir, entecavir, or tenofovir alafenamide Consider IV or oral NAC for up to 72 h ANA, SmAb, quantitative IgG, IgM, and IgA levels Transjugular liver biopsy required for diagnosis If histologically confirmed, methylprednisolone 20 mg IV every 8 h Consider IV or oral NAC up to 72 h Differential: acute fatty liver disease of pregnancy, HELLP syndrome, preeclampsia/eclampsia Liver imaging, urinalysis, lactate, long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency testing of acute fatty liver of pregnancy suspected Consider APAP, HSV, HEV testing based on history Suspect if alkaline phosphatase-to-bilirubin ratio <4, aspartate transaminase-to-alanine transaminase ratio >2.2, Coombs-negative hemolytic anemia Ceruloplasmin, 24 h urine copper, slit lamp eye examination, genetic testing Transjugular liver biopsy with copper quantification Oral chelators: zinc, trientine Plasmapheresis Avoid penicillamine, due to risk of neurologic deterioration Anti-HAV IgM HEV IgM/PCR, CMV IgM/PCR, EBV IgM/PCR, HSV IgM/PCR as clinically indicated Liver ultrasound with Doppler magnetic resonance imaging or CT with contrast for confirmation Possible venography and transjugular biopsy for staging Thrombophilia evaluation Each year there are >60,000 instances of acetaminophen (APAP) overdose in the United States and nearly 500 individuals who progress to ALF despite NAC treatment. APAP overdose accounts for nearly 50% of all adult ALF cases and up to 20% of pediatric ALF cases (predominantly in teenagers; Figure 1).[7, 8] Some patients intentionally ingest a large single dose of APAP, typically >4–6 g, as a suicide gesture, while others may unintentionally overdose on APAP containing narcotic congeners or over-the-counter products in the setting of an acute illness or chronic pain over several days. Cofactors for inadvertent APAP hepatotoxicity are increased hepatic oxidative metabolism due to chronic alcohol use and poor nutrition as well as fasting that can deplete intrahepatic glutathione stores.[7] Initial serum APAP drug levels are useful for risk stratification with single-time-point ingestions (i.e., Rumack nomogram) but often are low or undetectable in individuals with unintentional overdose.[7] At presentation, most patients with APAP overdose have markedly elevated serum aminotransferases, a variably elevated INR, and normal or minimally elevated total bilirubin level. Lactic acidosis, acute kidney injury, hypoglycemia, and cerebral edema may develop over the first 72 h. Transplantation-free survival remains high at 60%–70% even in patients with grade 3–4 hepatic encephalopathy.[7, 9] In patients with a single-time-point ingestion, ipecac syrup or gastric lavage with administration of activated charcoal is recommended within the first 12 h. Whenever APAP overdose is suspected, NAC therapy should be rapidly instituted via an enteral or intravenous route (Table 2). Loading dose: 140 mg/kg Subsequent doses: 70 mg/kg every 4 h for up to 72 h Dose 1. Loading dose: 150 mg/kg NAC in 200 ml D5W over 1 h Dose 2. 50 mg/kg NAC in 500 ml D5W over 4 h Dose 3. 125 mg/kg NAC in 1000 ml D5W over 19 h Dose 4. 150 mg/kg NAC in 1000 ml D5W over 24 h Dose 5. 150 mg/kg NAC in 1000 ml D5W over 24 h The majority of non-APAP ALF cases are caused by idiosyncratic drug-induced liver injury (DILI), hepatitis B virus (HBV) infection, autoimmune hepatitis (AIH), or ischemic hepatitis. Antimicrobials account for half of the DILI-related ALF cases with more recent studies demonstrating an increase in cases due to herbal and dietary supplements particularly among Asians.[10-12] The likelihood of an individual agent causing DILI can be determined by reviewing the LiverTox database and use of electronic causality assessment methods.[13, 14] A diagnosis of AIH is suggested by the presence of anti-nuclear antibody titers >1:80, anti-smooth muscle antibody titer >1:80, and an elevated immunoglobulin G (IgG) level.[15] However, not all patients with ALF AIH have detectable autoantibodies, and other forms of ALF can also be associated with detectable autoantibodies.[16] Fulminant AIH is one of the few etiologies where a liver biopsy for histological confirmation is recommended and particularly prior to initiating corticosteroids.[17, 18] HBV-related ALF is relatively uncommon but can arise from de novo infection or represent HBV reactivation that can be assessed by measuring HBsAg and quantitative anti-HBc IgM and HBV DNA levels.[19] Although anti-HBV oral nucleos(t)ide analogs are recommended, the majority of patients with HBV ALF still require urgent LT.[19-21] By contrast, hepatitis A virus (HAV)–related ALF is associated with a 50%–70% likelihood of TFS, although older individuals and those with preexisting liver disease may still need urgent LT.[22] The majority of patients with ischemia-related ALF have an identifiable cardiopulmonary insult or disease (e.g., hypotension, heart failure, arrhythmia) and will improve with supportive care and LT is rarely, if ever, indicated.[23] Other less common causes of non-APAP ALF are Wilson's disease; malignancy; and infection from Epstein–Barr virus, herpes simplex virus, hepatitis E virus, or cytomegalovirus that each account for <1% of all ALF cases.[24, 25] The causes of pregnancy-related ALF are acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, and preeclampsia/eclampsia. Although expedited delivery is recommended in all of these scenarios, a minority may still develop progressive ALF postpartum and require urgent LT.[26] Despite extensive diagnostic testing, nearly 5%–10% of American adults with ALF have an indeterminate etiology.[27] These patients frequently present with a viral prodrome and jaundice but fail to improve over time necessitating urgent LT evaluation.[1, 27] A 72-h course of intravenous or oral NAC should be considered in adults with DILI, HBV, AIH, and indeterminate ALF, as an improved TFS was reported in a randomized placebo-controlled clinical trial, particularly in those with grade 1–2 encephalopathy.[28] However, NAC is not recommended for children with non-APAP ALF due to inferior survival compared with placebo.[29] The Acute Liver Failure Study Group (ALFSG) prognostic index can be determined at the bedside with a smartphone application (“Acute Liver Failure Prognostic” in the Apple App Store). This model incorporates the encephalopathy grade, ALF etiology, vasopressor use, and total bilirubin and INR levels to predict the likelihood of 21-day TFS.[3] The model has demonstrated superior accuracy in predicting TFS compared with the Model for End-Stage Liver Disease (MELD) score and King's College Criteria. Individuals with APAP, ischemia, and HAV-related ALF or those who are pregnant have a higher rate of TFS (50%–70%), compared with all other causes (20%–50%).[3] Patients seen in the emergency room with a <80% projected TFS who are otherwise good candidates for LT should be considered for urgent transfer to an LT center (Figure 2). Individual patient prognosis can also be guided by serial assessment of arterial ammonia, lactate, phosphate, Factor V, and INR values every 8–12 h in the intensive care unit (ICU). The extent of hepatic necrosis on liver biopsy does not generally provide useful prognostic information in patients with ALF because of sampling artifact.[30] However, histologic confirmation of Wilson's disease, AIH, and malignant infiltration may be required, in which case a transjugular approach is recommended to minimize the risk of bleeding. Accurate, noninvasive tests of global hepatic function such as the 13C Methacetin breath test are needed to assist with bedside clinical decision making but are currently not available.[31] Patients with ALF should be cared for in an experienced ICU ideally by a multidisciplinary team of intensivists, hepatologists, and transplantation surgeons (Table 3). Initially, the patient must be stabilized (i.e., airway protection, hemodynamics) while the etiology and severity of disease are being assessed. Simultaneously, suitability for emergency LT should be undertaken particularly in patients with unfavorable etiologies and a poor prognosis. Critical decisions must be made in a short time; the median time from listing to transplantation or removal from the transplantation list due to irreversible decline or improvement is only 2–3 days.[32] Cerebral edema arises in patients with ALF due to hyperammonemia and astrocyte swelling early on with loss of intracranial blood flow autoregulation in later stages. A fever or infection can increase the risk of cerebral edema and should be minimized with cooling blankets and preemptive antibiotics, respectively. As arterial ammonia levels rise, intracranial pressure (ICP) may rapidly surge and lead to worsening mental status and unstable hemodynamics. Therefore, a number of general measures are recommended to prevent ICP hypertension including a quiet nursing environment, minimal positive end-expiratory pressure settings, keeping the head of the bed >30°, and avoiding fluid overload (Table 3). Similarly, avoidance of sedative and analgesic drugs is recommended in patients with grade 1–2 encephalopathy as they may be hypometabolized. When patients develop grade 3 hepatic encephalopathy, elective intubation is recommended to reduce the risk of aspiration along with hyperventilation to a partial pressure of arterial carbon dioxide (PaCO2) of 28–30 mm Hg to enhance cerebral vasoconstriction. Invasive ICP monitoring should be considered in selected patients with ALF with grade 3–4 encephalopathy because the physical examination, papilledema, and head computed tomography (CT) are insensitive means to detect cerebral edema. Although ICP monitoring can objectively detect surges in ICP and help guide medical therapy, it has not been shown to improve clinical outcomes.[33] Because patients with ALF are coagulopathic by definition, use of prophylactic recombinant factor VIIa, plasma factors, and desmopressin prior to insertion of intraparenchymal monitors is recommended to reduce the risk of hemorrhage from 10%–20% to <5%.[34] Once an ICP monitor is in place, the cerebral perfusion pressure (CPP) can be calculated (CPP = mean arterial pressure [MAP] – ICP) and management directed to keep the CPP >60 mm Hg while avoiding ICP surges of 10–20 mm Hg. Strategies for maintaining CPP include raising the MAP via vasopressors as well as hypertonic saline or mannitol boluses to reduce ICP. In addition, some refractory patients may require a pentobarbital coma to reduce cerebral oxygen utilization (Table 3). Although there are uncontrolled studies demonstrating the utility of therapeutic hypothermia in patients with ALF with refractory ICP, this modality is not recommended because the goal temperature and how to rewarm patients is not established.[35, 36] CRRT is frequently used to address oliguria, azotemia, volume overload, and hyperammonemia in patients with ALF with acute kidney injury, which arises in up to 50% of patients.[37] Some studies have demonstrated improved 21-day TFS in those receiving CRRT compared with untreated controls.[37] By contrast, liver support systems involving albumin dialysis, plasmapheresis, and bioartificial livers have not demonstrated convincing data on improving TFS.[38-40] If the patient develops decorticate/decerebrate posturing or has abrupt deterioration in mental status, an urgent noncontrast head CT should be performed to assess for cerebral herniation and/or intracranial hemorrhage. Transcranial Doppler flow measurements to estimate CPP are a promising noninvasive tool to assess ICP that requires further validation in patients with ALF. By contrast, optic nerve ultrasound and middle cerebral artery pulsatility index have not been shown to be useful.[41] Pupillometry using a handheld electronic device that measures the reactivity of pupils to a light stimulus shows promise in patients with head trauma but prospective studies in patients with ALF are needed.[42] In addition to an elevated INR, patients with ALF frequently have a multitude of other hemostatic abnormalities including thrombocytopenia, hypofibrinogenemia, and abnormal clot formation on rotational thromboelastography (ROTEM).[43, 44] However, ROTEM parameters did not track with bleeding nor clotting risk in 200 adult consecutive patients with ALF but did correlate with illness severity.[44] Interestingly, the incidence of spontaneous bleeding in patients with ALF has been only 5%–10% and usually involves mucosal and cutaneous surfaces. As a result, routine administration of fresh frozen plasma (FFP) is not recommended to correct INR and in fact may worsen outcomes, obscure the prognostic value of INR/Factor V, and exacerbate pulmonary and cerebral edema. However, ICP monitor placement and transjugular liver biopsy have increased risk of procedural bleeding (up to 10%–20%). Therefore, some transplantation centers use aggressive protocols to prevent a catastrophic hemorrhage, which could undermine the patient's transplantation candidacy. Although protocols still require prospective validation, most include administration of platelets to exceed 50,000/ml, cryoprecipitate to correct fibrinogen to >100 mg/dl, and FFP or plasma factor concentrate in combination with recombinant activated coagulation factor VIIa to achieve an INR <1.5.[34, 45] Infectious complications including pneumonia, urinary tract infections, line infections, and bacteremia may develop in up to 80% of patients with ALF during their hospital course. Furthermore, fungal infections may develop in up to 20% of patients.[46] Thus, patients should have two sets of blood cultures, urine culture, and a chest x-ray on admission and every 2–3 days thereafter, as well as when there is acute, unexplained worsening in mental status, laboratory parameters, or hemodynamics. Empiric broad-spectrum antibiotics to cover Gram-negative and Gram-positive organisms are recommended for most patients with ALF and especially those awaiting LT or if unexplained clinical deterioration is encountered. Overall, 20%–30% of patients with ALF undergo emergency LT but the number of patients being waitlisted has significantly declined over the past 20 years.[2, 47] Evaluation for LT includes blood tests, liver imaging, and a cardiac echo that can usually be completed in 12–24 h to ensure that there are no medical, cardiopulmonary, or psychosocial contraindications for LT. Eligible patients are then placed on the LT waiting list as a status 1 patient. In 2020, the Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) adopted a new liver allocation system that prioritizes candidates according to geographic distance from the donor hospital rather than UNOS regional boundaries. Because of their high short-term mortality, candidates with ALF qualify for status 1A listing, where they obtain the highest priority to receive an A, B, O compatible deceased brain-dead donor liver within 500 nautical miles. To be listed as an adult status 1A for ALF, the OPTN policy requires a patient with ALF to have a life expectancy of <7 days without LT and no preexisting diagnosis or signs and symptoms of liver disease (excluding LT recipients with primary nonfunction [PNF] or hepatic artery thromboses within 1 week of LT).[48] Patients with AIH and HBV-related ALF may still qualify if they did not have any signs or symptoms of liver disease prior to the development of ALF (Table 4). Among patients listed for LT, 60% may be removed from the list due to either improvement or development of contraindications to LT (Table 5).[4, 32] Rates of waitlist removal currently vary by location as well as the etiology of ALF with APAP overdose patients being more likely to be removed for improvement, while non-APAP patients are more commonly removed due to new contraindications.[4] Progressive or refractory cerebral edema is particularly problematic because it can lead to brain herniation with or without intracranial hemorrhage, which will preclude successful LT. Patients with PNF of their LT or those with early hepatic artery thromboses may also qualify for status 1A listing, but fortunately the incidence of PNF has been declining due to improved allograft selection.[49] Prior LT recipients Patients with primary nonfunction or hepatic artery thromboses within 7 days of LT with aspartate transaminase ≥3000 U/L and at least one of the following: Medical contraindications Psychosocial barriers Severe multiorgan failure Irreversible brain injury A whole cadaveric liver should be used for transplantation in patients with ALF whenever possible. Currently, 21-day post-LT survival is 92% and the 1-year posttransplantation survival is 80%–90%, which is slightly lower than the 1-year survival for all LT recipients (93%).[4, 5, 32] Compared with cirrhosis, ALF LT recipients tend to be younger and are more likely female and to be an ethnic minority.[4, 32] Split, partial, and living donor livers are infrequently used in patients with ALF as there may be undue pressure to be a living donor and potentially worse outcomes in US centers.[50] Access to emergency LT can be safely expanded by using hepatitis C–positive and anti-HBV-core antibody–positive donor livers. Auxiliary partial orthotopic LT and hepatocyte transplantation remain under investigation but demonstrate promise, particularly in children.[51, 52] The majority of ALF LT recipients receive an A, B, O identical or compatible graft, although some have received an A-, B-, O-incompatible graft with a higher incidence of allograft dysfunction.[53] ALF LT recipients frequently have a slower evolution of disease, less severe encephalopathy, and lower utilization of mechanical ventilation, pressors, and CRRT compared with listed patients who died without LT.[32] Patients who develop refractory hypotension on pressors, high supplemental oxygen requirements, refractory cerebral edema, or severe multiorgan failure may not do well with LT (Table 5). Further, LT may be futile in selected patients with irreversible brain injury (e.g., bilateral nonreactive pupils, no spontaneous ventilation, brain herniation), uncontrolled sepsis/shock, and multiorgan failure (Figure 2). The leading causes of death in those waitlisted include progressive infection, cerebral edema, and multiorgan failure. Most centers currently offer standard three-drug immunosuppression to their ALF LT recipients. However, because many of these patients are younger with intact immune systems, two or three drugs may be required for favorable long-term outcomes. A recent retrospective analysis of 3754 adult ALF LT recipients indicated poorer survival with the use of antithymocyte globulin induction compared with corticosteroids.[52] A 2-year prospective study demonstrated that ALF LT recipients were more likely to be alive compared with spontaneous APAP survivors (92% vs. 75%).[54] In addition, post-LT survival was associated with younger age, more days from jaundice to ALF onset, and less severe encephalopathy.[5] ALF LT recipients also had higher long-term rates of employment and lower long-term rates of psychiatric disease, substance use, and alcohol use compared with the spontaneous APAP survivors. This study and others suggest that successful long-term outcomes are related to selecting candidates with low or modifiable psychosocial risk. Robert J. Fontana received grants from Gilead." @default.
• W4280491934 created "2022-05-22" @default.
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• W4280491934 title "CAQ Corner: Acute liver failure management and liver transplantation" @default.
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