Acute liver failure (ALF) is that unique concatenation of

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1 2B: Liver Approach to Acute Liver Failure William M. Lee, MD, FACG Acute liver failure (ALF) is that unique concatenation of events when a previously healthy person develops acute hepatic injury of such severity that life is in the balance within, typically, seven days of disease onset. A number of viruses or toxins can produce this result but only in a small fraction of those exposed in most instances. Examples include acetaminophen, idiosyncratic drug reactions, autoimmune hepatitis, hepatitis B and a variety of other causes, that all narrow down to a common set of signs and symptoms: altered mentation, coagulopathy, renal dysfunction and susceptibility to infection. Because of its rarity, there are few experts in caring for ALF patients, but most busy United States transplant centers have good familiarity with this unusual syndrome. Nonetheless, every gastroenterologist will likely confront such patients at some point, and careful, thoughtful management will avert certain catastrophes. By contrast, colleagues in primary care or emergency medicine specialties seldom have experience with these patients so it is incumbent upon the specialist to become pro-active in this setting and to direct the patient s management. Definitions Acute liver failure (sometimes referred to as fulminant hepatic failure) is most commonly defined as the onset of coagulopathy (International Normalized Ratio [INR] 1.5 and encephalopathy (any degree of altered mentation) in a patient without preexisting liver disease or cirrhosis. 1 The typical interval from onset of symptoms to onset of encephalopathy is 1-2 weeks, but cases evolving more slowly, up to 6 months, may still be included in the definition. A clinical feature that is virtually unique to ALF is cerebral edema, swelling of the brain that may produce herniation of the uncus through the falx cerebrum, yielding brain stem compression and death. 2 The morbidity and mortality of ALF recorded in small case series in the pre-transplant era was extremely high, often exceeding 90%, the causes of death including multi-organ failure, hemorrhage, infection and cerebral edema. Fortunately, these dire outcomes have diminished somewhat due to a change in the causes of ALF to more benign etiologies over the past 40 years as Acknowledgments: The author acknowledges the support of the principal investigators and coordinators of the Acute Liver Failure Study Group and our NIDDK support as well under U-01-DK Tables 1 and 2 were adapted with permission from: Tujios S, Lee WM. Acute Liver Failure in Sherlock s Diseases of the Liver and Biliary System, 12th edition. Dooley J, Burroughs A, Heathcote J, Lok ASF, eds. London, well as to the introduction of liver transplantation. 3,4 Patients have been designated as hyperacute, acute and subacute in presentation depending on the interval from onset of disease to onset of encephalopathy. Different etiologies typically have a specific time frame. For example, most acetaminophen cases are hyperacute while those demonstrating a slower onset (acute or subacute) are typically the result of viral hepatitis, idiosyncratic drug reactions or indeterminate cause. 5 Whether there is a distinct difference in outcome based on the length of disease itself remains unclear; however, the etiologic diagnosis per se is likely the strongest determinant of outcome. Diagnosis Diagnosis seems straightforward: coma and coagulopathy; however, the correct diagnosis often eludes the initial medical contact. Anyone with an apparently severe acute hepatic illness and any degree of mental alteration (or none in the earliest stages) should be screened with a PT/INR and, if prolonged, admission and immediate intensive work up is warranted. Details of the workup algorithm are shown in Table 1. The principal aim is to determine the etiology and the severity, leading to the question of whether in this rapidly developing illness, listing for transplantation is necessary often it is! Overall, acetaminophen dominates in terms of numbers of cases (Figure 1). Management From first principles, many etiologic agents have specific therapies that need to be initiated once the diagnosis is made. Additionally, different causes carry different prognoses. For example, Wilson disease is virtually always fatal without liver transplantation. 6 It is particularly important to identify acetaminophen intoxication since giving N-acetylcysteine even late in the illness may have some value but giving it early is lifesaving. Specific features associated with acetaminophen are very high aminotransferases and a relatively low bilirubin level that indicates that this is a very acute (sometimes called hyperacute) setting. 7 The recent development of an assay to measure acetaminophen adducts in serum can confirm the presence of acetaminophen poisoning when the history does not clearly suggest it. 7,8 Etiology The causes of ALF are many and vary from country to country. In the era prior to transplantation, hepatitis B was very common and accounted for as many as 40-50% of U.S. cases. Prior to 1990, although a well-recognized problem in the 2B: Liver 177

2 United Kingdom, acetaminophen did not account for many U.S. ALF cases. Current U.S. figures provided by the ALF Study Group now show that acetaminophen-related acute liver failure accounts for nearly 50% of all cases, with hepatitis B responsible for only 7% (Figure 1). 9 The etiologic breakdown in the U.S. is similar to that found in Europe but is far different in the developing world, such as India, where drug-induced liver injury is limited solely to isoniazid, and acetaminophen injury is virtually unknown. 10 After acetaminophen, the most common causes are druginduced liver injury (idiosyncratic reactions to prescription drugs), autoimmune hepatitis and a variety of smaller groups. In many instances (~15%), the etiology remains unclear despite extensive history taking and laboratory assessment; these cases are termed indeterminate. Regardless of cause, the final common pathway is remarkably similar: worsening coma associated with coagulopathy but not necessarily bleeding, infection and renal failure. The overall survival without liver transplantation remains about 65% with about 40% requiring transplantation and 25-30% dying of their condition. Acetaminophen-related liver injury The U.S. ALF Study Group, in its first prospective series, recorded 39% of all ALF cases as due to acetaminophen between 1998 and 2001, 4 rising later to 51% in A more detailed snapshot of all acetaminophen-related cases, 11 focused in particular on the unintentional group. Of 275 patients roughly 45% of were considered unintentional (cause of pain, multiple time point ingestions, not overtly suicidal), while a similar percent were clearly suicidal (no pain issues, single time point, suicide admitted). Of these, 38% of the unintentional group took more than one acetaminophen-containing preparation and 62% were taking a narcotic combination such as hydrocodone and acetaminophen. The total quantity consumed over several days approximated that used in the suicidal cases (median ~24 gms), the apparent result of repeated overdosing when pain relief was not forthcoming. In many instances, individuals are using alcohol, hypnotics, hydrocodone or illicit drugs in combination, undoubtedly clouding judgment and often delaying hospitalization. Because patients with unintentional toxicity frequently exhibit signs of poly-substance abuse they may come to hospital later, and are less likely to receive a liver transplant. As might be expected, suicidal ingestions that eventuate in acute liver failure are associated with late presentation, alcohol or other concomitant drugs that may cloud the sensorium delaying presentation, and consumption of larger total doses, indicating more serious intent rather than a gesture. Even with late presentation, N-acetylcysteine orally (and now available as an intravenous preparation, Acetadote, Cumberland Pharmaceuticals) may provide some protection against fatal injury Figure 1: Bar graph showing the composition of etiologies of acute liver failure in the United States between 1998 and 2010, compiled from the Acute Liver Failure Study. Etiology of Acute Liver Failure in the USA Adult Registry (n = 1,696) 46% 12% Lee WM, ALF Study Group, Jan % and undoubtedly prevents severe injury when given within 12 hours following a single-time-point ingestion. 12 Although acetaminophen poisoning leading to ALF carries a very good prognosis, one third of those reaching the threshold of encephalopathy still die and only 9% undergo transplantation. 9 Once acute liver failure develops, the outcome for either type of overdose, suicidal or unintentional, is similar. Other issues associated with acetaminophen Acetaminophen ALF patients uniformly have very high aminotransferases and low bilirubin levels, while much lower aminotransferases and higher bilirubin levels characterize the more slowly evolving pictures. Using a recently developed assay that reliably detects acetaminophen-containing protein adducts released into plasma by dying hepatocytes, 18-20% of both adult and pediatric ALF patients with indeterminate etiology (no cause discerned after extensive investigation and testing) were found to be due to unrecognized acetaminophen poisoning. 13,14 Idiosyncratic drug reactions The developed world is particularly subject to rare acute liver failure due to idiosyncratic drugs reflecting the large number and variety of drugs we ingest. Still, prescription drugs are remarkably safe; the combined number of idiosyncratic drug cases thought to cause ALF in our series is dwarfed by the single agent, acetaminophen. Data from the ALFSG shows the difference in both clinical presentation and outcome for these cases as discussed in Table 2. The drug-induced ALF presentation is more subacute, the likelihood of survival is poorer, and this group more often receives liver transplants. Most frequently implicated drugs include antibiotics (most commonly anti-tuberculous medications, but also sulfa drugs 178 2B: Liver

3 and others). Next most common are non-steroidal anti-inflammatory agents and anti-convulsants. Viral hepatitis Cases of viral hepatitis that develop hepatic failure represent a small fraction of viral hepatitis (~1%) and are largely comprised of hepatitis B, with hepatitis A less frequent and hepatitis E quite prevalent in areas with poor sanitation. Outcome resembles that of other non-acetaminophen causes, being quite dismal for hepatitis B but less so for hepatitis A. 15 Other causes A variety of other etiologies have been implicated from autoimmune hepatitis, 16 Budd-Chiari syndrome (hepatic vein thrombosis 17 ), Wilson disease, 18 pregnancy-associated liver failure, 19 and the rapid evolution of metastatic or lymphomatous hepatic infiltration. 20,21 Indeterminate cases Despite our best efforts, in 15% of patients the diagnosis eludes us. Unrecognized acetaminophen toxicity is clearly implicated and there may be unrecognized autoimmune disease, since testing for autoantibodies and/or biopsy may not be performed routinely in this setting. 7 Occult and unreported drugs or toxins may be responsible in certain instances; another virus responsible for cases of acute liver failure seems unlikely at this point. Clinical Management The backbone of management of the ALF patient is good coma care, once the diagnosis of coagulopathy and encephalopathy is established. However, some special features deserve mention. Rapid evaluation (Table 2), consideration of listing for transplantation and initiation of antidotes where feasible are essential elements of care: N-acetylcysteine for acetaminophen poisoning, penicillin G and silybinin for mushroom poisoning and delivery of the fetus in the cases of pregnancy induced ALF are standard of care. Patients with ALF are uniquely considered as having the highest priority for transplantation (UNOS Status 1) based on their penchant for rapid deterioration. A detailed review of the management issues involved is beyond the scope of this presentation but has been well summarized recently. 22 Role of intracranial pressure monitoring Studies regarding use of ICP monitoring have shown that ICP utilization is center dependent with some sites frequently performing the procedure and others never doing so. Patients in whom a monitor is placed generally received more aggressive mannitol and other treatments when evidence was available clinically of increased ICP levels, and were more likely to be listed for transplantation, but outcomes did not appear to differ in the two groups. 23 Table 1: Initial Laboratory Investigations for Acute Liver Failure Patients Hematology Complete blood count: white blood cells, hemoglobin, hematocrit, platelets Coagulation panel: prothrombin time/inr, factor V Blood group Biochemical Serum chemistries: sodium, potassium, bicarbonate, chloride, urea, creatinine, calcium, magnesium, phosphate, glucose Hepatic panel: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin, total protein, total bilirubin Arterial blood gas ph, pco2, po2, lactate, ammonia Virology Hepatitis B antigen and IgM anticore Hepatitis A (IgM) antibody Hepatitis C antibody (for underlying chronic infection) HCV RNA Hepatitis E antibody (in endemic areas) Hepatitis D antibody if hepatitis B positive HSV, CMV, EBV PCR (if history of immunosuppression) Human immunodeficiency virus (if considering transplantation) Autoimmune Markers Antinuclear antibody (ANA) Anti-smooth-muscle antibody (SMA) Anti liver/kidney microsome 1 (LKM1) Immunoglobulins Toxicology Acetaminophen level Blood alcohol Urine drug screen Miscellaneous Ceruloplasmin Pregnancy test Microbiology Blood culture, aerobic and anaerobic Urine culture and microscopy Sputum culture and microscopy Studies Chest X-ray, electrocardiogram Liver ultrasound with Doppler measurement Electroencephalogram (EEG), non-contrast head CT 2B: Liver 179

4 Table 2: Management Considerations for Acute Liver Failure Patients Cerebral Edema/Intracranial Hypertension Grade I/II Encephalopathy Consider transfer to liver transplant facility and listing for transplantation Head CT: rule out other causes of decreased mental status; little utility to identify cerebral edema Avoid stimulation, avoid sedation if possible Antibiotics: surveillance and treatment of infection required; prophylaxis possibly helpful Lactulose: possibly helpful Grade III/IV Encephalopathy Continue management strategies listed above Intubate trachea (may require sedation) Elevate head of bed Consider placement of ICP monitoring device Immediate treatment of seizures required; prophylaxis of unclear value Mannitol ( g/kg IV bolus): use for severe elevation of ICP or first clinical signs of herniation, monitor urine output and serum osmolarity Hypertonic saline (30% 5-10 ml/hr): Goal serum sodium mmol/l, avoid rapid correction Hyperventilation: effects short-lived; may use for impending herniation Barbituate coma (pentobarbital 3-5 mg/kg IV bolus then 1-3 mg/kg/hr or thiopental 5-10 mg/kg IV bolus then 3-5 mg/kg/hr): watch for hypotension Continuous renal replacement, hypothermia (32-35 C), IV indomethacin (25 mg bolus) may have some benefit in refractory cases Infection Aseptic techniques Surveillance for and prompt antimicrobial treatment of infection required Antifungal coverage for patients not responding to broad spectrum Antibiotic prophylaxis possibly helpful but not proven Coagulopathy Vitamin K (10 mg IV or subcutaneous) FFP: give only for invasive procedures or active bleeding Platelets: give for platelet counts < 10,000/mm3 or invasive procedures Recombinant activated factor VII (40 µg/kg bolus): give 30 min before procedure if coagulopathy refractory to FFP Cryoprecipitate: for fibrinogen < 100 mg/dl and bleeding Exchange plasmapheresis: allows transfusion of large amount of FFP Prophylaxis for stress ulceration: give H2 blocker or PPI Hemodynamics/Renal Failure Arterial line Pulmonary artery catheterization Volume replacement Check cortisol and cosyntropin stimulation test; hydrocortisone mg/day for adrenal insufficiency Pressor support (norepinephrine preferred over dopamine or epinepherine) as needed to maintain adequate mean arterial pressure Avoid nephrotoxic agents Continuous modes of hemodialysis if needed Vasopressin: potentially harmful Pulmonary Sedation for endotracheal intubation and suctioning to prevent increased ICP Ventilator management: tidal volumes 6 ml/kg, low PEEP, aim for pco mmhg Metabolic Concerns Follow closely: glucose, potassium, magnesium, phosphate Consider nutrition: enteral feedings preferred over total parenteral nutrition Role of transplantation There is no clear therapy for this devastating clinical syndrome. Prior to 1980, ALF series demonstrated survival in less than 10%. In this setting, transplantation initially and still seems nothing short of a miracle. In the current era, however, overall survival is approximately 67%, a considerable improvement in the last three decades that is not entirely due to liver grafting. Transplants are only performed on 25% of patients, suggesting that overall survival has improved partly due to different etiologies (more acetaminophen, less hepatitis B), but also due to better intensive care and the use of transplantation. Even in the transplant era, nearly 30% of patients do die with ALF. Reasons for the failure to transplant more patients have included lack of available organs, late presentation and too rapid deterioration, substance abuse issues, repeated suicidal behavior or other organ system involvement (malignancy, heart failure) that would preclude grafting in any case. Patients undergoing transplantation for ALF are typically young and otherwise healthy and thus should be quite optimal candidates compared to their cirrhosis counterparts. Nevertheless, short term and one year survival figures are below that for cirrhotic patients (91% at three weeks in our study), in part because of the extreme emergency conditions often encountered. There is no option for deferring transplant in these patients until a more optimal condition can be developed. Similarly, living related donations might solve the organ shortage; however, it is extremely difficult to prepare a donor adequately and perform the surgery in a timely fashion B: Liver

5 Despite full physical recovery, many patients have some mental impairment that may be life long. Because of these considerations, we are conducting a long-term follow-up study of patients with ALF to ascertain how much loss of cognitive abilities follows from the exposure to the conditions of encephalopathy and increased brain edema. Summary Acute liver failure challenges our best clinical and surgical skills because of its rarity, rapid progression and frequently bad outcomes. The small numbers of patients do not readily lend themselves to controlled trials and are studied only with great difficulty. Nevertheless, descriptive information aids our understanding of what to expect and where small gains might be made in this condition. Patients are particularly vulnerable to infection, bleeding and cerebral edema and seek medical care typically with very advanced hepatic injury. It is unlikely that there is one overall therapy that will improve hepatic function and restore hepatocyte mass in this condition. Rescue therapies that provide temporary liver support, or other treatments short of transplantation that don t enhance hepatic regeneration, are likely to fail unless there is reconstitution of functional hepatic mass, probably via stem cells. References 1. Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F, eds. Progress in liver diseases. New York: Grune & Stratton. 1970: Ritt DJ, Whelan G, Werner DJ, et al. Acute hepatic necrosis with stupor or coma. An analysis of thirty-one patients. Medicine 1969;48: Tujios S, Lee WM. Acute Liver Failure in Sherlock s Diseases of the Liver and Biliary System, 12th edition. Dooley J, Burroughs A, Heathcote J, Lok ASF, eds. London, Lee WM, Squires RH Jr, Nyberg SL, et al. Acute liver failure: Summary of a workshop. Hepatology 2008;47: Benhamou J-P. Fulminant and subfulminant liver failure: Definition and causes. In: Williams R, Hughes RD, eds. Acute liver failure. Improved understanding and better therapy. London: SmithKline Beecham Pharmaceuticals;1991: Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: A comparison of currently available diagnostic tests. Hepatology 2008;48: Khandelwal N, James LP, Sanders C, et al, and the Acute Liver Failure Study Group. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. Hepatology 2011;53: Davern II, TJ, James LP, Hinson JA, et al, and the ALFSG. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006:130: Ostapowicz GA, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137: Acharya SK, Dasarathy S, Kumer TL, et al. Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. Hepatology 1996;23: Larson AM, Fontana RJ, Davern TJ, et al, and the ALF- SG. Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study. Hepatology 2005:42: Makin AJ, Williams R. Acetaminophen-induced hepatotoxicity: predisposing factors and treatments. Adv Intern Med 1997;42: Davern II, TJ, James LP, Hinson JA, et al, and the ALFSG. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006:130: James LP, Alonso EM, Hynan LS, et al, and the Pediatric Acute Liver Failure Study Group. Detection of acetaminophen-protein adducts in children with acute liver failure of indeterminate cause. Pediatrics 2006;118:e Schiødt FV, Davern TJ, Shakil OA, et al. Viral hepatitis-related acute liver failure. Am J Gastroenterol 2003;98: Czaja AJ. Treatment of autoimmune hepatitis. Semin Liv Disease 2002; 22: Ringe B, Lang H, Oldhafer K-J, et al. Which is the best surgery for Budd-Chiari syndrome: Venous decompression or liver transplantation? A single center experience with 50 patients. Hepatology 1995;21: Roberts E, Schilsky ML. A practice guideline on Wilson disease. Hepatology 2003;37: Ockner RS, Brunt EM, Cohn SM, et al. Fulminant hepatic failure caused by acute fatty liver of pregnancy treated by orthotopic liver transplantation. Hepatology 1990;11: Rowbotham D, Wendon J, Williams R. Acute liver failure secondary to hepatic infiltration: A single centre experience of 18 cases. Gut 1998;42: Agarwal K, Jones DE, Burt AD, et al. Metastatic breast carcinoma presenting as acute liver failure and portal hypertension. Am J Gastroenterol 2002;97: Polson J, Lee WM. AASLD Position Paper: Acute Liver Failure. Hepatology 2005,41: Vaquero J, Fontana RJ, Larson A, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transplant 2005;11: B: Liver 181

MANAGEMENT OF ACUTE HEPATIC FAILURE

MANAGEMENT OF ACUTE HEPATIC FAILURE -NEW CONCEPT PROF. DR.MD ZAKIR HOSSAIN PROFESSOR & HEAD DEPARTMENT OF MEDICINE RANGPUR MEDICAL COLLEGE & HOSPITAL Rangpur Medical College & Hospital Begum Rokeya Shakhawat