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Acute Fulminant Hepatic Failure

Abstract Premashish Kar, Rajiv Singla, Delhi (ALF) is a clinical syndrome characterized by sudden loss of hepatocyte function due to a large spectrum of etiologies in previously normal individuals. In India, acute viral cases, while patients with clinical presentation suggestive of is leading cause for ALF, with hepatitis E being the hepatitis but without any identifiable viral marker constitute 15 to 47 % of the cases in different studies.3-5 Hepatitis E remains most common followed by hepatitis B. In western countries, 3-5 drug induced hepatotoxicity, mostly due to acetaminophen the leading etiology (23 – 41% of the cases). Acute hepatitis B infection contributes significant number of ALF cases (11- (paracetamol) overdose, is the leading cause of ALF. Sepsis and 3-5 cerebral edema with encephalopathy are two most common 27%). Acetaminophen has been implicated in very few cases complication of ALF leading to death. Sepsis occurs due to altered in causation of ALF in India. On the other hand, acetaminophen is single most common etiology responsible for ALF in western immunity and loss of opsonic activity in serum. Cerebral edema 1 is caused by alteration in permeability of blood-brain barrier. ALF countries (30-35% in USA and 60% of cases in Europe). Non- carries grave prognosis with mortality rate varying from 30 – 40% acetaminophen drug toxicity is next common etiology followed with intensive care and liver transplantation to around 70% in by viral hepatitis. Females constitute more than half of the cases countries like India, where facilities for liver transplantation are worldwide, irrespective of etiology of ALF. In a study by Khuroo and Kamili, ratio of male to female was 1:1.6 with higher prevalence limited. Early identification of etiology and institution of specific 6 therapy, if any, can be life saving in patients with acute liver failure. of females in HEV (79.7%) than those in the non-E group (47.5%). Newer advances in form of temporary liver support systems hold Twenty-five to 30 per cent of the women patients are pregnant, whereas the frequency of pregnancy among women in the general a bright promise in bridging the crisis period till recovery or liver 3,5 transplantation. population at any time in India is 3%. The prevalence of HEV in pregnant women with ALF was 95.8% as against 41.2% in non- pregnant women (P < 0.001).6 Introduction Outcome of acute liver failure remains dismal, especially in ALF is defined by occurrence of coagulopathy (INR > 1.5) and developing countries like India due to limited availability of intensive onset of encephalopathy with in 26 weeks of acute liver insult care units and liver transplantations. Most of the published studies due to any etiology, in absence of any pre-existing liver disease. are from tertiary care centers having good intensive care facilities Patients with pre-existing Wilson disease, vertically-acquired HBV, but limited or no facilities for liver transplantation. These studies or autoimmune hepatitis may be included in this definition in report a mortality rate of 60-70%; which would be much higher spite of the possibility of cirrhosis, if their disease has only been in population overall, as not all patients with ALF have access to recognized for <26 weeks.1,2 In children, signs and symptoms of ICU care. In western countries, centers with facilities for liver encephalopathy are slow to occur and are difficult to recognize, transplantation report, much lesser though still unacceptably leading to a growing consensus for defining ALF in children in high, mortality rate of around 30-35%. Cerebral edema and sepsis presence of severe coagulopathy (INR > 2) alone, in addition to contributes towards majority of deaths. Respiratory failure and standard definition1. ALF has traditionally been sub-classified on renal failure also contributes significantly towards mortality in basis of duration of disease into hyperacute/fulminant (<7 days), patients with ALF. Coagulopathy, if identified and corrected timely, acute (7-21 days) and subacute (>21 days and <26 weeks) liver do not lead to death per se. failure. But, Indian as well as western studies have failed to show any prognostic significance of this classification and its use is no King’s college hospital criteria (Table 1) and Ph < 7.30 are two longer recommended2,3. most commonly accepted and well validated prognostic criteria for assessing survival in patients with ALF.2 Other factors which Epidemiology and etiology have been evaluated, either alone or in various combinations, include age, duration of disease, elevated serum creatinine, In India, 90 – 95 % of cases are considered to be due to viral encephalopathy grade, and prothrombin time elevation, decreased hepatitis.3-5 Hepatotropic viruses constitute 42% to 85% of Acute Fulminant Hepatic Failure

Table 1: King’s College Hospital Criteria for poor prog- and fungal sepsis is common in ALF and endotoxemia leads to nosis in Acute Liver Failure like state. Acetaminophen-induced disease Acute hepatic failure, even in absence of infection, has been Arterial pH <7.3 (irrespective of the grade of encephalopathy) postulated to be associated with adrenal insufficiency because of or its pathophysiological similarity with septic shock. In liver disease, Grade III or IV encephalopathy, and low levels of high density lipoproteins (HDL) have been postulated Prothrombin time >100 seconds, and Serum creatinine >3.4mg/dl to be responsible for decreased synthesis of cortisol, leading to All other causes of fulminant hepatic failure adrenal insufficiency. Some other factors, which are common to Prothrombin time >100 seconds (irrespective of the grade of encepha- liver disease and sepsis, contributing to adrenal insufficiency are lopathy) increased levels of endotoxin and proinflammatory cytokines, or which suppress corticotrophin releasing hormone and Any three of the following variables (irrespective of the grade of encepha- adrenocorticotrophic hormone levels; inactivation of cortisol to lopathy) cortisone; and peripheral resistance to action of cortisol. 1. Age <10 years or >40 years 2. etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyncratic Management drug reactions 3. Duration of jaundice before onset of encephalopathy >7 days Initial evaluation of ALF has to very extensive to confirm the 4. prothrombin time >50 seconds diagnosis, ascertain etiology and institution of specific therapy, 5. Serum bilirrubin >18 mg/dl establish prognosis and referral for liver transplantation, if indicated and available. Any patient with clinical features suggestive factor V level, the Acute Physiology and Chronic Health Evaluation of acute hepatitis should immediately undergo evaluation for (APACHE) II score and Gc globulin (vitamin D binding protein, altered mental status and prothrombin time. Prolongation of a liver-derived component of the actin-scavenging system). In a prothrombin time with INR > 1.5 and slightest evidence of altered study by Ostapowicz et al, ALF due to acetaminophen, hepatitis A, sensorium establishes the diagnosis of ALF and admission becomes shock liver, or pregnancy related disease showed >50% transplant mandatory. As ALF progresses very rapidly, rigorous monitoring of free survival, while all other etiologies showed <25% transplant- mental status and early admission in ICU is highly recommended. free survival.7 Other less validated factors include alfa-fetoprotein History should include ingestion of any drug especially levels, factor VIII, adrenal insufficiency and cytokine levels. acetaminophen and possible exposure viral infection. Past history for presence of predisposing factor for chronic liver disease Pathogenesis of Acute Liver Failure should be elicited. Physical examination must include any stigmata Acute liver failure is characterized by massive necrosis of of chronic liver disease. Inability to palpate the liver or even to hepatocytes and hence loss of synthetic and metabolic functions. percuss a significant area of dullness over the liver can be indicative Deficiency of clotting factors synthesized by liver, factors II, V, of decreased liver volume due to massive hepatocyte loss. VII, IX, and X, account for the prolonged prothrombin time An enlarged liver may be seen early in viral hepatitis or with and partial-thromboplastin time observed.8 Hypoalbuminemia malignant infiltration, congestive heart failure, or acute Budd- contributes towards loss of intravascular volume and interstitial Chiari syndrome. edema. Impaired metabolism leads to accumulation of toxic substances, including benzodiazepines-like substances, leading to Initial laboratory investigations include routine blood chemistries hepatic encephalopathy. Impaired gluconeogenesis and impaired including Prothrombin time/INR, serum electrolytes, glucose, AST, hepatic uptake of insulin leads to hypoglycemia. ALT, alkaline phosphatase, total bilirubin, albumin, renal function tests, arterial blood gas, complete blood count, blood type and Impaired regulation of cytokine regulation results in systemic pro- screen, pregnancy test (females) and ammonia levels(arterial if inflammatory state. Levels of tumor necrosis factor, prostaglandin possible). Other investigations to ascertain etiology consist of viral E2 and thromboxane are raised in patients with ALF.9 This pro- hepatitis serologies (anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HEV, inflammatory state leads to subclinical intravascular coagulation anti-HCV), acetaminophen level, toxicology screen, ceruloplasmin and low grade fibrinolysis resulting in thrombocytopenia and DIC level and autoimmune markers (ANA, ASMA, Immunoglobulin like state. Impaired vascular permeability leads to aggravation levels), whenever indicated according to clinical features. of hypoalbuminemia, interstial edema and increased leakage of cytokines in tissues resulting in enhanced oxygen demand with Therapy for ALF consist of general supportive measures, specific resultant hypoxia at tissue level. All these factors results in cerebral therapies for some of the etiologies, liver transplantation and edema and decrease in intracranial cerebral perfusion pressure other methods of temporary liver support. and hence precipitate hepatic encephalopathy. General supportive ICU care (Table 2) includes management Altered immunity, due to impaired cytokine metabolism, results of raised intracranial pressure, correction of coagulopathy, in loss of cell mediated as well as humoral immunity. Bacterial prevention and aggressive treatment of infection, pulmonary and

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Table 2: General supportive measures for Acute Liver Table 3 : Specific therapies for Acute Liver Failure Failure Acetaminophen overdose: gener- • Activated charcoal, if presentation Raised Intracranial pressure • Avoid sedatives ates the highly reactive interme- within 4 hours of ingestion and Hepatic Encephalopathy • Early transfer to ICU diate, N-para-aminoquinonimine • Oral NAC (140 mg/kg by mouth or • Brain imaging to rule out other causes of (NAPQI).When glutathione is nasogastric tube diluted to 5% solu- encephalopathy depleted, NAPQI binds to cell tion, followed by 70 mg//kg by mouth • Lactulose: no survival benefit proteins to yield cysteine adducts. q 4 h X 17 doses)2 • Mannitol, head elevation and intubation • If active gastrointestinal or for encephalopathy grade III/IV worsening mental status, intravenous • Short acting barbiturates for refractory NAC (loading dose is 150 mg/kg in raised ICP 5% dextrose over 15 minutes; main- • Role of continuous ICP monitoring +/- tenance dose is 50 mg/kg given over • Phenytoin for seizures 4 hours followed by 100 mg/kg ad- Coagulopathy • Intravenous vitamin K ministered over 16 hours).2 • Fresh frozen plasma, if active bleeding or Mushroom poisoning • Silymarin 30-40 mg/kg/day invasive procedure • Penicillin G 5-7 million unit/kg/day Infection Role of prophylactic antibiotics and anti Autoimmune Hepatitis Prednisolone 40-60 mg/day fungal not definitive; but are usually given at Acute fatty liver of pregnancy / Early termination of pregnancy most centers HELLP syndrome GI bleeding Prophylactic proton pump inhibitors Acute hepatitis B Role of antiviral treatment (lamivudine/ Hemodynamic/ Renal dys- • Adequate fluid replacement adefovir) unclear function • Central venous pressure monitoring for fluid replacement Table 4: Indications for liver transplantation in Acute • Ionotropic support for hypotension; Liver Failure vasopressin avoided United States of • Life expectancy without transplantation of <7 days • If dialysis required, continuous mode America • Onset of hepatic encephalopathy within 8 weeks of should be used the first symptom of liver injury Others Avoiding hypoglycemia, dyselectrolytemia • Age ≥18 years and at least one of the following o ventilator dependence renal dysfunction and reversal of metabolic derangements. o receiving renal replacement therapy o international normalized ratio >2.0 For raised ICP, apart from measures listed above, hypothermia, United Kingdom Poor prognosis, as indicated by King’s College Hospital hyperventilation and hypertonic saline have also been used less Criteria for Liver Transplantation in Acute Liver Failure 2 commonly at some centers. Corticosteroids have also been used Japan At least two of the following five criteria are satisfied at but have failed to show any evidence of benefit. If an ICP monitor is the time of onset of ≥ Grade II hepatic encephalopathy. placed, key parameters to follow are both ICP and CPP. ICP 1. Age ≥ 45 years. should be maintained below 20-25 mm Hg if possible, with CPP 2. interval from the appearance of the initial symptoms maintained above 50-60 mm Hg. N-acetylcysteine, the standard to development of hepatic encephalopathy ≥ 11 days. antidote for acetaminophen overdose, has recently been suggested 3. prothrombin time < 10% of the standardized value. 4. Serum bilirubin concentration ≥ 18.0 mg/dL. to be beneficial in other forms of ALF, possibly through its effects 5. ratio of the direct to total bilirubin concentration < on hemodynamics in multiorgan failure and its renal protective 0.67. actions.1 in central perfusion pressure to < 40 mmHg.10 Specific therapies have to be instituted for acetaminophen poisoning, autoimmune hepatitis and mushroom poisoning (Table Liver support systems are used in patients who have contraindication 3). for liver transplantation or for whom liver tissue is not available. Liver support systems can be non-biological detoxification systems Liver transplantation has improved the outcome of ALF. or they can be cell based systems. Cell based systems are more Orthotopic liver transplant has traditionally been preferred complicated and costly, but have advantage of providing metabolic over living donor transplantation, because of time constraints for as well as detoxification support. Emerging liver support therapies evaluating donors and ethical concerns. But, living donor transplant include hepatocyte transplantation and liver tissue engineering on is being increasingly used to overcome donor organ shortage. 2-D or 3-D synthetic extracellular matrix.1 Indications for liver transplantation vary slightly in different countries and are summarized in Table 4. Contraindication for liver transplantation in ALF include extrahepatic malignancy, multi- Conclusion system organ failure, irreversible brain damage, refractory raised ALF is a rapidly progressing and life threatening medical emergency. ICP with sustained elevation of ICP > 50 mmHg and a decrease ALF due to Acetaminophen, shock, and hepatitis A have more

540 Acute Fulminant Hepatic Failure favorable outcome than other etiologies. Key to survival is early prognostic factors in hepatic failure in central India. Trop. Gastroenterol. institution of specific therapy and liver transplantation. 1996; 17: 217–20. 5. Khuroo MS. Acute liver failure in India. Hepatology 1997;26: 244–6. Facilities for intensive care and liver transplantation needs to 6. Khuroo MS, Kamili S. Aetiology and prognostic factors in acute liver strengthened on urgent basis to improve outcome of ALF in India. failure in India. J Viral Hepat. 2003 May;10(3):224-31. 7. Ostapowicz G, Fontana RJ, Schiodt FV, et al: Results of a prospective References study of acute liver failure at 17 tertiary care centers in the United 1. lee WM, Squires RH, Jr., Nyberg SL, et al. Acute liver failure: Summary States. Ann Intern Med 2002; 137:947-954. of a workshop. Hepatology 2008; 47:1401-1415. 8. lee WM. Acute liver failure [published correction appears in N Engl J 2. polson J, Lee WM. AASLD Position Paper: The management of acute Med. 1994;330:584]. N Engl J Med. 1993;329 :1862 –1872. liver failure. Hepatology, 2005; 41:1179-1197. 9. muto Y, Nouri-Aria KT, Meager A, Alexander GJM, Eddleston ALWF, 3. Acharya SK, Panda SK, Saxena A, Gupta SD. Acute Hepatic Failure in In- Williams R. Enhanced tumour necrosis factor and interleukin-1 in ful- dia: A Perspective from the East. J Gastroenterol Hepatol. 2000;15:473- minant hepatic failure. Lancet 1988;2:72-74. 479. 10. Shenoy S. Liver transplantation in acute liver failure. Indian J Gastroen- 4. Jaiswal SB, Chitnis DS, Asolkar MV, Naik G, Artwani KK. Aetiology and terol 2006, 25:S13-S18.

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