Dr. Arun Aggarwal Gastroenterologist : Acute Liver Failure

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Dr. Arun Aggarwal Gastroenterologist - Near diffuse marked hepatocellular ballooning degeneration. Scattered hepatocyte apoptosis, ~ 15-20%. Mild to moderate lobulitis; lymphocytes and neutrophils.

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The Failing Liver…..Do we have Rich experience…:

The Failing Liver…..Do we have Rich experience… Dr. Arun Aggarwal Gastroenterologist, M.D. Pediatric GI Fellow Westchester Medical Center Dr. Arun aggarwal Gastroenterologist

Slide 2:

2 yr old male c/o yellowish discoloration X 1 wk Vomiting X 2-3 days No h/o fever, rash, loose stools, medication use No significant past medical or family history O /E: liver palpable 3 cm BCM, otherwise unremarkable. Dr. Arun aggarwal Gastroenterologist

Hb, WBC and PLT:

Hb , WBC and PLT Dr. Arun aggarwal Gastroenterologist

AST, ALT and Bilirubin:

AST, ALT and Bilirubin Dr. Arun aggarwal Gastroenterologist

Slide 5:

Dr. Arun aggarwal Gastroenterologist

Slide 6:

Dr. Arun aggarwal Gastroenterologist

Liver biopsy:

Liver biopsy Near diffuse marked hepatocellular ballooning degeneration. Scattered hepatocyte apoptosis, ~ 15-20 %. Mild to moderate lobulitis ; lymphocytes and neutrophils . Hepatocytic and canalicular cholestasis, mild. No stainable iron identified. No PAS+ diastase resistant granules identified. Dr. Arun aggarwal Gastroenterologist

Definition :

Definition Acute onset of liver disease with no known evidence of chronic liver disease. Biochemical and/or clinical evidence of severe liver dysfunction: Hepatic based coagulopathy (PT ≥ 20 or INR ≥2) that is not corrected by Vit K and/or Hepatic encephalopathy (if PT is 15-19.9 or INR is 1.5-1.9) The lack of preexisting liver disease: implies that recovery is possible if the patient can be supported, the cause is eliminated and the liver retains its capacity to regenerate. Squires et al: Acute liver failure: the first 348 patients in the pediatric acute liver failure study group. J Pediatrics 2006; 148 (5):652-8 Dr. Arun aggarwal Gastroenterologist

NOMENCLATURE Dependent on J-E Interval:

NOMENCLATURE Dependent on J-E Interval Hepatic Failure 1. Acute - onset 8-28 days 2. Hyperacute - within 1st week 3. Subacute - 29 days -12 weeks 4. Fulminant- within 2 weeks 5. Subfulminant - 2 weeks –3mos 6. Late-onset- 8-24 weeks 1-3: O’Grady JG et al. Lancet 1993 4-6: Bernuau J et al. Hepatology 1986 Dr. Arun aggarwal Gastroenterologist

Epidemiology :

Epidemiology Frequency of ALF in all age groups is ~10 to 20,000/year (~17 cases/ 100,000 population/ year). Frequency in the pediatric age group is unknown. ALF accounts for 10-15% of pediatric liver transplants performed in the USA annually. Dr. Arun aggarwal Gastroenterologist

Etiology :

Etiology Dr. Arun aggarwal Gastroenterologist

Causes of neonatal liver failure:

Causes of neonatal liver failure Dr. Arun aggarwal Gastroenterologist

Etiology in Neonates:

Etiology in Neonates Infections Herpes virus, Echovirus, Adenovirus, Hepatitis B virus Inborn errors of metabolism Galactosemia , Hereditary fructose intolerance, Tyrosinemia Immune mediated Neonatal hemochromatosis Ischemia and abnormal perfusion Congenital heart disease, cardiac surgery, myocarditis, severe asphyxia Other Hemophagocytic syndrome Dr. Arun aggarwal Gastroenterologist

Etiology in Infants:

Etiology in Infants Infectious Hepatitis A virus, Hepatitis B virus, NANB hepatitis, Herpes virus Drugs and toxins Valproate, Isoniazid, Acetaminophen, Amanita Inborn errors of metabolism Hereditary fructose intolerance, others Immune mediated Macrophage activation syndrome, hemophagocytic syndrome Ischemia and abnormal perfusion Congenital heart disease, cardiac surgery, myocarditis, severe asphyxia Other malignancy Dr. Arun aggarwal Gastroenterologist

Etiology in 2-10 years:

Etiology in 2-10 years Infectious NANB hepatitis, Hepatitis A virus, Hepatitis B virus, Herpes virus Drugs and toxins Valproate, Isoniazid, Acetaminophen, Amanita Immune mediated Autoimmune hepatitis, macrophage activation syndrome, hemophagocytic syndrome Ischemia and abnormal perfusion Budd chiari syndrome, Congenital heart disease, cardiac surgery, myocarditis, severe asphyxia Metabolic Wilson disease Other Malignancy, hyperthermia Dr. Arun aggarwal Gastroenterologist

Etiology in 10-18 years :

Etiology in 10-18 years Infectious NANB hepatitis, Hepatitis A virus, Hepatitis B virus, Herpes virus Drugs and toxins Acetaminophen overdose, Valproate, Isoniazid, Amanita Immune mediated Autoimmune hepatitis, macrophage activation syndrome, hemophagocytic syndrome Ischemia and abnormal perfusion Budd chiari syndrome, Congenital heart disease, cardiac surgery, myocarditis, severe asphyxia Metabolic Wilson disease, fatty liver of pregnancy Other Malignancy, hyperthermia Dr. Arun aggarwal Gastroenterologist

Pediatric ALF:

Pediatric ALF Cause Age less than 3 y (%) Age greater than 3 y (%) Total (%) Acetaminophen 2 (2) 33 (24) 35 (15) Indeterminate 55 (60) 63 (46) 118 (52 ) Metabolic 15 (27) 8 (6) 23 (10) Autoimmune 5 (5) 9 (7) 14 (6) Drug and toxin 1 (1) 10 (7) 11 (5) Infectious 4 (4) 3 (2) 7 (3) Shock 2 (2) 5 (4) 7 (3) Other 8 (9) 6(4) 14 (16) * Bucuvalas J et al. Clin Liver Dis 2006 Dr. Arun aggarwal Gastroenterologist

Pediatric ALF:

Pediatric ALF *Lee WM et al, Hepatology 2008 Dr. Arun aggarwal Gastroenterologist

Infective hepatitis:

Infective hepatitis Risk of developing ALF in acute Hepatitis A is 0.1-0.4% Incidence of ALF owing to Hepatitis B is 1-4% There is a theoretical risk of developing ALF after Hepatitis C infection. Risk of developing ALF after Hepatitis E infection is 0.6-2.8% (significantly higher in pregnant) Hepatic dysfunction in sepsis is the result of decreased hepatic perfusion, hypoxia and lactic acidosis. Dr. Arun aggarwal Gastroenterologist

Drugs :

Drugs Most common (90%) liver injury pattern owing to drugs is hepatocellular necrosis, others could be cholestatic (biliary damage), mixed or steatosis . Valproate can unmask underlying mitochondrial cytopathies → detailed investigation to exclude mitochondrial hepatopathies should be undertaken. Acetaminophen → hepatocyte necrosis is caused by accumulation of the N - acetylparabenzoquine amide. Serum acetaminophen levels after 4 hours of ingestion are useful in identifying high-risk patients but are not informative in patients in whom toxicity is secondary to chronic administration. Dr. Arun aggarwal Gastroenterologist

Slide 21:

children with autoimmune hepatitis presenting with ALF along with encephalopathy do not respond to any form of immunosuppression and need urgent liver transplant . Galactosemia is usually associated with hypoglycemia and gram-negative septicemia . Tyrosinemia presents with severe coagulopathy, mild jaundice , and rickets . Neonatal hemochromatosis (NH) is a disorder of iron handling of antenatal onset with excess iron deposition in the nonreticuloendothelial system . NH: elevation of ferritin as a diagnostic test is sensitive but not specific. Magnetic resonance imaging of the liver or pancreas to demonstrate iron is not usually rewarding Documentation of iron in salivary glands in buccal mucosa is diagnostic of NH. Dr. Arun aggarwal Gastroenterologist

Pathology and Biochemistry:

Pathology and Biochemistry Liver cell necrosis is characteristic of ALF resulting from viral infections, most toxic injuries, ischemic injury, and some metabolic diseases. Establishing a pathological diagnosis by liver biopsy has not been considered critical in patient management, largely because of associated risks. Aminotransferase values are not predictive of outcome. Rapidly falling aminotransferase values signify “exhaustion” of the hepatocyte mass and indicate imminent ALF. Dr. Arun aggarwal Gastroenterologist

Slide 23:

Marked jaundice often accompanies hepatic necrosis. Rate of increase in bilirubin often exceeds than expected with a normal rate of production and zero clearance. Increased production may result from catabolism of hepatic heme proteins or from hemolysis. Initially, bilirubin is in conjugated form. Later, majority of bilirubin may be unconjugated (indicating loss of conjugation ability and poor prognosis since only 1% of normal conjugation is required to maintain bilirubin concentration). Dr. Arun aggarwal Gastroenterologist

Pathogenesis :

Pathogenesis Exposure Immaturity of immune function may be the key reason for susceptibility of newborns to herpes virus. Severity of injury in HBV infection may be related to the vigor of the immune response. Individual biochemical polymorphism may play a role in susceptibility to certain drug induced injuries. Dr. Arun aggarwal Gastroenterologist

Pathogenesis contd..:

Pathogenesis contd.. Hepatocyte injury Hepatocyte necrosis is prominent in a large proportion of patients with ALF. Mechanism: virus either is directly cytopathic or induces an immune response that injures the cell. General cellular dysfunction is apparent in many metabolic disorders e.g. hereditary fructose intolerance. (cell necrosis is limited) Dr. Arun aggarwal Gastroenterologist

Pathogenesis contd..:

Pathogenesis contd.. Regeneration Liver cell necrosis → regeneration Several growth factors are mediators of hepatic regeneration: epidermal growth factor, transforming growth factor α , and human hepatocyte growth factor. Dr. Arun aggarwal Gastroenterologist

Pathogenesis contd..:

Pathogenesis contd.. Termination (three possibilities) Terminal hepatic failure. Spontaneous recovery. Overall process may become muted, slowed down by events taking place in the host → may result in chronicity e.g. Hepatitis B infection. Dr. Arun aggarwal Gastroenterologist

Clinical manifestations and complications:

Clinical manifestations and complications Dr. Arun aggarwal Gastroenterologist

Encephalopathy :

Encephalopathy Earliest abnormalities (stage I) may not be detectable by clinical assessment but are apparent to family members. Personality changes. Regression of behavior In brain, urea cycle enzymes are absent; hence, ammonia is cleared by the formation of glutamine by enzyme glutamate synthetase . γ- Aminobutyric acid (GABA), a principal inhibitory neurotransmitter in the brain, is increased in ALF. Dr. Arun aggarwal Gastroenterologist

Hepatic Encephalopathy:

Hepatic Encephalopathy Dr. Arun aggarwal Gastroenterologist

Physical Findings:

Physical Findings Dr. Arun aggarwal Gastroenterologist

Role of ammonia in HE:

Role of ammonia in HE Dr. Arun aggarwal Gastroenterologist

Clinical stages of hepatic encephalopathy:

Clinical stages of hepatic encephalopathy Dr. Arun aggarwal Gastroenterologist

Slide 34:

Blood ammonia concentration does not correlate with the development or degree of hepatic encephalopathy (many centers don't rely on repeated ammonia levels to follow the course of encephalopathy). Not all children with elevated ammonia have encephalopathy. Ammonia is of gut origin → makes it a target for treatment. Increased conc or availability of endogenous benzodiazepines contribute to HE. Dr. Arun aggarwal Gastroenterologist

Intracranial hypertension and Cerebral edema:

Intracranial hypertension and Cerebral edema Brain death associated with cerebral edema is the most frequent cause of death in most series of ALF. Dr. Arun aggarwal Gastroenterologist

Intracranial hypertension and Cerebral edema:

Intracranial hypertension and Cerebral edema Phase 1: Episodic increase in ICP either spontaneously or in response to stimuli involved in the routine care of the patient. An intact Cushing reflex at this stage can maintain cerebral perfusion by increasing mean arterial pressure. Phase 2 : MAP does not increase with further surges in ICP, leading to neuronal hypoxic injury . Phase 3: poor cerebral perfusion either owing to very high ICP or low mean arterial pressure , leading to hypoxic brain injury. Dr. Arun aggarwal Gastroenterologist

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Dr. Arun aggarwal Gastroenterologist

Factors worsening ICP:

Factors worsening ICP Hypotension Hypoxia Hypoglycemia Sepsis Electrolyte disturbances (hyperkalemia ) Gastrointestinal bleeding . Dr. Arun aggarwal Gastroenterologist

Renal failure:

Renal failure Incidence of renal failure is 10–15% Functional renal failure ( hepatorenal syndrome) usually progresses to tubular damage as the encephalopathy advances . Avid sodium retention (urinary sodium < 20 mmol /L) and normal urine sediment may help to differentiate between functional renal failure and tubular damage. The hepatorenal syndrome recovers rapidly after liver transplant, whereas established tubular damage requires prolonged renal replacement therapy. Dr. Arun aggarwal Gastroenterologist

Metabolic derangements:

Metabolic derangements Hypoglycemia is present in 40% of patients with ALF. This is due to increased plasma insulin levels owing to reduced hepatic uptake and reduced gluconeogenesis . Metabolic acidosis is present in about 30% of patients with acetaminophen induced ALF and is a bad prognostic marker. Hypokalemia is common and is due to excessive urinary potassium loss with inadequate replacement . Hyponatremia may be dilutional owing to excessive antidiuretic hormone secretion, or it may represent a true sodium-depleted state in patients who are vomiting . Hypophosphatemia is most commonly associated with acetaminophen-induced ALF when renal function is preserved . Other electrolyte disturbances include hypocalcemia and hypomagnesemia . Dr. Arun aggarwal Gastroenterologist

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Hemodynamic abnormality: hyperdynamic circulation. Cardiac arrhythmias: usually caused by electrolyte disturbance. Pulmonary complications: aspiration of gastric contents, atelectasis, infection, intrapulmonary hemorrhage , respiratory depression, or pulmonary edema. Acute pancreatitis. Adrenal hyporesponsiveness . Dr. Arun aggarwal Gastroenterologist

Coagulopathy :

Coagulopathy The liver synthesizes not only the coagulation factors ( except factor VIII) but also inhibitors of coagulation and factors involved in the fibrinolytic system. ALF is characterized by decreased synthesis of clotting factors (factors II, V, VII, IX , and X), accelerated fibrinolysis, and impaired hepatic clearance of activated clotting factors and fibrin degradation products . Factors V and VII have the shortest half-lives of all of the coagulation factors and are theoretically more sensitive markers than INR of hepatic synthetic function . Thrombocytopenia may develop rapidly. Common sites of internal hemorrhage include the gastrointestinal tract , nasopharynx , lungs, and retroperitoneum . Intracranial hemorrhage is uncommon. Dr. Arun aggarwal Gastroenterologist

Infections :

Infections Patients with ALF are at increased risk of bacterial infections because of poor host defenses . The additional predisposing factors are poor respiratory effort and cough reflex and the presence of an endotracheal tube, urinary catheters , and central venous and arterial lines . An active uncontrolled infection can render potential candidates disqualified for emergency liver transplant. More than two thirds of bacterial infections are due to gram-positive bacteria , usually Staphylococcus aureus , but streptococci or gram negative organisms such as coliforms are also isolated . Candida is the most common fungal infections. Deterioration of HE after initial improvement, a markedly raised leukocyte count , pyrexia unresponsive to antibiotics, and established renal failure are strong indicators of fungal infection. Dr. Arun aggarwal Gastroenterologist

Prognosis :

Prognosis PT is the best indicator of survival. Factor V concentration has been used as a prognostic marker , especially in association with encephalopathy ( Clichy criteria). In children, a factor V concentration of less than 25% of normal suggests a poor outcome. Liver biopsy is rarely helpful in ALF and is usually contraindicated because of the presence of coagulopathy. Hepatic parenchymal necrosis of more than 50% is associated with a reduced survival. A small liver or, more particularly, a rapidly shrinking liver is an indictor of a poor prognosis. Dr. Arun aggarwal Gastroenterologist

Wilson’s disease index:

Wilson’s disease index A score of 11 or more indicates high mortality. Dr. Arun aggarwal Gastroenterologist

Indicators of poor prognosis in Acetaminophen induced ALF:

Indicators of poor prognosis in Acetaminophen induced ALF Dr. Arun aggarwal Gastroenterologist

Indicators of poor prognosis in Nonacetaminophen etiologies of ALF:

Indicators of poor prognosis in Nonacetaminophen etiologies of ALF Dr. Arun aggarwal Gastroenterologist

Treatment :

Treatment Dr. Arun aggarwal Gastroenterologist

Diagnostic tests of the causes of ALF:

Diagnostic tests of the causes of ALF Dr. Arun aggarwal Gastroenterologist

Investigations in infants and children with ALF:

Investigations in infants and children with ALF Dr. Arun aggarwal Gastroenterologist

General measures:

General measures Dr. Arun aggarwal Gastroenterologist

Slide 52:

Should be nursed in a quiet environment with as little stimulation as possible to minimize acute increase in the ICP . Monitoring of nonventilated ALF patients should include the following: Continuous oxygen saturation monitoring 6-hourly urine output 6-hourly vital signs including blood pressure, neurologic observations , and blood glucose estimation 12-hourly electrolyte and coagulation studies (INR) Daily full blood count along with surveillance blood and urine cultures Dr. Arun aggarwal Gastroenterologist

Slide 53:

patients on assisted ventilation have an arterial line for invasive blood pressure monitoring and frequent blood sampling. Blood gas analysis is performed every 4 hours, and electrolytes and PT are measured every 8 hours . Hypoglycemia should be avoided by use of intravenous glucose infusion or by ensuring adequate enteral intake. Total fluid intake is restricted to two-thirds maintenance if there is no evidence of dehydration, with the idea of decreasing the possibility of development of cerebral edema. Prophylactic broad-spectrum antibiotics and antifungals significantly reduce the incidence of infective episodes . In neonatal liver failure, intravenous acyclovir should be commenced. Dr. Arun aggarwal Gastroenterologist

Slide 54:

To maintain ammonia production at a minimum, some protein (0.8-1g/kg) should be administered parenterally to reduce catabolism. Antibiotics reduce ammonia absorption by reducing bacterial urease and proteases responsible for ammonia production in gut. Lactulose acts principally as a cathartic, but also acidifies the colonic contents (trapping NH4+) and qualitatively alters the bacterial flora. Dr. Arun aggarwal Gastroenterologist

Slide 55:

Many of the complications of ALF increase the potential for ammonia accumulation and its neurotoxicity: Prevent GI hemorrhage. Dehydration and electrolyte and acid base disturbances should be corrected. Blood glucose conc should be maintained. Dr. Arun aggarwal Gastroenterologist

Management of specific complications:

Management of specific complications Dr. Arun aggarwal Gastroenterologist

Neurologic Complications:

Neurologic Complications Ammonia-lowering measures such as dietary protein restriction, bowel decontamination, or lactulose are of limited or no value in rapidly advancing encephalopathy. The use of branched-chain amino acids , flumazenil , and extracorporeal circuits has only shown transient improvement in encephalopathy. Dr. Arun aggarwal Gastroenterologist

Slide 58:

The aim of ICP monitoring is to maintain cerebral perfusion pressure (mean arterial blood pressure – ICP) at more than 50 mm Hg. If the cerebral perfusion pressure falls below 50 mm Hg, the adequacy of sedation and paralysis should be checked, along with PaCO2 levels (in ventilated patients , PaCO2 should be kept between 4 and 4.5 kPa ). If the PaCO2 is more than 4.5 kPa , then hyperventilation may be helpful . Dr. Arun aggarwal Gastroenterologist

Pathway for the management of raised ICP:

Pathway for the management of raised ICP Dr. Arun aggarwal Gastroenterologist

Slide 60:

Mannitol remains the mainstay of treatment for increased ICP because of its property as an osmotic diuretic. A rapid bolus of 0.5 g/kg as a 20% solution over a 15-minute period is recommended, and the dose can be repeated if the serum osmolarity is less than 320 mOsm /L. Dr. Arun aggarwal Gastroenterologist

Slide 61:

Studies have shown sodium thiopental to be an effective agent in controlling mannitol -resistant cerebral edema. A bolus dose of 2 to 4 mg/kg over 15 minutes is followed by a slow intravenous infusion of between 1 and 2 mg/kg/h. Major concerns are hemodynamic instability and increased incidence of infective complications following its administration . Forbes A, Alexander GJ, O’Grady JG, et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 1989;10:306–10. Dr. Arun aggarwal Gastroenterologist

Slide 62:

Hypothermia (core body temperature of 32°C) has been shown to be effective in the management of severe intracranial hypertension with lowering of ICP and improvement of cerebral perfusion pressure. Jalan R, Damink SW, Deutz NE, et al. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure . Lancet 1999;354:1164–8. Dr. Arun aggarwal Gastroenterologist

Slide 63:

Presence and maintenance of hypernatremia (serum Na >145mmol/L) significantly decreases ICP and improve CPP in pediatric traumatic brain injury. Khanna et al. Use of hypertonic saline in the treatment of severe refractory posttraumatic ICP in pediatric traumatic brain injury. Crit Care Med 2000; 28:1144-51 Dr. Arun aggarwal Gastroenterologist

Slide 64:

Hepatectomy with a portacaval shunt has been shown to stabilize the patients hemodynamically with reduction of ICP up to 48 hours followed by successful liver transplant . N - Acetylcysteine has been shown to increase the cerebral blood flow and cerebral metabolic rate, thereby improving the microcirculatory stability . Ytrebo et al. NAC increases CPP in pigs with fulminant hepatic failure. Crit care Med 2001; 29:1989-95. Dr. Arun aggarwal Gastroenterologist

Infections :

Infections Bacterial and fungal infections have been documented in about 82 and 34% of patients with ALF, respectively. About 60 % of deaths in ALF have been attributed to sepsis. Prophylactic intravenous antibiotics have been shown to reduce the incidence of culture-positive bacterial infection from 61.3 to 32.1%. The respiratory tract is the most common site ( 47%), followed by the urinary tract (23 %). Gram positive bacteria are the most common organism isolated in about 70% of cases, 35% of these isolates being S. aureus . Dr. Arun aggarwal Gastroenterologist

Hemodynamic instability :

Hemodynamic instability Despite the presence of edema , frequently these patients have intravascular volume depletion and need an appropriate combination of colloids, crystalloids , or blood products. In the presence of persistent hypotension despite normal filling, pressure vasopressors such as noradrenaline and adrenaline are inotropic agents of choice. N AC has been shown to improve the parameters of oxygen metabolism. Dr. Arun aggarwal Gastroenterologist

Care pathway for the management of hypotension :

Care pathway for the management of hypotension Dr. Arun aggarwal Gastroenterologist

Coagulopathy :

Coagulopathy The possible advantage of reduced bleeding by repletion of coagulation factors with fresh frozen plasma has not been established by clinical studies. Because coagulopathy is a very good tool for assessment of prognosis and monitoring of disease progression, correction of coagulopathy is indicated only if the patient is already listed for transplant or prior to an invasive procedure such as insertion of a central line or ICP monitors. There has been a poor correlation between the severity of prolongation of PT and bleeding tendencies, but associated thrombocytopenia is an important risk factor for hemorrhage ; hence , the platelet count should be maintained above 50 × 10 9 / dL . The most common site of bleeding is the GI tract . Prophylactic ranitidine or PPI have been shown to decrease the incidence of gastric bleeding. Dr. Arun aggarwal Gastroenterologist

Types of liver assist devices:

Types of liver assist devices Dr. Arun aggarwal Gastroenterologist

Liver transplantation:

Liver transplantation ALF accounts for 5 to 7% of all liver transplants. Contraindications for liver transplant are fixed and dilated pupils, uncontrolled sepsis, and severe respiratory failure (ARDS). Relative contraindications are accelerating inotropic requirements, infection under treatment, CPP of < 40 mm Hg for more than 2 hours, and a history of progressive or severe neurologic problems. After successful transplant, cerebral edema can persist for 12 hours, and cerebral autoregulation is restored within 48 hours. Dr. Arun aggarwal Gastroenterologist

Predictors of Poor Outcome “King’s College Criteria”:

Predictors of Poor Outcome “King’s College Criteria” Arterial pH < 7.30 Or, all of the following: PT > 100sec (INR>6.5) creatinine > 3.4mg/dL gr 3/4 encephalopathy PT > 100sec Or, any 3 of the following: NANB/DILI J-E > 7d age < 10 or > 40y PT > 50sec (INR>3.5) bilirubin >17.4mg/dL Acetaminophen: Non-Acetaminophen: *O’Grady JG et al. Gastroenterology 1989 Dr. Arun aggarwal Gastroenterologist

Prognostic Indicators Acute Liver Failure:

Prognostic Indicators Acute Liver Failure Sensitivity Specificity INR ≥4 86 73 Bilirubin ≥13.7mg/dL 85 65 Age <2 yr 93 52 WBC >9 × 10 6 /mL 89 71 *Dhawan A et al, Pediatric Transplantation 2004 92% (33/36) children transplanted with ALF had two or more parameters Mortality associated with degree of encephalopathy: G rade I-II - 44% Grade II-IV - 78% Dr. Arun aggarwal Gastroenterologist

Future Directions:

Future Directions Auxillary liver transplantation Hepatocyte transplantation Dr. Arun aggarwal Gastroenterologist

Disease specific therapies:

Disease specific therapies Dr. Arun aggarwal Gastroenterologist

Survival: ALF vs CLF:

Survival: ALF vs CLF Dr. Arun aggarwal Gastroenterologist

Summary:

Summary Rare but devastating disease process Most pediatric cases are indeterminate; however clues exist No general proven therapy to promote liver regeneration Dr. Arun aggarwal Gastroenterologist

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