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Acute Liver Failure, Pediatric

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Acute Liver Failure, Pediatric

Basics

Description

The major causes of ALF can be grouped into the following broad categories:

The cause of ALF can be indeterminate in up to 50% of cases across all age groups. Etiologic subgroups include the following:

  • A set of criteria has been proposed to diagnose pediatric acute liver failure (ALF).Biochemical evidence of liver injury due to rapid loss of hepatocyte functionNo previous history of chronic liver diseaseCoagulopathy not responsive to vitamin K administrationInternational normalized ratio (INR) >1.5 in presence of encephalopathy or INR >2 without encephalopathy
  • In older children, in whom hepatic encephalopathy can be more easily assessed, ALF may more simply be defined as follows:Onset of encephalopathy <8 weeks after the onset of symptoms referable to liver dysfunction in a patient without preexisting liver disease
  • Biochemical evidence of liver injury due to rapid loss of hepatocyte function
  • No previous history of chronic liver disease
  • Coagulopathy not responsive to vitamin K administration
  • International normalized ratio (INR) >1.5 in presence of encephalopathy or INR >2 without encephalopathy
  • Onset of encephalopathy <8 weeks after the onset of symptoms referable to liver dysfunction in a patient without preexisting liver disease

Epidemiology

  • Exact frequency of ALF in children is unknown but accounts for 10-15% of pediatric liver transplants in the United States annually.
  • In infants and children <3 years of age, indeterminate and metabolic etiologies predominate.
  • In older children, drug-induced toxicity (especially acetaminophen), autoimmune hepatitis become more common.
  • Infectious etiologies, (e.g., viral hepatitis) vary in prevalence based on geographic region.

Pathophysiology

  • Hepatocellular necrosis leads to release of growth factors that promote hepatic regeneration.
  • Hepatic failure may become irreversible if:The initial insult overcomes the liver's regenerative capacity.The offending agent or derangement is not eliminated or corrected.Secondary complications, such as shock or disseminated intravascular coagulation, lead to further injury.
  • The initial insult overcomes the liver's regenerative capacity.
  • The offending agent or derangement is not eliminated or corrected.
  • Secondary complications, such as shock or disseminated intravascular coagulation, lead to further injury.

Etiology

  • Indeterminate
  • Drug-induced/toxin
  • Metabolic/genetic
  • Infectious
  • Vascular/ischemic
  • Malignancy
  • Immune dysregulation

Diagnosis

History

  • Age: may suggest possible etiologic subgroup
  • Toxin exposure: prescription, over-the-counter, herbal, or supplemental medications
  • Symptoms of viral prodrome
  • Travel history, exposure history
  • Length of symptoms, acuity of onset
  • Associated symptoms/ROS:Jaundice, bleeding, bruisingWeakness, fatigueAbdominal distension, pain, diarrheaPruritus secondary to cholestasis
  • Jaundice, bleeding, bruising
  • Weakness, fatigue
  • Abdominal distension, pain, diarrhea
  • Pruritus secondary to cholestasis

Physical Exam

  • Skin: jaundice, bruising
  • Eyes: scleral icterus
  • Abdomen: hepatomegaly, ascites with dullness to percussion or fluid wave, splenomegaly
  • NeurologicSequential mental status exams are paramount to monitor for change and should include age-appropriate questions.Assess for presence of encephalopathy:Grade I: confused, altered sleep; reflexes normal, may have tremor or apraxiaGrade II: drowsy, inappropriate behavior; hyperreflexic or asterixis; dysarthria or ataxiaGrade III: stupor but may obey simple commands, sleepy; hyperreflexic, asterixis, Babinski-positive; increased general toneGrade IV: comatose; reflexes absent; decerebrate or decorticate posturing
  • Sequential mental status exams are paramount to monitor for change and should include age-appropriate questions.
  • Assess for presence of encephalopathy:Grade I: confused, altered sleep; reflexes normal, may have tremor or apraxiaGrade II: drowsy, inappropriate behavior; hyperreflexic or asterixis; dysarthria or ataxiaGrade III: stupor but may obey simple commands, sleepy; hyperreflexic, asterixis, Babinski-positive; increased general toneGrade IV: comatose; reflexes absent; decerebrate or decorticate posturing
  • Grade I: confused, altered sleep; reflexes normal, may have tremor or apraxia
  • Grade II: drowsy, inappropriate behavior; hyperreflexic or asterixis; dysarthria or ataxia
  • Grade III: stupor but may obey simple commands, sleepy; hyperreflexic, asterixis, Babinski-positive; increased general tone
  • Grade IV: comatose; reflexes absent; decerebrate or decorticate posturing

Diagnostic Tests & Interpretation

  • Abdominal ultrasound with Doppler: visualization of both hepatic parenchyma and vasculature (direction of portal flow, presence of thrombosis)
  • Head CT scan without IV contrast in presence of encephalopathy or neurologic signs to rule out intracranial hemorrhage or cerebral edema
  • Initial laboratory testingHepatocellular injury: aminotransferases (AST, ALT) often markedly elevated; degree of elevation may depend on mechanism and time frame of injury.Biliary injury/obstruction: elevated alkaline phosphatase, γ-glutamyl transpeptidase (GGT), total/conjugated bilirubinGeneral labs: CBC with differential, electrolytes, glucose, blood urea nitrogen and creatinine, amylase/lipase
  • Assessment of synthetic functionProlonged PT/INR (with adequate supply of vitamin K)Depressed factors V, VII levelsHypoalbuminemiaHypoglycemia: Frequent glucose measurements should be followed during initial evaluation and with any mental status or neurologic change.
  • Encephalopathy: ammonia level (has not been proven to correlate directly to presence or grade of encephalopathy)
  • Tests to determine etiologyTesting priority should be guided by the age group and population, and for conditions amenable to specific therapies.Toxin: urine or serum drug screen, serum acetaminophen and aspirin levelsInfectious: hepatitis virus serologic testing, comprehensive viral cultures; PCR testing for EBV, CMV, HSV, and other viruses; antibody testsAutoimmune hepatitis: antinuclear, anti-smooth muscle/F-actin, anti-LKM antibodies, total IgGWilson disease: decreased serum ceruloplasmin (may not be reliable in setting of ALF), increased serum or urinary copper, Coombs-negative hemolytic anemiaPregnancy test in adolescent femalesMetabolic: urine succinylacetone, reducing substances, and organic acids; plasma amino acids, acylcarnitine profile, lactate/pyruvate, creatinine kinase; newborn screenHemophagocytic lymphohistiocytosis: ≥2 cytopenias, elevated ferritin, elevated triglycerides, and low fibrinogenGestational alloimmune liver disease (neonatal hemochromatosis): severe hypoglycemia and coagulopathy, elevated ferritin with near-normal aminotransferase. Evidence of iron deposition on buccal biopsy or abdominal MRI
  • Liver biopsy: Generally, not considered critical for management or diagnosis due to substantial risks of hemorrhage. Transjugular approach may reduce risks. May be appropriate to attempt to identify a specific etiology that may influence treatment strategy (e.g., Wilson disease). Severity of necrosis may not predict potential liver recovery.
  • Hepatocellular injury: aminotransferases (AST, ALT) often markedly elevated; degree of elevation may depend on mechanism and time frame of injury.
  • Biliary injury/obstruction: elevated alkaline phosphatase, γ-glutamyl transpeptidase (GGT), total/conjugated bilirubin
  • General labs: CBC with differential, electrolytes, glucose, blood urea nitrogen and creatinine, amylase/lipase
  • Prolonged PT/INR (with adequate supply of vitamin K)
  • Depressed factors V, VII levels
  • Hypoalbuminemia
  • Hypoglycemia: Frequent glucose measurements should be followed during initial evaluation and with any mental status or neurologic change.
  • Testing priority should be guided by the age group and population, and for conditions amenable to specific therapies.
  • Toxin: urine or serum drug screen, serum acetaminophen and aspirin levels
  • Infectious: hepatitis virus serologic testing, comprehensive viral cultures; PCR testing for EBV, CMV, HSV, and other viruses; antibody tests
  • Autoimmune hepatitis: antinuclear, anti-smooth muscle/F-actin, anti-LKM antibodies, total IgG
  • Wilson disease: decreased serum ceruloplasmin (may not be reliable in setting of ALF), increased serum or urinary copper, Coombs-negative hemolytic anemia
  • Pregnancy test in adolescent females
  • Metabolic: urine succinylacetone, reducing substances, and organic acids; plasma amino acids, acylcarnitine profile, lactate/pyruvate, creatinine kinase; newborn screen
  • Hemophagocytic lymphohistiocytosis: ≥2 cytopenias, elevated ferritin, elevated triglycerides, and low fibrinogen
  • Gestational alloimmune liver disease (neonatal hemochromatosis): severe hypoglycemia and coagulopathy, elevated ferritin with near-normal aminotransferase. Evidence of iron deposition on buccal biopsy or abdominal MRI

Differential Diagnosis

  • Drug-induced/toxinAcetaminophen: most common in older children and adolescentsSalicylates, iron compounds, anticonvulsants, antibioticsRecreational drugsAmanita species (mushrooms)
  • Metabolic/genetic/misc: early infancyGalactosemia, tyrosinemiaGestational alloimmune liver diseaseStorage diseasesMitochondrial disordersFatty acid oxidation disordersHereditary fructose intolerance
  • Metabolic/genetic/misc: older childrenAutoimmune hepatitisWilson diseasePregnancy (HELLP syndrome, AFL)Reye syndrome
  • InfectiousHepatitis virus: A, B, E; less commonly CHerpes virus: HSV, EBV, CMV, VZV, HHV6Echovirus, especially in neonatesParvovirus, adenovirus
  • Vascular/ischemicCongestive heart failureHypotensive shockBudd-Chiari syndrome: hepatic venous outflow obstructionVeno-occlusive disease: Nonthrombotic occlusion of hepatic venules, typically occurs following stem cell transplantation.
  • MalignancyPrimary: hepatoblastoma, hepatocellular carcinomaOther: leukemia, lymphoma, hemophagocytic lymphohistiocytosis
  • Heatstroke, hyperthermia, rhabdomyolysis
  • Acetaminophen: most common in older children and adolescents
  • Salicylates, iron compounds, anticonvulsants, antibiotics
  • Recreational drugs
  • Amanita species (mushrooms)
  • Galactosemia, tyrosinemia
  • Gestational alloimmune liver disease
  • Storage diseases
  • Mitochondrial disorders
  • Fatty acid oxidation disorders
  • Hereditary fructose intolerance
  • Autoimmune hepatitis
  • Wilson disease
  • Pregnancy (HELLP syndrome, AFL)
  • Reye syndrome
  • Hepatitis virus: A, B, E; less commonly C
  • Herpes virus: HSV, EBV, CMV, VZV, HHV6
  • Echovirus, especially in neonates
  • Parvovirus, adenovirus
  • Congestive heart failure
  • Hypotensive shock
  • Budd-Chiari syndrome: hepatic venous outflow obstruction
  • Veno-occlusive disease: Nonthrombotic occlusion of hepatic venules, typically occurs following stem cell transplantation.
  • Primary: hepatoblastoma, hepatocellular carcinoma
  • Other: leukemia, lymphoma, hemophagocytic lymphohistiocytosis

Treatment

Medication

  • HematologicVitamin K: Administer IV or SQ/IM for prolonged PT/INR, and monitor response with repeat PT/INR 4-6 hours afterward.FFP and cryoprecipitate should be reserved for acute severe bleeding or prior to invasive procedure; their use prohibits subsequent monitoring of PT/INR or specific factor levels.Recombinant factor VIIa can be used in cases of acute severe bleeding.
  • Neurologic/hepatic encephalopathySedatives, especially benzodiazepines, should be avoided, as they may worsen encephalopathy.Lactulose (oral, enema forms) should be used if encephalopathy present; goal is to acidify stool (pH <6) and increase frequency of stool but not cause diarrhea.Oral or rectal administration of antibiotics (neomycin, rifaximin) may be effective by reducing ammonia production in the gut.Elevated arterial ammonia levels may help predict development of encephalopathy and intracranial hypertension.
  • Infectious diseaseProphylactic antibiotics and antifungal medications if febrile, after obtaining cultures from any central venous access or catheterization.
  • RenalNephrotoxic drugs should be avoided when possible. Diuretics should be used with caution; renal dose medications if renal compromise presentRenal replacement therapy as indicated
  • Other:N-acetylcysteine is the treatment for acetaminophen-induced hepatic toxicity.IV acid suppression should be considered.Removal of offending agent when identified
  • Vitamin K: Administer IV or SQ/IM for prolonged PT/INR, and monitor response with repeat PT/INR 4-6 hours afterward.
  • FFP and cryoprecipitate should be reserved for acute severe bleeding or prior to invasive procedure; their use prohibits subsequent monitoring of PT/INR or specific factor levels.
  • Recombinant factor VIIa can be used in cases of acute severe bleeding.
  • Sedatives, especially benzodiazepines, should be avoided, as they may worsen encephalopathy.
  • Lactulose (oral, enema forms) should be used if encephalopathy present; goal is to acidify stool (pH <6) and increase frequency of stool but not cause diarrhea.
  • Oral or rectal administration of antibiotics (neomycin, rifaximin) may be effective by reducing ammonia production in the gut.
  • Elevated arterial ammonia levels may help predict development of encephalopathy and intracranial hypertension.
  • Prophylactic antibiotics and antifungal medications if febrile, after obtaining cultures from any central venous access or catheterization.
  • Nephrotoxic drugs should be avoided when possible. Diuretics should be used with caution; renal dose medications if renal compromise present
  • Renal replacement therapy as indicated
  • N-acetylcysteine is the treatment for acetaminophen-induced hepatic toxicity.
  • IV acid suppression should be considered.
  • Removal of offending agent when identified

Additional Treatment

  • Close monitoring, preferably in an ICU setting with a liver transplant program
  • General supportive careFluid restriction: 75-95% of maintenance requirements to prevent worsening of portal hypertension, ascites, and pulmonary edemaSodium restriction: Patients should typically not receive >0.25 NS as maintenance fluids. A total sodium intake of 1 mEq/kg/24 h is usually adequate. Hyponatremia should not be corrected with hypertonic saline, as this can worsen fluid overload and encephalopathy.Glucose infusion: Maintenance fluid typically should include 10% dextrose; glucose infusion may need to be increased, as patients are at risk for hypoglycemia.Nutrition: Adequate nutrition should be maintained either via enteral route or TPN.Blood products should be given slowly to avoid rapid expansion of intravascular space.Minimize invasive catheterization when possible due to infection risk.
  • Fluid restriction: 75-95% of maintenance requirements to prevent worsening of portal hypertension, ascites, and pulmonary edema
  • Sodium restriction: Patients should typically not receive >0.25 NS as maintenance fluids. A total sodium intake of 1 mEq/kg/24 h is usually adequate. Hyponatremia should not be corrected with hypertonic saline, as this can worsen fluid overload and encephalopathy.
  • Glucose infusion: Maintenance fluid typically should include 10% dextrose; glucose infusion may need to be increased, as patients are at risk for hypoglycemia.
  • Nutrition: Adequate nutrition should be maintained either via enteral route or TPN.
  • Blood products should be given slowly to avoid rapid expansion of intravascular space.
  • Minimize invasive catheterization when possible due to infection risk.

Surgery/Other Procedures

  • Those more likely to require liver transplantation include children with ALF secondary to indeterminate cause, idiosyncratic drug toxicity, hepatic vein thrombosis, or Wilson disease.
  • Transplant-free survival >50% for ALF due to acetaminophen, hepatitis A, shock liver or pregnancy-related disease, whereas all other etiologies have <25% transplant free survival.
  • Currently, available liver support systems are not recommended outside of clinical trials.

Inpatient Considerations

  • Initial evaluation should include assessment of neurologic status.
  • Elective intubation as well as ICP monitoring should be considered in grade III or IV encephalopathy with somnolence.
  • Aggressive initial fluid resuscitation should be avoided unless there is evidence of hemodynamic compromise.
  • Central venous access should be considered to allow for higher glucose infusion rates and for central nutrition.

Ongoing Care

Prognosis

  • Etiology of ALF provides good indicator of prognosis and also dictates management.
  • Existing liver failure scoring systems based on biochemical markers (e.g., INR) and/or clinical features, including the Kings College Hospital Criteria, have not been shown to be useful for predicting survival or death in pediatric ALF.
  • Decisions for liver transplantation in pediatric ALF often challenging due to uncertainty of diagnosis and possibility of spontaneous recovery, potential morbidity/mortality of the transplant procedure itself, and the limited number of organs available.
  • Overall 1-year survival following liver transplant is lower in patients transplanted for ALF compared to chronic liver failure; however, after the 1st year this trend is reversed and ALF patients have better long-term survival.

Complications

  • Complications are a direct consequence of loss of hepatic metabolic function:Hepatic encephalopathy: decreased elimination of neurotoxins or depressantsCerebral edema: pathogenesis incompletely understoodCoagulopathy: failure of hepatic synthesis of clotting and fibrinolytic factorsHypoglycemia: impaired glucose synthesis and release, decreased degradation of insulinAcidosis: failure to eliminate lactic acid or free fatty acidsHepatorenal syndrome: typically low urine sodium and no improvement with volume expansion; continuous venovenous hemofiltration or dialysis may be necessary.
  • In cases of suspected hepatic encephalopathy, consider other etiologies of neurologic change including hypoglycemia, intracranial hemorrhage, acute infection, or sepsis.
  • There is often rapid progression through the stages of encephalopathy. Increased intracranial pressure can develop quickly and can lead to irreversible neurologic sequelae.
  • Hepatic encephalopathy: decreased elimination of neurotoxins or depressants
  • Cerebral edema: pathogenesis incompletely understood
  • Coagulopathy: failure of hepatic synthesis of clotting and fibrinolytic factors
  • Hypoglycemia: impaired glucose synthesis and release, decreased degradation of insulin
  • Acidosis: failure to eliminate lactic acid or free fatty acids
  • Hepatorenal syndrome: typically low urine sodium and no improvement with volume expansion; continuous venovenous hemofiltration or dialysis may be necessary.

Additional Reading

  • Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081. [View Abstract]
  • Bucuvalas J, Yazigi N, Squires RH Jr. Acute liver failure in children. Clin Liver Dis. 2006;10(1):149-168. [View Abstract]
  • Kortsalioudaki C, Taylor RM, Cheeseman P, et al. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008;14(1):25-30. [View Abstract]
  • Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology. 2012;55(3):965-967. [View Abstract]
  • Miyake Y, Sakaguchi K, Iwasaki Y, et al. New prognostic scoring model for liver transplantation in patients with non-acetaminophen-related fulminant hepatic failure. Transplantation. 2005;80(7):930-936. [View Abstract]
  • Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006;148(5):652-658. [View Abstract]
  • Sundaram SS, Alonso EM, Narkewicz MR, et al. Characterization and outcomes of young infants with acute liver failure. J Pediatr. 2011;159(5):813-818. [View Abstract]

Codes

ICD09

  • 570 Acute and subacute necrosis of liver

ICD10

  • K72.00 Acute and subacute hepatic failure without coma
  • K71.10 Toxic liver disease with hepatic necrosis, without coma

SNOMED

  • 197270009 Acute hepatic failure (disorder)
  • 413438002 acute hepatic failure due to drugs (disorder)

FAQ

  • Q: What are the most common causes of ALF in infants?
  • A: Up to 40-50% of cases are indeterminate, followed by neonatal hemochromatosis, viral infection, and metabolic disorders.
  • Q: What is the risk of bleeding in ALF-associated coagulopathy?
  • A: Spontaneous, clinically significant bleeding in ALF is generally rare, despite abnormal INR. Thromboelastography (TEG), which assesses overall hemostasis including the cumulative effects of procoagulant and anticoagulant proteins, fibrinogen, platelets, and red blood cells, may be a better guide for administration of blood products in ALF than INR.
  • Q: Is the initial level of elevation of transaminases is directly correlated to the prognosis of patient?
  • A: False. In viral hepatitis and acetaminophen toxicity, initial transaminases can be in 1,000s, but patients can have complete recovery.