DESCRIPTION

• 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 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
• 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

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.

ETIOLOGY

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

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

HISTORY

• Age: may suggest possible etiologic subgroup
• Toxin exposure: prescription, over-the-counter, herbal, or supplemental medications
• Symptoms of viral prodrome (fever)
• Travel history, exposure history
• Length of symptoms, acuity of onset
• History of developmental delay or seizures may suggest metabolic defect.
• Associated symptoms/ROS:
  • Jaundice, bleeding, bruising
  • Weakness, fatigue
  • Abdominal distension, pain, diarrhea
  • Pruritus secondary to cholestasis
  • Change in mental status

PHYSICAL-EXAM

• Skin: jaundice, bruising
• Eyes: scleral icterus
• Abdomen: hepatomegaly, ascites with dullness to percussion or fluid wave, splenomegaly
• Neurologic
  • 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 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

DIFF-DIAGNOSIS

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

• Intrinsic hepatotoxins and idiosyncratic hepatotoxic effects:
  • Acetaminophen: most common in older children and adolescents
  • Salicylates, iron compounds, anticonvulsants, antibiotics
  • Recreational drugs (cocaine, MDMA)
  • Amanita species (mushrooms)
• Metabolic/genetic/misc: early infancy
  • Galactosemia, tyrosinemia
  • Gestational alloimmune liver disease (neonatal hemochromatosis)
  • Storage diseases
  • Mitochondrial disorders
  • Fatty acid oxidation disorders
  • Hereditary fructose intolerance
  • α₁-antitrypsin deficiency
• Metabolic/genetic/misc: older children
  • Autoimmune hepatitis
  • Wilson disease
  • Pregnancy (HELLP syndrome, AFL)
  • Reye syndrome
• Infectious
  • Hepatitis virus: A, B, E; less commonly C
  • Herpes virus: HSV, EBV, CMV, VZV, HHV6
  • Echovirus, especially in neonates
  • Parvovirus, adenovirus
• Vascular/ischemic
  • Congestive heart failure
  • Hypotensive shock
  • Budd-Chiari syndrome: hepatic venous outflow obstruction
  • Venoocclusive disease: Nonthrombotic occlusion of hepatic venules, typically occurs following stem cell transplantation.
• Malignancy
  • Primary: hepatoblastoma, hepatocellular carcinoma
  • Other: leukemia, lymphoma, hemophagocytic lymphohistiocytosis
• Heatstroke, hyperthermia, rhabdomyolysis

TESTS

GENERAL-MEASURES

• Close monitoring, preferably in an ICU setting with a liver transplant program
• General supportive care:
  • 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 to maintain serum glucose between 90 and 110 mg/dL.
  • 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.

MEDICATION

• Hematologic
  • Vitamin K: Administer IV or SQ/IM for prolonged PT/INR, and monitor response with repeat PT/INR 4 to 6 hours afterward.
  • PT and INR however are not good markers for risk of bleeding in ALF due to decreased production of both procoagulant and anticoagulant proteins.
  • 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 encephalopathy
  • 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.
  • Restriction of protein intake to no more than 1 g/kg/24 h may help reduce ammonia production.
  • Elevated arterial ammonia levels may help predict development of encephalopathy and intracranial hypertension.
• Infectious disease
  • Prophylactic antibiotics and antifungal medications if febrile, after obtaining cultures from any central venous access or catheterization
• Renal
  • Nephrotoxic drugs should be avoided when possible. Diuretics should be used with caution; renally dose medications if renal compromise present
  • Renal replacement therapy as indicated
• Other:
  • N-acetylcysteine is the treatment for acetaminophen-induced hepatic toxicity.
  • Plasma exchange may be helpful for removal of copper in Wilson disease.
  • IV acid suppression should be considered.
  • Removal of offending agent when identified

SURGERY

• 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, artificial liver support systems, such as molecular adsorbent recirculating system (MARS) are not recommended outside of clinical trials.

IN-PATIENT-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.

PROGNOSIS

• Etiology of ALF provides good indicator of prognosis and also dictates management.
• One half of pediatric ALF patients will die or receive liver transplant.
• Existing liver failure scoring systems based on biochemical markers (e.g., INR) and/or clinical features, including the King’s 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 are 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 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.
• 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.

ICD9

• 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)