Background, definitions, etiology, outcomes

Liver failure is defined as the loss of normal liver function that includes synthesis of serum proteins, including clotting factors and albumin; metabolism and storage of glucose and fatty acids; and detoxification and excretion of exogenous and endogenous molecules, such as drugs and products of protein metabolism, most notably ammonia. Evidence of liver failure is reflected in elevations of prothrombin time, bilirubin, and ammonia. In the United States, the incidence of PALF has been estimated at 17 cases per 100,000 per year.

Diagnosis of hepatic encephalopathy (HE) in children is challenging, as it might be present only in very late stages of the disease. This makes the definition of adult acute or fulminant liver failure, which includes the onset of HE within 8 weeks of the first signs of liver disease, to be difficult to apply to infants and children. Subacute liver failure has been defined as the development of HE after 8 weeks and before 24 weeks from the onset of liver disease in the absence of preexisting chronic liver disorders.

Etiologies

PALF is a heterogeneous condition, with a broad range of etiologies. It is age dependent, including infections, toxin- and drug-related injuries; metabolic disorders; and immunologic, ischemic, and irradiation damage. Despite the many known causes of PALF, a specific etiology is not determined in up to 50% of cases, ^, accounting for 40% of PALF among patients younger than age 3 years and 60% in those age 3 years and older. The large number of indeterminate causes is due to several factors, including hepatic improvement prior to finishing clinical workup, lack of current available testing for all etiologies, or lack of a thorough workup. The term indeterminate etiology should prompt further investigation. Liver biopsy is indicated, as it can further help with diagnosis and treatment. Liver biopsy can be performed safely via transjugular or percutaneous approach, but the risk of bleeding should be evaluated case by case.

Of the known etiologies, severe viral hepatitis—especially due to enteroviruses, adenovirus, and herpesvirus—may occur in the neonatal population. Infantile causes of ALF also include gestational autoimmune liver disease (GALD), inborn errors of metabolism, and hemophagocytic lymphohistiocytosis (HLH). HLH is a challenging diagnosis, as it can present at any age with PALF, and correct diagnosis is very important due to specific treatment (see also Chapter 106 ). Acute hepatitis A and B infections are rare causes of PALF in North America but are a common cause of PALF in school-aged children in developing countries. Drug-induced liver disease is more common in older children, especially secondary to intentional acetaminophen overdose ( Box 96.1 ).

To determine outcomes, investigate prognostic factors, and further decipher etiologies, the Pediatric Acute Liver Failure Study Group (PALF-SG)—involving 24 pediatric liver centers in the United States, Canada, and the United Kingdom—formed in 1999. The study’s entry criteria include evidence of hepatic injury without known chronic liver disease manifesting as an international normalized ratio (INR) of 1.5 and encephalopathy or INR of 2.0 with or without encephalopathy. The group has reported data on 348 subjects over a 6-year period and concluded that survival and the need for liver transplantation depend on age and diagnosis. For established PALF etiologies, liver transplantation is necessary in 20% to 33% of cases versus 46% in indeterminate cases, whereas spontaneous recovery ranged from 46% to 60% depending on diagnosis and age categories.

Prognostic assessment

Several attempts to produce prognostic tools based on a snapshot of clinically available data either at presentation or at peak values have been attempted, but all have been found wanting. Three of the more often quoted include the King’s College Hospital Criteria (KCHC), the liver injury unit (LIU) score, and the Clichy criteria. The Clichy criteria are primarily derived from adult patients with acute hepatitis B infection; thus, its utility in the pediatric population has always been in doubt. The KCHC applied to the PALF-SG cohort fails to reliably identify those patients at risk of death. The LIU score predicted those who eventually underwent transplantation but was not a reliable predictor of death. This is not particularly surprising, as the LIU calculation is based on levels of bilirubin, ammonia, and prothrombin time (PT), all of which are used clinically to determine who might benefit from transplantation and, as such, were self-fulfilling predictors. All of these tools suffer from the fact that no account is taken for the dynamic nature of PALF. Further work would benefit from examining the trends over time rather than data at a single time point. ^,

Diagnosis and workup

The care team should obtain a full history, including information about infectious illnesses, behavior changes, the time course of the development of jaundice, and foreign travel. It is important to establish what medications the child has taken, including over-the-counter preparations, acne medications, folk remedies, and herbal supplements, as well as determining what other medications might be in the household. In adolescents, inquiries should be made about the use of illicit drugs, potential for self-harm, and sexual contact.

Acute hepatic dysfunction often first manifests as jaundice and general malaise. Hepatomegaly may be present, but the liver edge is frequently soft and difficult to palpate. Splenomegaly is unusual, and its presence may point to a metabolic or hematologic diagnosis. Petechiae or ecchymoses can be associated with coagulopathy. The patient’s level of consciousness and degree of HE ( Box 96.2 ) should be established using a reliable scale, ^{, ,} and a complete central nervous system examination should be performed, including examination of reflexes and mental status. Parental help in the assessment of mental status is perhaps one of the best indicators of deviation from baseline neurologic status. Serial neurologic examinations should be conducted once the baseline is established to identify any progression of encephalopathy as there is significant risk for increased intracranial pressure (ICP) and herniation due to cerebral edema or intracranial bleeding. The presence of moderate to severe impaired central nervous system function or rapid neurologic deterioration in the setting of acute liver disease should be an indication for admission to the PICU. Work of breathing should be assessed and assisted with positive pressure or mechanical ventilation if needed to ensure adequate ventilation and oxygenation. Monitoring of and, if necessary, intervention for glycemic control, acid–base balance, and adequate tissue perfusion should be included in the care plan. Antibiotics and antiviral medications should be started if an infectious cause is suspected.

Once in the PICU, a central venous catheter should be placed for administration of medication and intravenous fluids, including parenteral nutrition and high glucose infusion rate, as well as for hemodynamic monitoring and frequent blood draws. An arterial line should be considered for patients with clinical deterioration or with HE. Urinary catheter placement can also be considered to ensure accurate fluid balance estimation and assessment of kidney function ( Table 96.1 ).

A basic workup for PALF with investigations reflecting age-dependent etiologies is suggested in Box 96.3 . Initial monitoring of blood work should include complete blood count, blood gases, lactate levels, glucose, electrolytes, aminotransferases, PT/INR, creatinine, bilirubin, and ammonia. Monitoring blood work should be repeated every 6 to 12 hours until the clinical course is determined. If the patient may require liver transplantation, a referral to a pediatric liver transplant center should be initiated in a timely manner, prior to clinical decompensation.

• BOX 96.3

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; GGT, γ-glutamyltransferase; hCG, human chorionic gonadotropin; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IL, interleukin; INR, international normalized ratio; PT, prothrombin time.

Diagnostic Workup

Hematology

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  CBC with differential

  
  
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  PT/INR

  
  
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  Factor V level

  
  
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  Factor VII level

  
  
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  Fibrinogen level

  
  
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  ABO/Rh typing

Chemistry

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  Electrolytes

  
  
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  Calcium, magnesium, phosphorus

  
  
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  BUN, creatinine

  
  
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  Glucose

  
  
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  Lactate, pyruvate

  
  
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  Bilirubin conjugated and unconjugated

  
  
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  AST, ALT

  
  
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  GGT

  
  
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  Alkaline phosphatase

  
  
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  Cholesterol, triglycerides

  
  
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  Ferritin

  
  
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  Blood gases

  
  
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  α-fetoprotein

  
  
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  Acylcarnitine profile (children ≤3 mo)

  
  
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  Amino acid quantitative

  
  
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  Ceruloplasmin (children ≥3 y)

  
  
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  Copper (children ≥3 y)

  
  
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  β-hCG (females ≥12 y)

Immunology

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  IgG level

  
  
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  Antinuclear antibody (children ≥3 y)

  
  
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  Antismooth muscle antibody (children ≥3 y)

  
  
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  Antiliver kidney microsomal antibody (children ≥3 y)

  
  
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  Antineutrophil cytoplasmic antibody (children ≥3 y)

  
  
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  Antisoluble liver antigen

  
  
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  Soluble IL-2 receptor

Microbiology

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  HSV DNA

  
  
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  Enterovirus DNA (children ≤3 mo)

  
  
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  CMV DNA

  
  
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  EBV DNA

  
  
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  Varicella DNA

  
  
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  Adenovirus DNA

  
  
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  Parvovirus B19 DNA

  
  
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  Toxoplasma IgG and IgM (children ≤3 mo)

  
  
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  Hepatitis A IgM

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