Acute Liver Failure in Children

• ABSTRACT
• ETIOLOGY
• Acetaminophen/Paracetamol
• Hepatotoxins, Herbals, and Non-Acetaminophen Drug-Induced ALF
• Infection
• Immune Dysregulation
• Metabolic
• Other Causes
• Indeterminate
• MANAGEMENT
• Characterize the Presentation
• Monitor and Support the Patient and Organ Systems
• Identify and Treat Complications66 118 119 120 121 122 123 124 125 126 127
• NEUROLOGICAL
• HEMATOLOGICAL
• GASTROINTESTINAL
• RENAL CONSIDERATIONS
• METABOLIC
• INFECTIOUS
• Diagnostic Priorities
• Treatment and Management Tools
• PLASMAPHERESIS/PLASMA EXCHANGE
• STEROIDS
• MOLECULAR ABSORBENTS RECYCLING SYSTEM
• TRANSPLANT
• THERAPY FOR SPECIFIC DISORDERS
• OUTCOME
• CONCLUSIONS
• i ACKNOWLEDGMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Acute liver failure (ALF) in children differs from that observed in adults in both the etiologic spectrum and the clinical picture. Children, particularly very young ones, do not demonstrate classical features of encephalopathy and the definition of ALF has been revised to include patients with advanced coagulopathy, regardless of mental status. A significant number of these children will go on to require transplant or die. Etiologies vary by age with metabolic and infectious diseases prominent in the first year of life and acetaminophen overdose and Wilson's disease occurring in adolescents. In almost 50% of cases, however, the child has an indeterminate cause for ALF. Management requires a multidisciplinary approach and is directed at establishing the etiology where possible and monitoring, anticipating, and managing the multisystem complications that occur in children with ALF. Overall, short-term outcomes are better in children than adults but are dependent upon the degree of encephalopathy and diagnosis.

Acute liver failure (ALF) is not a diagnosis but a clinical syndrome. ALF was initially characterized in adults with biochemical evidence of severe hepatic dysfunction (e.g., jaundice and coagulopathy) complicated by hepatic encephalopathy that develops within 8 weeks of the onset of the signs and symptoms of liver disease.[1] [2] [3] Initial studies in children utilized the adult definition of ALF.[4] [5] [6] However, recognition of hepatic encephalopathy in children is difficult and may not be clinically apparent until the terminal stages of the disease process.[6] Thus, more recent single site reviews of ALF have included children without clinical encephalopathy.[7] [8]

The Pediatric Acute Liver Failure (PALF) Study Group was formed in 2000 as a multisite, multinational consortium to prospectively study ALF in children from birth up to 18 years of age. A consensus reached by 21 PALF investigators defined entry criteria of the study: (1) no evidence of a known chronic liver disease; (2) hepatic-based coagulopathy that is not corrected by parenteral administration of vitamin K; (3) hepatic encephalopathy must be present if the uncorrected prothrombin time (PT) or international normalized ratio (INR) was between 15 and 19.9 seconds or 1.5 to 1.9, respectively; and (4) hepatic encephalopathy was not required if the PT or INR was greater than or equal to 2.0 seconds or 2.0, respectively.[9] Other presentations of liver failure such as subfulminate hepatic failure,[10] [11] acute-on-chronic liver failure,[12] [13] and primary nonfunction following liver transplantation[14] were excluded from the PALF study and will not be covered in this discussion.

ETIOLOGY

In North America and the United Kingdom, the etiology of ALF differs quite dramatically between adults and children.[9] [15] In adults, almost 50% of cases are due to acetaminophen overdose, either intended or unintended, with hepatitis B and non-acetaminophen drug-induced liver injury occurring playing a prominent role. In children, acetaminophen overdose accounts for fewer than 20% of cases, while metabolic disease, autoimmune disease, and infectious hepatitis, due primarily to herpes viruses occurring in infants, are the more commonly diagnosed conditions. Unfortunately, a diagnosis is not established in up to 50% of children.

Acetaminophen/Paracetamol

Since its introduction into the pediatric pharmacopeia in the mid-1950s, acetaminophen (N-acetyl-p-aminophenol; APAP) has become the first-line analgesic/antipyretic medication for children.[16] The usual pediatric dose ranges from 10 to 15 mg/kg/dose administered every 4 hours to a maximum of 80 mg/kg/day. Reports of accidental ingestion first surfaced in the British literature in the 1970s, but serious consequences were not initially apparent. Acetaminophen is not hepatotoxic in standard doses, but is a dose-related toxin if detoxification is overwhelmed, resulting in cell death.[17] Recent studies have identified a potentially useful biomarker, APAP-cysteine protein adducts, which are detected in the plasma of patients with liver injury due to APAP long after the parent compound has been metabolized.[18]

APAP is the most common identifiable cause of ALF in children living in the United States and United Kingdom.[9] The PALF study has confirmed at least two clinical presentations; the first is an acute, intentional ingestion and the second, referred to as a “therapeutic misadventure,” relates to the ingestion of multiple doses taken over a few days' time with the intent to treat clinical symptoms. The clinical presentation for both conditions includes a profound uncorrectable coagulopathy and dramatically elevated serum aminotransferase levels that can reach over 10,000 IU/mL coupled with a normal or mildly elevated total bilirubin. Encephalopathy is uncommon or, if present, is typically grade 1 to 2. If a biopsy is performed, typical findings would include centrilobular (zone 3) necrosis associated with few other abnormalities.

ALF following ingestion of a single overdose of APAP is preventable with prompt patient identification and early intervention with either oral or intravenous N-acetylcysteine (NAC). The “toxic” dose of APAP can vary among patients.[19] However, ingestion of ≥ 140 mg/kg should be considered potentially toxic.[20] Two deaths were registered in our prospective study; both presented with late stages of encephalopathy, one with a possible underlying defect in fatty acid metabolism.[21] The use of the serum APAP concentration-versus-time nomogram developed by Rumack provides the best guide to potential toxicity but is only applicable when the time of ingestion is known and occurred at only a single time point.[22]

The “therapeutic misadventure” resulting in ALF was first described in 1986 and subsequently confirmed by others.[22] [23] [24] [25] APAP is often used for systemic symptoms that precede the recognition of ALF and may confound the etiologic role of APAP in a particular case when fever or other symptoms have been present. However, a careful history often reveals daily dosing beyond the recommended 80 mg/kg/day. Adult tablets or suppositories have been used in children with the false assumption that APAP is safe at any dose. Altered metabolism of APAP occurs when glutathione stores are reduced during prolonged fasting associated with an extended illness.[26] Whether APAP toxicity can occur in children receiving the recommended dose is unclear, but it has been described in adults with regular alcohol consumption.[27] One might imagine an unfortunate alignment of circumstances that would include a prolonged febrile illness, coupled with poor intake, multiple “around-the-clock” doses of APAP, and possibly an underlying susceptibility (e.g., fatty acid oxidation defect, altered cytochrome P-450 enzymes); all might contribute in part to the development of ALF. In a small study of children with indeterminate ALF, we found 12.5% of children with positive APAP-cys protein adducts suggesting APAP led to ALF despite a lack of history of excessive APAP ingestion, further suggesting that histories can be quite misleading.[28]

Hepatotoxins, Herbals, and Non-Acetaminophen Drug-Induced ALF

Drug or toxin-induced liver injury is uncommon in children and is rarely identified as a cause of ALF.[9] [29] Children are increasingly exposed to a variety of over-the-counter, prescription, and herbal medications as well as environmental toxins and recreational drugs. Assessment of causality, however, must be determined by circumstantial evidence culled from a detailed history, degree of clinical suspicion, and clinical presentation.[30] [31] Differences in drug metabolism as well as the absence of comorbidities between children and adults may also play a role in the frequency, demographics, and clinical manifestation of hepatotoxic injury.[32] [33] [34]

Amatoxin is a known hepatotoxin found in nine Amanita species of wild mushrooms and is associated with ALF in children.[35] While ingestion of these wild mushrooms is more common in Western Europe, mushroom hepatotoxicity does occur in the United States.[9] [36] Therapeutic medications reported to cause ALF in children include amiodarone,[37] isoniazid,[38] minocycline,[39] and pemoline.[40]

As herbal medications are increasingly popular, a proportionate increase in adverse reactions associated with these products is to be expected.[41] Pyrrolizidine alkaloids found in Jamaican “bush tea,” Symphytum (comfrey), Heliotropium, and Senecio are metabolized by cytochrome P450 to highly reactive species that result in a dose-dependent direct hepatotoxic injury.[42] A history of ingestion of an herbal cocktail should be sought if a child presents with clinical and/or histological features of veno-occlusive disease (VOD). However, there is at least one report of a newborn infant presenting with VOD who was exposed to herbal tea throughout the pregnancy.[43]

Antiseizure medications constitute the highest percentage of medication-induced ALF in children.[9] Valproic acid (VA) is metabolized via mitochondrial β-oxidation and can cause ALF by either direct injury to liver cell mitochondria[44] or by unmasking a more generalized mitochondrial disorder.[45] [46] The population at greatest risk for VA-associated ALF is children less than 2 years of age with developmental delay and receiving multiple anticonvulsant medications, although it can occur in older children and adults.[47] Carbamazepine, phenobarbital, and phenytonin can cause an idiosyncratic reaction or result in multisystem injury that is recognized as the antiepileptic hypersensitivity syndrome.[48] The clinical presentation is typically associated with fever, skin rash, and progressive pulmonary symptoms. The underlying mechanism is likely immune mediated as early recognition with treatment utilizing intravenous gamma globulin and steroids can result in significant clinical improvement.

Infection

An infectious etiology is often considered when children present with nonspecific symptoms such as myalgia, fever, decreased appetite, and listlessness and ALF. Interestingly, we identified an infectious etiology in only 17/331 (5%) of children with ALF presenting in North America and the United Kingdom.[9] Infections are identified more frequently in the younger population, particularly those in the first 4 weeks of life. The infectious agents found in young infants include herpes simplex, adenovirus, enterovirus, and paramyxovirus, while Epstein-Barr virus (EBV) occurred more frequently in older patients. Overall, we found only three children with hepatitis A, one child with hepatitis C, and no child was identified with hepatitis B. This pattern of infectious causes of ALF is quite distinct from that seen with North American adults where hepatitis A and B account for 3% and 7% of cases, respectively.[15] Reasons for this discrepancy are likely related to routine immunizations in children for hepatitis B and, more recently, hepatitis A.[49] [50]

Hepatitis A virus is a common cause in areas where it is endemic or referral centers for endemic areas,[8] [51] but not in developed countries in the absence of an outbreak.[52] While hepatitis B is a reported cause of ALF in infants,[53] it occurs more commonly in adults and risk factors include older age and genotype D.[54] Hepatitis C virus is a very rare primary cause of ALF. Hepatitis E occurs within endemic areas such as India, Africa, and Mexico. Pregnant women who become infected with hepatitis E are at a greater risk of developing ALF.[55] [56] Adenovirus should be considered when patients present with nasopulmonary symptoms in the setting of an immunocompromised patient,[57] [58] but can occur in apparently normal patients.[59] The role of human herpesvirus-6 in ALF is unclear as it has been found in explanted livers of children with ALF and in “control” livers.[60] Echo virus is described primarily in newborns or neonates and is usually associated with systemic viral sepsis.[61] [62] Parvovirus B19 has been proposed as a cause for ALF,[63] but whether it is a primary cause or a confounding factor in the setting of other viral diseases (e.g., hepatitis A, EBV) is not clear.[64] [65] Parvovirus has been implicated in those patients with ALF who subsequently develop aplastic anemia,[66] but sufficient proof of the association has not been gathered. Epstein-Barr virus is known to be a cause of ALF[67] [68] and can be associated with hemolytic anemia[69] and hemophagocytic syndrome.[70] It is more commonly an issue in children with immunodeficiencies. Herpes simplex occurs most commonly in the first 2 weeks of life and is almost always associated with systemic disease.

Immune Dysregulation

Autoimmune hepatitis (AIH) typically presents as a chronic, inflammatory liver disease. However, ~2 to 5% of patients with AIH will present with signs and symptoms of acute liver failure manifested by progressive jaundice, encephalopathy, and uncorrectable coagulopathy over a period of 1 to 6 weeks without an antecedent history of an underlying liver disease. Patients will have at least one positive autoimmune marker (e.g., antinuclear antibody, anti-smooth muscle antibody, liver-kidney microsomal antibody, or soluble liver antigen) and may or may not have an elevated IgG level. Unfortunately, nonspecific elevation of autoimmune antibody titers can occur in children with ALF, making the diagnosis difficult.[71] Liver histology supporting a diagnosis of autoimmune liver disease may be helpful and should be performed before initiating therapy. However, histology is not always confirmatory.[72] [73] [74] Approximately 5% of children with ALF were diagnosed with AIH in the PALF study.[9]

Hemophagocytic lymphohistiocytosis (HLH) presents as an overwhelming inflammatory condition associated with fever, hepatosplenomegaly, and cytopenia with some cases associated with liver failure.[75] [76] It can be a primary disorder or it can be associated with other immune deficiencies such as Chediak-Higashi syndrome and X-linked lymphoproliferative disease. HLH can also develop following viral or bacterial infection in both normal and immunocompromised (e.g., transplant, chemotherapy) patients.[77] The underlying mechanism for some patients appears to be natural killer cell (NK-cell) dysfunction that results in an unbridled inflammatory process.[78] Celiac disease, an immune-mediated enteropathy, has been associated with ALF.[79] [80] Sclerosing cholangitis is a rare cause of ALF.[81]

Metabolic

Metabolic causes of ALF may be observed in all age groups, but is more common in children less than 1 year of age.[9] [82] Galactosemia and hereditary tyrosinemia type 1 can present with liver failure before the results of the newborn screen are available and should be strongly considered in the setting of a profound, uncorrectable coagulopathy with minimal aminotransferase elevation. Mitochondrial disorders typically present with multisystem involvement that includes skeletal and/or cardiac myopathy, renal tubular dysfunction, seizures, developmental delay, and some degree of hepatic dysfunction. Liver failure does not occur in all children with mitochondrial disorders, but it may be the initial presenting feature for some,[83] due to mitochondrial depletion[84] or a specific mitochondrial DNA (mDNA) or nuclear gene mutation affecting the respiratory chain complex[85] or mitochondrial fatty acid oxidation.[86] [87] Fatty acid oxidation disorders associated with ALF include defects in long-chain fatty acid transport,[88] medium-chain acyl-coenzyme A dehydrogenase deficiency, short-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency,[89] and long-chain 3-hydroxyacyl-coenzyme a dehydrogenase deficiency.[90] Complex disorders involving both mitochondrial complex and fatty acid oxidation have been observed.[91] More patients with fatty acid oxidation defects associated with ALF will likely be identified with advancing technology and increased clinical suspicion.[21] Identification of a multisystem mitochondrial disorder, such as Alpers' disease, would be a contraindication for a liver transplant.[92]

Wilson's disease is currently the most common metabolic disease presenting with ALF in older children and adolescents.[9] Clinical features often include a nonspecific prodrome of fever and listlessness followed by deepening jaundice. Biochemical features of Wilson's disease include evidence of hemolysis, markedly elevated serum bilirubin, and a normal or low serum alkaline phosphatase.[93] [94] [95]

Other Causes

Neonatal hemochromatosis presents in the first few days to weeks of life with a profound coagulopathy with normal aminotransferase levels, ascites, and multiorgan failure associated with the accumulation of iron into extrahepatic tissues that include the pancreas and heart. The nomenclature surrounding this condition is confusing as it has no relationship to hemochromatosis diagnoses in adults. Our understanding of the underlying pathology of this disorder has advanced over the last few years.[96] Recent studies by Whitington and Malladi suggest that it is an allo-immune disorder with maternal antibody generated against an antigen found in the fetal liver.[97] Other causes of ALF include Budd-Chiari syndrome,[98] [99] VOD,[100] malignancy,[101] [102] shock and other low-output cardiac states,[103] [104] [105] and heat stroke.[106]

Indeterminate

A specific diagnosis is not identified in ~50% of children with ALF.[9] Previously indeterminate cases were classified as either non-A non-B hepatitis, neonatal hepatitis, or non-A through non-E hepatitis. Efforts to identify novel or unexpected hepatotropic viruses have not yet been undertaken in children, but such searches in adults were unrevealing.[107] [108] Identification of APAP-cys adducts in almost 12% of children with indeterminate ALF without a clear toxic exposure to APAP suggests that within the indeterminate group are undiagnosed or unsuspected etiologies that include infections, metabolic disease, drug or toxin, and/or immunological disorders.[109] [110] [111]

MANAGEMENT

Close collaboration between gastroenterology/hepatology, intensive care, neurology, neurosurgery, nephrology, metabolic disease specialists, and transplant surgeons will afford the child the best opportunity to survive. After the initial characterization of the patient presentation, proper patient management follows along multiple parallel paths: (1) monitor and support the patient and organ systems, (2) identify and treat complications, (3) develop an age-appropriate diagnostic prioritization strategy, and (4) treat the patient to maximize health and survival.[112] [113] [114] [115]

Characterize the Presentation

The chaos surrounding the patient with ALF makes the initial assessment challenging, but a detailed history and physical examination cannot be overlooked or abbreviated. If a specific diagnosis can be secured, an effective treatment could alter the natural history of the disease.

The history should include the onset of symptoms such as jaundice, change in mental status, easy bruising, vomiting, and fever. Exposure to contacts with infectious hepatitis, history of blood transfusions, a list of prescription and over-the-counter medications in the home, intravenous drug use or a family history of Wilson's disease, α-1 antitrypsin deficiency, infectious hepatitis, infant deaths, or autoimmune conditions might lead to a specific diagnosis. Evidence of developmental delay and/or seizures should prompt an early assessment for metabolic disease. Pruritus, ascites, or growth failure might suggest a chronic liver condition.

Physical assessment should include a review of growth, development, and nutrition status and evidence of jaundice, bruises, and petechiae. Hepatomegaly alone or with splenomegaly, ascites, and peripheral edema are often present. Kayser-Fleischer rings are usually not present in patients with Wilson's disease who present with ALF. Fetor hepaticus, a sweet unique aroma to the breath associated with hepatic encephalopathy, is present only rarely. Findings suggestive of chronic liver disease include digital clubbing, palmar erythema, cutaneous xanthoma, and prominent abdominal vessels suggesting long-standing portal hypertension.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepatic dysfunction.[116] Changes in behavior, cognition, neurological examination, and electroencephalogram (EEG) are assessed to characterize the patient as having one of five clinical stages of encephalopathy, ranging from stage 0 with minimal or no evidence of neurological dysfunction to stage 4 coma (Table [1]). Clinical staging of HE was originally developed to assess patients with cirrhosis and not ALF, but in the absence of a better clinical tool, it has been found to have important clinical and prognostic implications. The patient should be clinically assessed initially and then multiple times during the day for each component of the HE score, as clinical progression can be devastatingly rapid. The clinical utility of the EEG and other neurophysiological studies should be clarified in future investigations.[117]

Initial laboratory tests should be prioritized in three areas: (1) general laboratories to assess hematological, renal, pancreatic, and electrolyte abnormalities; (2) liver-specific tests to assess the degree of inflammation, injury, and function; and (3) diagnostic tests. As over 30% of children with ALF are younger than 3 years of age, limitations on the volume of blood that can be drawn can be problematic. In addition, required blood work in preparation for a liver transplant also competes for this limited resource. Proactive coordination of laboratory and diagnostic tests is helpful to ensure that high-priority tests are performed expeditiously.

Monitor and Support the Patient and Organ Systems

Admission to a highly skilled nursing environment which, in most cases, will be an intensive care unit, should also ensure a quiet environment to avoid unnecessary stimulation from visitors, television, or hospital personnel that can aggravate encephalopathy and increase intracranial pressure. Patients with HE can become combative. To ensure patient and provider safety, padding should be placed on the side rails of the bed and more than one provider should be at the bedside for any intervention. Patient restraint is required under some circumstances. A cardiorespiratory and oxygen saturation monitor should not serve as a substitute for careful and frequent bedside assessment by an experienced nurse or clinician. Input and output should be strictly monitored. Caregivers must carefully examine the child multiple times during the day and night to assess evidence of changing mental status or HE, increased respiratory effort, changing heart rate or changes in blood pressure which might be signs of infection, increasing cerebral edema, or electrolyte imbalance.

Laboratory monitoring should include a complete blood count, electrolytes, renal function tests, glucose, calcium, phosphorous, ammonia, coagulation profile, total and direct bilirubin, and blood cultures. Diagnostic laboratory studies should be prioritized. While obtaining an arterial ammonia level is ideal, it is not practical in children with stages 0 to 2 HE; a venous ammonia obtained from a free-flowing catheter and promptly placed on ice and transported to the laboratory may be a suitable substitute. Placement of arterial and central catheters should be reserved for patients who show signs of clinical deterioration to late grade 2 or grade 3 HE.

Intravenous fluids should be restricted to between 85% and 90% of maintenance fluids to avoid over-hydration yet still provide sufficient glucose and phosphorus to achieve normal values. Adjustment in fluid rates are based upon the clinical conditions, but relative fluid restriction should be an underlying principal. Nutritional support, including protein, should be provided if the patient can eat safely, or with intravenous nutritional support. Some protein restriction may be necessary, but protein should not be eliminated.

Identify and Treat Complications[66] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127]

NEUROLOGICAL

Hepatic encephalopathy is not always clinically apparent in infants and young children. Distinguishing a hepatic-based encephalopathy from other causes of an altered mental status such as sepsis, hypotension, electrolyte disturbances, anxiety, or “ICU psychosis” is difficult for all age groups. Hyperammonemia plays a central role in the development of HE in most cases.[128] However, a specific level of ammonia does not result in a predictable degree of encephalopathy. Clinical characteristics of HE are outlined in Table [1]. The role of other modalities, such as visual-evoked potentials,[129] continuous EEG monitoring, and monitoring S-100b and neuron-specific enolase,[130] in the assessment of HE are unclear at the present time. Initial treatment would include minimizing excess stimulation, reduction of protein intake, treating suspected sepsis, and removing sedative medications that would affect mental status. Medical therapy with lactulose should be initiated with clinical evidence of HE. Bowel “decontamination” with neomycin can be used as a second-tier treatment, but ototoxicity and nephrotoxicity are potential risks. Sodium benzoate was reported to be beneficial in adults with cirrhosis,[131] but concerns about increasing blood ammonia with this treatment have been raised.[132]

Not all patients with HE develop a clinically important increase in intracranial pressure. However, those who do can experience devastating consequences. Direct intracranial pressure monitoring is the most sensitive and specific test when compared with less-invasive neuroradiographic procedures, such as cranial CT.[133] Monitoring of intracranial pressure remains controversial due to associated complications of the procedure and no evidence of improved survival for those who were monitored.[134]

HEMATOLOGICAL

The PT and INR are used in virtually all prognostic schemes to assess the severity of liver injury in the setting of ALF and are assumed to be markers for the risk of bleeding in ALF patients as well. In patients with ALF, both procoagulant proteins (e.g., factors V, VII, X, and fibrinogen) and anticoagulant proteins (e.g., antithrombin, protein C, and protein S) are reduced.[135] This balanced reduction in the pro- and anticoagulant proteins may account for the relative infrequency of clinically important bleeding in the ALF patient in the absence of a provocative event such as infection or increased portal hypertension. Therefore, the PT/INR may reasonably reflect the reduction of some of the liver-based coagulation proteins, but not the relative risk of bleeding. Efforts to “correct” the PT/INR with plasma or other procoagulation products such as recombinant factor VII should occur primarily in the setting of active bleeding or in anticipation of an invasive surgical procedure.

Bone marrow failure, characterized by a spectrum of features ranging from mild pancytopenia to aplastic anemia, occurs in a significant minority of children with ALF.[136] It is identified most commonly in the setting of indeterminate ALF and may not be clinically evident until after emergent liver transplantation.[137] Treatment includes immunomodulatory medications that include steroids, cyclosporine A, antilymphocyte or antithymocyte globulin as well as hematopoietic stem cell transplant.

GASTROINTESTINAL

Ascites develops in some but not all patients. Precipitating factors include hypoalbuminemia, excessive fluid administration, and infection. Treatment includes fluid restriction and diuretics, but should be reserved for those patients who experience respiratory compromise or discomfort due to the fluid accumulation. Spironolactone is the drug of choice to initiate therapy, but furosemide may also be required. Overly aggressive diuresis may precipitate hepatorenal syndrome.

Gastrointestinal bleeding occurs surprisingly infrequently, given the degree of coagulopathy. Prophylactic use of acid-reducing agents is often initiated when the patient is admitted, but their usefulness is difficult to assess. Causes for bleeding include gastric erosions or ulcers due to nonsteroidal anti-inflammatory medications, varices or gastropathy due to portal hypertension, or idiopathic gastroduodenal ulceration. Infection can precipitate bleeding in this vulnerable population, so blood cultures and initiation of antibiotics should also be considered when bleeding develops. Administration of platelets, blood, and plasma is necessary if bleeding is hemodynamically significant.

RENAL CONSIDERATIONS

Evidence of renal insufficiency and ALF on admission should be assessed for evidence of a medication or toxin as the precipitating cause. Prerenal azotemia can develop if fluid restriction is too excessive for the patient's needs. Acute deterioration of renal function after presentation with ALF may result from systemic hypotension due to sepsis or hemorrhage. Hepatorenal syndrome (HRS) is a feared renal complication associated with ALF, although it occurs more commonly in the setting of chronic liver disease with established cirrhosis.[138] HRS can progress rapidly over the course of 2 weeks (type 1 HRS) or more slowly (type 2 HRS).[139] The diagnosis is suspected when there is evidence of deteriorating renal function in the absence of bleeding, hypotension, sepsis, or nephrotoxic medications and in association with failure to improve with volume expansion. The urine sodium is typically low. Renal replacement therapy with continuous veno-venous hemofiltration or dialysis may be necessary in some cases, but only liver transplantation can reverse HRS.

METABOLIC

Hypoglycemia results from impaired gluconeogenesis and depleted glycogen stores. Glucose infusion rates of 10 to 15 mg/kg/minute may be required to achieve stable serum glucose levels and will require a central venous catheter for hypertonic glucose solutions. Hypokalemia may occur secondary to dilution from volume overload, ascites, or renal wasting. Serum phosphorus should be monitored frequently as hypophosphatemia can be profound and patient outcome is enhanced if the phosphorous can be maintained in the normal range.[140] Acid-base disturbances can be complicated with respiratory alkalosis from hyperventilation, respiratory acidosis from respiratory failure, metabolic alkalosis from hypokalemia, and metabolic acidosis from hepatic necrosis, shock, or increased anaerobic metabolism.

INFECTIOUS

Patients with ALF have an enhanced susceptibility to bacterial infection and sepsis from immune system dysfunction.[141] [142] Evidence of infection may be subtle, such as tachycardia, intestinal bleeding, reduced renal output, or changes in mental status. Fever may not be present. Blood cultures should be obtained daily or with any evidence of clinical deterioration and antibiotics initiated with a clinical concern for sepsis.

Diagnostic Priorities

The etiology of ALF in children differs between age groups (Table [2]). A specific diagnosis is more likely to be established if diagnostic tests are prioritized based upon age.

1 More common.

Treatment and Management Tools

PLASMAPHERESIS/PLASMA EXCHANGE

Plasmapheresis facilitates the removal of suspected toxins in the blood to promote a milieu in which the liver might recover or regenerate. Evidence of its usefulness in children with ALF is sparse; however, in a study from the Children's Hospital of Philadelphia, 243 therapeutic plasma exchanges in 49 children with ALF resulted in improvement of coagulation profiles, but had no impact on neurological outcome or ability of the liver to recover spontaneously.[143] One potential disadvantage of this procedure is the nonselective removal of potentially helpful substances such as hepatocyte growth factor. The use of selective filters to facilitate retention of this potentially beneficial substance would make this therapy more attractive.[144]

STEROIDS

Supraphysiological doses of corticosteroid medications may reduce inotrope requirements in septic shock. In addition, adrenal dysfunction may occur in patients with acute hepatic necrosis and steroids are thought to be beneficial for that reason. However, a double-blind, randomized control trial of hydrocortisone or placebo in 64 adult patients showed no therapeutic effect.[145] A retrospective review of 20 patients with ALF and norepinephrine dependence did show a reduction in norepinephrine requirement, but unfortunately revealed a significant increase in the frequency of bacteremia due to resistant organisms and no improvement in outcome.[146] Steroids may benefit patients with ALF due to autoimmune hepatitis. Selective use of corticosteroids in patients with ALF may be warranted, but cannot be recommended for most ALF patients.[72]

MOLECULAR ABSORBENTS RECYCLING SYSTEM

In the elaborate detoxification molecular absorbents recycling system (MARS), a membrane with albumin-related binding sites separates the patient's blood from an albumin dialysate. Albumin-bound substances, such as bilirubin, aromatic amino acids, and endogenous benzodiazepine-like substances can be transferred to the membrane binding sites and then to the albumin within the dialysate for removal. Unbound, free low-molecular-weight molecules, such as ammonia, can pass freely down a concentration gradient into the dialysate.[147] The MARS system has been used to treat children with mushroom poisoning and as a bridge for retransplantation.[148] [149] However, in the absence of randomized trials, its relevance in the overall treatment of ALF is uncertain.[150]

TRANSPLANT

Hepatocyte transplantation may serve as a bridge to transplant or, perhaps, a “cure” for some children with metabolic diseases. It has been used in a small number of children with ALF.[151] [152] However, technical challenges as well as lack of a readily available source for hepatocytes have limited the opportunity for this procedure at most centers.[153]

Liver transplantation has improved overall survival for children with ALF. A cadaveric whole, split, or cut-down liver transplant was used in nearly 86% of all transplants for ALF in children in a recent report from the Studies of Pediatric Liver Transplant consortium.[154] Living donor liver transplant for children with ALF and concurrent multiorgan failure is associated with improved 30-day and 6-month survival compared with recipients of a cadaveric liver allograft.[155] Improved outcome for patients receiving a living donor liver transplant is likely related to decreased cold ischemia time and wait time, resulting in a more expeditious time to transplant for these seriously ill children. Auxiliary liver transplantation has been used as a “bridge” to provide needed time for the native liver to regenerate.[156] The challenge rests with the determination of the likelihood that the liver will sufficiently regenerate to allow for withdrawal of immunosuppression and involution of the transplanted graft.[157]

THERAPY FOR SPECIFIC DISORDERS

Identification of a condition amenable to therapy will allow for early therapeutic intervention in hope that liver failure can be reversed and transplant or death can be avoided. Specific conditions and therapies are listed in Table [3].

OUTCOME

Short-term (21-day) outcome for children with ALF varies by diagnosis, age, and degree of encephalopathy.[9] Survival without liver transplant was highest in the APAP group (94%), while children with non-APAP drug-induced ALF (41%), metabolic disease (44%), or indeterminate ALF (43%) fared less well. The risk of death increases with the degree of encephalopathy. However, 20% of children in the PALF study who never developed encephalopathy either died or underwent liver transplant and those who presented with grade 4 encephalopathy fared better than those who progressed to grade4 during the course of the study.

The ideal model to predict outcome would ensure that all patients who need a transplant receive one (positive predictive value), and all patients who would survive would not (negative predictive value), but presently none exists.[158] Virtually all of the prognostic models to date are based upon data and experiences with adult patients. King's College criteria were the first and are the standard upon which others are judged. King's criteria take into account patient demographics that include diagnosis and age, degree of clinical encephalopathy, as well as biochemical determination of coagulopathy, arterial pH, serum bilirubin, and creatinine.[159] Several other models have been developed and include the use of serum lactate[160]; albumin, lactate, valine, and pyruvate[161]; α-fetoprotein[162]; phosphate[163]; APACHE III measurements[164]; and most recently actin-free Gc-globulin.[165] Most have not been tested independently in children.

In a retrospective analysis of 97 children admitted to the Liver Unit of Birmingham Children's Hospital in the United Kingdom, multivariate analysis identified the significant independent predictors for death or liver transplant were time to onset of hepatic encephalopathy > 7 days, PT > 55 seconds, and alanine aminotransferase ≤ 2384 IU/L on admission.[8] Another single-site study from the University of California/Los Angeles with 66 patients identified cerebral edema, a rising bilirubin associated with falling serum aminotransferases, prolonged PT not responding to fresh-frozen plasma infusions, and a delay in the onset of encephalopathy to be poor prognostic factors.[6] A recent study from Denver, CO, expanding the reseachers' experience with a Liver Injury Unit score based upon total bilirubin, INR, and ammonia at presentation and with “peak” values, appears to effectively predict survival without liver transplant; further prospective analyses will be necessary to confirm these findings.[166]

Post-transplant survival in pediatric ALF has improved with time, but remains lower than that observed for children who receive transplants for other reasons. One- and four-year survival rates are 74% and 69% for children with ALF, compared with 88.2% and 85.6% for children transplanted for reasons other than ALF, respectively.[154] In addition to survival, one must also consider quality of life following transplant. Conditions that will not be improved by transplant, such as systemic mitochondrial disorders, should be identified.[167] In the absence of sound markers for patient outcome, we are left with clinical judgment in concert with laboratory and clinical parameters to make the best decision to proceed with liver transplantation, to delay with the hope of recovery, or to remove the child from the list because transplant would be futile.

CONCLUSIONS

Children presenting with ALF require a prompt multidisciplinary approach to maximize outcomes. Diagnostic studies must be prioritized based upon age and clinical presentation and potential for a medical cure. The indeterminate group offers a real opportunity for study. Multicenter consortia such as the National Institutes of Health-sponsored PALF study that collects prospective clinical data and important biosamples will enhance our understanding of ALF in children, refine prognostic indicators, and provide an opportunity to improve diagnosis and management in these critically ill children.

ACKNOWLEDGMENTS

The site principal investigators, coordinators, the Data Coordinating Center of the Pediatric Acute Liver Failure Study Group (www.palfstudy.org), and Dr. Patricia Robuck with the NIDDK. The PALF Study Group is supported by NIH-NIDDK 1 U01 DK072146-01.

ABBREVIATIONS

• AIH autoimmune hepatitis

• ALF acute liver failure

• APAP n-acetyl-p-aminophenol, acetaminophen

• EBV Epstein-Barr virus

• EEG electroencephalogram

• HE hepatic encephalopathy

• HLH hemophagocytic lymphohistiocytosis

• HRS hepatorenal syndrome

• INR international normalized ratio

• MARS molecular absorbents recycling system

• mDNA mitochondrial DNA

• NAC N-acetylcysteine

• NK-cell natural killer cell

• PALF Pediatric Acute Liver Failure [Study Group]

• PT prothrombin time

• VA valproic acid

• VOD veno-occlusive disease

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Robert H SquiresJr. M.D. 

Clinical Director of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh

3705 Fifth Avenue, Pittsburgh, PA 15213

Email: squiresr@upmc.edu

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Robert H SquiresJr. M.D. 

Clinical Director of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh

3705 Fifth Avenue, Pittsburgh, PA 15213

Email: squiresr@upmc.edu