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1The etiology of acute liver failure in children differs from that in adults, with metabolic conditions being commoner in Europe and North America and hepatitis A being the commonest cause in Asia and South America.
2Encephalopathy usually is a late feature and is not essential for the diagnosis.
3Unlike adults, there are no good prognostic criteria that can predict survival without liver transplantation.
4It is important to exclude genetic multisystem disorders before liver transplantation is considered.
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Acute liver failure (ALF) is the final common pathway of a variety of insults to the liver. There is considerable variation in the etiologies around the world, with acute viral hepatitis and drugs accounting for the majority of cases. In children, acute viral hepatitis is the most common identified cause in most of the series, but there is a lot of geographical variation, with hepatitis A being the most common cause in Asia, whereas in Europe and North America, the etiology in most stays indeterminate.1 The etiologies of ALF, as seen in a tertiary pediatric liver center and in the multicenter Paediatric Acute Liver Failure Study, are shown in Table 1 and Fig. 1. A list of causes responsible for ALF in children is shown in Tables 2 and 3.
Table 1. Etiologies of Acute Liver Failure in Neonates and Children (King's College Hospital, London, England)
n = 31
n = 100
Disseminated herpes simplex virus
Other viral infection
Transplacental acetaminophen toxicity
Endocrine (isolated cortisol deficiency)
Table 2. Causes of Acute Liver Failure
Viral hepatitis (A, B, B+D, and E)
Adenovirus, Epstein-Barr virus, and cytomegalovirus
Varicella and measles
Rarely Lassa, Ebola, Marburg, dengue, and Toga virus
Nonsteroidal anti-inflammatory drugs
Antibiotics (penicillin, erythromycin, tetracyclines, sulfonamides, and quinolones)
Synergistic drug interactions
Isoniazid + rifampicin
Trimethoprim + sulfamethoxazole
Barbiturates + acetaminophen
Amoxycillin + clavulinic acid
Amanita phalloides (mushroom poisoning)
Carbon tetrachloride (CCl4)
Hereditary fructose intolerance
Niemann-Pick disease type C
Congenital disorder of glycosylation
Acute fatty liver of pregnancy
Type 1 autoimmune hepatitis
Type 2 autoimmune hepatitis
Giant cell hepatitis with Coomb's positive hemolytic anemia
Acute circulatory failure
Acute cardiac failure
Table 3. Causes of Neonatal Liver Failure
Perinatal herpes simplex virus infection
Congenital disorder of glycosylation
Severe birth asphyxia
Infection with hepatotropic viruses is probably the most identifiable cause of ALF. Patients usually present with icterus and markedly raised serum transaminase levels. The magnitude of transaminase elevation and the rate of decline do not predict prognosis. In patients who spontaneously recover, serum bilirubin, the international normalized ratio (INR), and serum transaminases gradually decline, whereas continued increases in bilirubin levels and INR, despite declining serum transaminase levels, indicate massive hepatocyte necrosis and poor prognosis.
Hepatitis A virus (HAV) infection is the most common cause of ALF in the Indian subcontinent and South America.2–4 A higher incidence of ALF is suggested when HAV infection occurs in patients with underlying chronic liver disease. The diagnosis of acute hepatitis A is made by the detection of the anti-HAV immunoglobulin M antibody in serum. In 95% of cases, the anti-HAV immunoglobulin M antibody is present at the time of presentation, and the remaining 5% become positive on repeat testing.
Hepatitis B virus as a cause of ALF is less common in children than in adults as the perinatal infection in most of the babies leads to a chronic state; however, infants born to mothers positive for the antibody to hepatitis B e antigen are a special group that can present with ALF around 3 weeks to 3 months of age.5
Hepatitis E virus infection, a water-borne infection like hepatitis A and a well-recognized cause of ALF, is common in the Indian subcontinent and Africa. A study from northern India reported 7 of 44 children with ALF had isolated hepatitis E infection, and another 16 of 44 had mixed hepatitis E and hepatitis A infection.5
Non–A-E hepatitis (seronegative hepatitis) is the most common cause of ALF in the Western world. In our series, out of 100 cases of ALF, 45 were due to non–A-E hepatitis.6 A similar experience was reported from Chicago, with 26 of 42 children with ALF being diagnosed with non–A-E hepatitis.7 The diagnosis is one of exclusion in which other causes of ALF are eliminated with appropriate laboratory investigations and clinical examination. Non–A-E hepatitis is characterized by its propensity to cause severe hepatitis, its high fatality rate (low spontaneous remission) without liver transplantation, and its association with bone marrow failure in up to 10% of patients.8 Bone marrow failure can develop even after a few weeks of the onset of symptoms of ALF.
Other Hepatotropic Viruses
Herpes simplex virus, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus, members of the herpesvirus family, can cause severe hepatic necrosis, particularly in immunocompromised patients and neonates. Herpes simplex infection–induced ALF in the neonatal period has a very high case fatality ratio. The diagnosis is suspected in an unwell neonate with or without a vesicular lesion along with remarkably raised serum transaminases and coagulopathy. Parvovirus B19 infection can cause severe hepatitis, ALF, and rarely bone marrow failure in children. Echovirus, Coxsackieviruses, and adenoviruses are the other viruses that can cause ALF, particularly in newborn babies.
ALF, acute liver failure; APAP, N-acetyl-p-aminophenol; HAV, hepatitis A virus; INR, international normalized ratio; PALFSG, Paediatric Acute Liver Failure Study Group; WCC, white cell count.
DRUGS AND TOXINS
Drugs and toxins are well known to cause liver failure in children. In general, risk factors for drug-induced hepatotoxicity are age (very young children or adolescents), abnormal renal function, concurrent use of other hepatotoxic agents, drug interactions, and preexisting liver diseases. Drug-induced hepatoxicity can be a dose-dependent response, an idiosyncratic reaction, or a synergistic reaction (Table 3).
Paracetamol (acetaminophen APAP), the most common drug associated with ALF, is a safe drug when used in therapeutic doses in healthy individuals. It is normally a dose-dependent hepatotoxic agent. Consequently, even therapeutic doses of acetaminophen can lead to an accumulation of N-acetyl-para-benzoquinone imide causing ALF. The inadvertent administration of higher doses of acetaminophen can lead to ALF in children.9 Serum acetaminophen levels after 4 hours of ingestion are useful in identifying high-risk patients but are not informative in patients in which toxicity is secondary to chronic administration.
Autoimmune hepatitis can present as ALF, most of these patients being liver/kidney microsome antibody–positive. The diagnosis may be difficult as some cases may not show antibody response at presentation. In our experience, children with autoimmune hepatitis presenting with ALF along with encephalopathy do not respond to any form of immunosuppression and need urgent liver transplantation.
Inherited disorders of metabolism merit special attention in a differential diagnosis when ALF is being investigated in pediatric patients, particularly newborn babies. Although all these patients have variable degrees of liver damage before clinical presentation of ALF, overt signs and stigmata of chronic liver disease are usually absent. A high index of suspicion is important as urgent intervention such as dietary manipulation or disease specific treatment may be lifesaving. Conditions that are common to the neonatal age group are listed in Table 3.
Galactosemia is usually associated with hypoglycemia and gram-negative septicemia. Immediate exclusion of galactose (from the diet and medications) usually leads to a quick recovery, but some cases do progress to liver failure. Tyrosinemia presents with severe coagulopathy, mild jaundice, and rickets. Hereditary fructose intolerance is rare, but a history of administration of fructose as in fruits, sugar, or honey may coincide with clinical symptoms.
Neonatal hemochromatosis is a disorder of iron handling of antenatal onset with excess iron deposition in the nonreticuloendothelial system. Liver failure usually presents in the first few days of life, but liver disease is generally present at birth. Maternal viral infection in the antenatal period or metabolic disease in the fetus has been suggested as an underlying cause. Although an underlying genetic basis for neonatal hemochromatosis has been suspected, no test is available for predictive analysis in at-risk pregnancies. The diagnosis should be considered in every case of neonatal liver failure. Commonly used as a diagnostic test, ferritin elevation is sensitive but not specific as ferritin elevation in sick babies is usually observed. A laboratory test of value is hypersaturation of transferrin with relative hypotransferrinemia. Magnetic resonance imaging of the liver or pancreas to demonstrate iron is not usually rewarding, but a punch biopsy specimen of buccal mucosa is a useful diagnostic tool. Documentation of iron in salivary glands in buccal mucosa is diagnostic of neonatal hemochromatosis. To ensure the presence of salivary glands in the buccal mucosal biopsy specimen, a frozen-section examination is advisable. The treatment with high-dose immunoglobulin of pregnant mothers (with a previous history) with suspected neonatal hemochromatosis has been shown to modify the course of the illness in the affected baby.10
Wilson's disease, an autosomal recessive disorder, may present as ALF in an older child. The acute hepatic presentation is characterized by the presence of liver failure, Coomb's negative hemolytic anemia, and low alkaline phosphatase. The demonstration of Kayser-Fleisher rings is diagnostic of Wilson's disease in a patient who presents with ALF. Serum ceruloplasmin is usually but not invariably low, and the serum free copper concentration can be increased or normal. A serum alkaline phosphatase to total bilirubin ratio of <2.0 has also been suggested as a diagnostic tool to discriminate Wilson's disease from other causes of ALF.
In recent years, mitochondrial respiratory chain disorders have been implicated in the etiology of ALF in children. This group of disorders encompasses a wide variety of diseases, including Pearson syndrome, mitochondrial DNA depletion syndrome, nuclear DNA defects, Alper disease, and intestinal pseudo-obstruction with liver disease. Presenting symptoms can be hypoglycemia, vomiting, coagulopathy, acidosis, and increased lactate with or without neurological symptoms. The presence of high serum lactate in the mother and a history of sibling deaths are suggestive of this condition. Diagnosis involves a quantitative assessment of the respiratory chain enzyme complexes in the affected tissues (muscle, liver, and skin fibroblast culture). Isolated hepatic involvement with successful liver transplantation has been reported; however, the follow-up of these patients is not long enough to rule out future neurological deterioration.
Rarely, fatty acid oxidation defects and inborn errors of bile acid synthesis, especially Δ4-3-oxosteroid 5β-reductase enzyme deficiency, can present as ALF.
Hemophagocytic lymphohistiocytosis is a spectrum of inherited and acquired conditions with disturbed immune regulation, and it encompasses 2 main conditions that have common clinical and pathobiological characteristics: familial (primary) hemophagocytic lymphohistiocytosis and secondary hemophagocytic lymphohistiocytosis. Familial (primary) hemophagocytic lymphohistiocytosis is an invariably fatal inherited disease seen mostly in infancy and early childhood, but secondary hemophagocytic lymphohistiocytosis can affect any age and may subside spontaneously. Various forms of hematological malignancies, such as leukemia and lymphoma, can present with ALF. Diagnostic clues include high fever, hepatosplenomegaly, high alkaline phosphatase, lactate dehydrogenase, and abnormalities on peripheral blood film. A bone marrow examination is diagnostic.
The prognosis of ALF varies greatly with the underlying etiology. In an adult series from King's College Hospital (London, England), 50% of patients survived after an acetaminophen overdose, whereas the survival rate was only 12.5% after halothane-induced ALF, 66% for hepatitis A, and 39% for hepatitis B.11
The prothrombin time is the best indicator of survival.12 Bhaduri and Mieli-Vergani12 showed that the maximum INR reached during the course of illness was the most sensitive predictor of the outcome, with 73% of children with an INR < 4 surviving versus only 4 of 24 (16.6%) with an INR > 4.
In children, a factor V concentration of <25% of normal suggests a poor outcome, and in France, this criterion is used for listing for liver transplantation.13
Liver biopsy is rarely helpful in ALF and is usually contraindicated because of the presence of coagulopathy.14
Wilson's disease presenting with encephalopathy is invariably fatal and can be treated only by liver transplantation, but the decision to list a child with Wilson's disease without encephalopathy is very difficult. In our experience, a prognostic score (Table 4) has been useful in identifying the patients who carry a high risk of mortality without liver transplantation.15 It incorporates bilirubin, INR, aspartate aminotransferase, white blood count, and albumin at presentation. A score of 11 or more indicates high mortality with 93% sensitivity and 96% specificity. Survival depends on the ability of the liver to recover from the ensuing insult, but it is very difficult to predict the potential for recovery. There is no single criterion that can predict the outcome with absolute certainty and be universally applicable to all patients with ALF with different etiologies. However, the prediction of a low level of survival (chance < 20%) is clinically useful in deciding to list the patient for orthotopic liver transplantation, which has a 1-year survival rate of 75%.