7.7 Hepatic failure
Introduction
Acute liver failure (ALF) is a rare but devastating presentation in children. The major functions of the liver include synthetic and metabolic functions. Synthetic functions include production of coagulation factors and albumin; while metabolic functions include: glucose metabolism, and waste product processing (e.g. bilirubin, nitrogenous compounds, drug elimination). ALF in children may be due to many causes (Table 7.7.1). The manifestations of coagulopathy, hypoglycaemia, jaundice, encephalopathy and hypoalbuminaemia, reflect common disturbances of liver function.1 ALF may be an immediate life-threatening process or a subacute process, with a spectrum of severity between those extremes. Medical management is multifaceted and focuses on supporting vital functions while hepatic recovery occurs or liver transplantation can be performed.
ALF has been defined in adults by clinical and laboratory criteria:
The Pediatric Acute Liver Failure Study Group2 has defined ALF in children as:
ALF classification, using the time interval between the onset of jaundice and encephalopathy, has aetiological and prognostic importance (Table 7.7.2), despite the difficulties in identifying encephalopathy mentioned above. O’Grady et al3,4 and Poddar et al5 found that, in comparison with patients suffering acute or subacute liver failure, those with hyperacute liver failure had a better prognosis.
| Interval between onset of jaundice and encephalopathy | Classification |
|---|---|
| 7 days or less | Hyperacute |
| 8 to 28 days | Acute |
| 5 to 12 weeks | Subacute |
Aetiology
Table 7.7.1 demonstrates the variety of diagnoses that may cause ALF in children. The aetiology can be grouped according to onset prior to or after the first year of life. In broad terms, infection, immune dysregulation, toxicity (including medication), infiltration, and inborn errors of metabolism are the causative pathways that may lead to ALF. Cases where the cause is not determined predominate in children under 3 years.
Neonates and infants
In the neonatal population, the estimated incidence of liver disease is approximately 1:2500. Biliary atresia and neonatal idiopathic hepatitis contribute 60% of all cases of cholestasis. In 80 infants under 12 months with ALF, inherited metabolic conditions were responsible for 42.5% of cases: neonatal haemochromatosis 16%, acute viral hepatitis 15%, and miscellaneous causes (toxins, autoimmune, malignancy) 10%. 16% of neonatal cases were undetermined.6 Metabolic causes of liver failure include: disorders of the mitochondrial electron transport chain; disorders of protein, carbohydrate and lipid metabolism; and inherited causes of cholestasis.
Infectious hepatitis
Worldwide, infectious hepatitis is the greatest cause of ALF. Five RNA viruses (hepatitis A, C, D, E and G) and one DNA virus (hepatitis B) can infect the liver. Transmission of A and E is via the faecal-oral route. The remainder are transmitted via body fluids. Acute viral hepatitis is a clinical syndrome with systemic symptoms occurring after a virus-dependent incubation period. Jaundice ensues after hepatocyte necrosis reduces the liver’s capacity to metabolise bilirubin. Fulminant hepatitis occurs in less than 1% of children with hepatitis A and in 1–2% of cases of hepatitis B. Fulminant disease occurs with hepatitis D in approximately 10% of cases and is more likely with superinfection. Hepatitis C can cause acute and chronic infection and rarely fulminant hepatitis. Severe acute hepatitis E infection is a leading cause of ALF in the tropics. Epstein–Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus, varicella zoster virus, human herpesvirus 6 and parvovirus B-19 are non-hepatotropic viruses that can rarely cause ALF. Consideration of, and investigation for, these viruses is important because specific therapy with antiviral medication is available for some of these pathogens.7
Toxins and medication
Paracetamol
Paracetamol toxicity is the most common cause of ALF in the developed world. Paracetamol is an analgesic and antipyretic freely available in many countries. It is metabolised by the hepatocyte and toxicity exhausts hepatic glutathione stores. Generation of toxic metabolites leads to centrilobular necrosis. Toxicity is unlikely with single doses under 150 mg kg–1. Children are often given multiple doses of paracetamol and this can lead to toxicity if the cumulative daily dose is greater than 60 mg kg–1 day–1. Factors predictive of hepatotoxicity include: age (lower incidence in children under 5), genetics (cytochrome isoenzyme polymorphisms are inherited), alcohol and tobacco use (relevant in adolescents), other medications and nutritional status.8 Treatment of toxicity is discussed elsewhere in the text.
Anticonvulsants
Genetic predisposition has been purported for anticonvulsant induced hepatotoxicity.2 Sodium valproate causes intracellular fat accumulation within the hepatocyte, and may be related to a primary defect of respiratory chain enzyme function.2 Impaired metabolic functions within the cell may lead to necrosis. Children under 2 years and those on multiple medications are at highest risk. Carbamazepine may cause hepatitis and/or cholestasis during the first months of therapy. Clinically significant hepatotoxicity is rare.
Aspirin and Reye’s syndrome
Mitochondrial dysfunction leading to acute encephalopathy, selective hepatic dysfunction and visceral fatty infiltration has been called Reye’s syndrome.9 Metabolic disorders have been later identified in some children initially diagnosed with Reye’s syndrome. Mitochondrial oxidative phosphorylation and fatty acid β-oxidation are the metabolic pathways affected in Reye’s syndrome. Preceding viral infection (classically varicella), immune mediators and aspirin (or its metabolites) all can limit normal functioning of these pathways. The association of aspirin with this disorder remains unclear despite a study by Forsyth et al,10 which identified a dose–response relationship, and population studies that demonstrate that the decline in Reye’s syndrome mirrors a decline in aspirin usage.9,11
Metabolic diseases associated with liver failure
Zellweger’s syndrome (cerebrohepatorenal syndrome)
Autosomal recessive inheritance of this peroxisomal abnormality leads to abnormal bile acid synthesis, and abnormal fatty-acid oxidation. Multiorgan involvement (cardiac, pulmonary, neurological, renal) with failure to thrive and hypotonia are major early features. Jaundice occurs in 50% of cases. Therapy has not been shown to prolong life although histological improvement may occur on liver biopsy. Biopsy demonstrates abnormal mitochondria and absent peroxisomes. More information can be found at http://www.ncbi.nlm.nih.gov/omim/214100.
