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.

Table 7.7.1 Aetiology of liver failure

ALF has been defined in adults by clinical and laboratory criteria:

Hepatocellular dysfunction (jaundice, coagulopathy, etc.) of rapid onset, and

Encephalopathy within 8 weeks of jaundice.

The Pediatric Acute Liver Failure Study Group ² has defined ALF in children as:

Biochemical evidence of liver injury (usually less than 8 weeks’ duration)

No history of known chronic liver disease

Coagulopathy not corrected with vitamin K

International normalised ratio (INR) greater than 1.5 if accompanied by encephalopathy or INR greater than 2 if not accompanied by encephalopathy.

This definition has been developed because the identification of encephalopathy, especially in infants and young children, can be very difficult. In addition, the onset of the illness may not be clear, particularly in metabolic disorders. For children with chronic liver disease who present with features of ALF, management principles are similar, although where specific therapy is available for an underlying disease then this should be considered as well.

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.

Table 7.7.2 Classification of ALF
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.

Total parenteral nutrition

The aetiology of TPN-associated liver disease is largely unknown. The associations of sepsis, surgery, and other medications, which often co-exist, cannot be ignored as possible aetiological agents. This form of liver dysfunction will present in the intensive-care setting rather than the emergency department (ED).

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