Hepatic failure

Published on 23/06/2015 by admin

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7.7 Hepatic failure

David Krieser

Essentials

1 Acute liver failure implies evidence of hepatocellular failure. Synthetic and metabolic processes may be affected.

2 Acute liver failure is a rare but serious problem in the paediatric population.

3 Many aetiologies require consideration: infectious, toxin-mediated, congenital (structural or metabolic) or infiltrative (malignancy, storage disease).

4 Infectious hepatitis is the most common cause worldwide, paracetamol toxicity the most common in the developed world.

5 Clinical information is vital to target appropriate investigation and treatment.

6 Management is largely supportive, and aims to maintain homeostasis until hepatic recovery or transplantation occurs.

7 Liaison with and transport to a paediatric liver transplantation centre is usually required. Consultation should occur early.

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:

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

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.

α₁-Antitrypsin deficiency

Approximately 1:4000 live births are affected by this autosomal recessive disorder. Cholestasis in the neonatal period, in the context of intrauterine growth retardation, hepatomegaly and failure to thrive is suggestive of this disease. Coagulopathy may occur in 2% of such infants and is usually responsive to vitamin K. Phenotyping of protease inhibitor (Pi) by isoelectric focus classifies children as: Pi ZZ (most commonly associated with liver disease), Pi SZ, Pi SS, Pi FZ and MZ (carrier state). Up to 50% of children with Pi ZZ will develop chronic hepatic failure leading to transplantation after development of cirrhosis. Bronchiectasis is rare in children. Liver transplantation will lead to functional restoration and phenotypic cure.

Tyrosinaemia

Linked to a gene on chromosome 15, tyrosinaemia is an autosomal recessive condition due to deficiency of fumarylacetoacetase which is the last enzyme in the processing of phenylalanine (pathway available at http://www.ncbi.nlm.nih.gov/omim/Images/tyrosine.html). This autosomal recessive disorder is characterised by progressive liver parenchymal damage and renal tubulopathy with generalised aminoaciduria. It is particularly common in parts of Quebec. Rapid progression may occur in infancy or an indolent course leading to hepatic cell carcinoma may occur in up to 37% of those over 2 years.

Biliary atresia

Complete absence of all extrahepatic biliary structures is the usual malformation, leading to a clinical picture of jaundice, pale (acholic) stools and dark urine due to cholestasis. A choledochal cyst may present in identical fashion and may co-exist with biliary atresia. Presentation is usually with prolonged neonatal jaundice or delayed onset of jaundice (age 2–3 weeks). This occurs in approximately 1:10 000 to 1:20 000 live births, with equal gender incidence. Following diagnostic testing (ultrasonography, nuclear medicine scan, occasionally liver biopsy), management is by surgical hepatoportoenterostomy (Kasai procedure) prior to 8 weeks of age, if possible, as earlier surgery improves outcomes.¹²

Mushrooms

Edible and inedible mushrooms can be difficult to distinguish. Amanita phalloides produces amatoxin, which is hepatotoxic. The toxin is a heat stable octapeptide. After a period of 6–48 hours the affected patient will start vomiting, complain of abdominal pain, develop diarrhoea, before neurological symptoms (coma, seizures) and hepatic failure commence, with a mortality of up to 30%. Cholinergic symptoms via muscarinic receptors may also occur and respond to atropine. Charcoal should be given to reduce absorption. Silibinin and high-dose penicillin G may assist in limiting hepatic damage.¹³ Identification of the mushroom is important and may require referral to local botanists or mycologists.

Pathophysiology

Exposure to hepatotoxic agents such as: drugs, products of metabolism or infectious particles, in addition to immune responses, initiates hepatocyte injury that may progress to necrosis. Biopsy, when performed, reveals multilobular or bridging necrosis with reticulin framework collapse. Patterns related to aetiology can be seen, such as centrilobular necrosis in paracetamol toxicity or with circulatory shock. When normal regenerative processes do not occur, liver failure follows.¹⁴ Astrocyte oedema may be seen and may be due to altered cell wall permeability, glutamate, ammonia, and neurotransmitter balance.¹⁵

Hepatic encephalopathy occurs through the interplay of three factors:

Reduction in synthesis of substances essential for normal brain function;

Production of substances that are neurotoxic; and

Reduced elimination of neurotoxins.

Contributions from ammonia, inflammatory cytokines, benzodiazepine-like compounds and manganese ¹⁶ lead to neuronal dysfunction and altered interaction of astrocytes with neurons. This leads to the clinical manifestations of hepatic encephalopathy. The balance of inhibitory (e.g. GABA) versus excitatory (e.g. glutamate) neurotransmission is altered in hepatic encephalopathy.⁹ Ammonia appears to augment inhibitory neurotransmission. In addition, the role of sepsis, either via systemic immune response¹⁷ or via lipopolysaccharides directly,¹⁸ hypoglycaemia and raised intracranial pressure is important in the development of encephalopathy.

Presentation

History

History and examination findings are significantly influenced by the age of the child. Neonates may present with jaundice and care must be taken to differentiate physiological jaundice or ‘breast milk’ jaundice from pathological jaundice. The presence of acholic (pale) stools is characteristic of cholestasis. Investigation (see below) will be directed at identifying the cause of cholestasis. Jaundice in the context of dysmorphic features, cardiac murmur and ocular abnormalities suggest Alagille’s syndrome. The development of jaundice after a change in diet may suggest metabolic abnormalities of carbohydrate metabolism such as galactosaemia or hereditary fructose intolerance.

Infants and older children may present with a history of loss of appetite, vomiting, fevers, or abdominal pain, prior to the development of jaundice. Infectious hepatitis (e.g. hepatitis A, EBV or CMV) is the most likely cause in this situation. EBV infection may be suggested by a history of sore throat and lymphadenopathy. A dietary and travel history for hepatitis A may be relevant. Hepatitis B and C infection needs to be considered if a history of exposure is obtained. In adolescents, the use of illicit drugs and sexual activity must be explored confidentially. In areas where strict screening is performed, children who receive blood product transfusions (e.g. malignancy, renal failure, haemophilia, haemoglobinopathy) are at very low risk for the acquisition of hepatitis B and C. An infant presenting with encephalopathy and jaundice may have a metabolic disease (fatty acid oxidation, carbohydrate metabolism) and the possibility of consanguinity needs exploration. Previous surgery for a choledochal cyst or for biliary atresia is important in the context of a child presenting with jaundice and/or hepatic failure. Exposure to hepatotoxins such as paracetamol, anticonvulsants, aspirin or mushrooms must be identified, as specific treatments can be implemented. Pruritus with jaundice, dark urine and pale stools may be the presenting features of cholestasis in an older child.

Examination

Hepatomegaly and jaundice are the most frequent findings. The character of the liver edge may offer additional information: for example, a firm, nodular surface suggesting cirrhosis or fibrosis; tenderness suggesting acute hepatitis. Note that in cirrhosis liver span may be reduced. Splenomegaly suggests portal hypertension or infiltration (e.g. storage disease, extramedullary haematopoiesis, malignancy). Abdominal examination will also identify ascites if present.

As discussed above, specific diseases associated with liver failure will have other features. The phenotypes of galactosaemia, Alagille’s syndrome, α₁-antitrypsin deficiency and Wilson’s disease may be identified by careful clinical examination. Neurological evaluation is essential and the presence of asterixis important in a child with liver failure in order to assess for, and classify a stage of, hepatic encephalopathy, if present (Table 7.7.3). In young children encephalopathy, which occurs late, is difficult to detect. Cutaneous features such as bruising, petechiae or bleeding may indicate an associated coagulopathy. In children with chronic liver disease there may be signs such as spider naevi, caput medusae or finger clubbing.

Investigations

Investigation of the child with hepatic failure focuses on identifying the extent of liver dysfunction and on identifying the cause. History and examination findings must guide investigation. ED screen should include a full blood examination, liver function tests including conjugated and unconjugated bilirubin, blood glucose, coagulation screen, renal function and arterial blood gases. Further potentially relevant investigations such as viral serology, copper and caeruloplasmin levels, Pi typing, lactate level, drug screens, urine metabolic screen, or imaging should be determined after discussion with a paediatric hepatologist. Note that the international normalised ratio for coagulation and the serum bilirubin concentration are not predictive of post-transplant survival, while renal dysfunction requiring dialysis is associated with a higher mortality.¹⁴ Escudie et al¹⁹ found a prothrombin index below 10% (INR approx 6) 4 days after Amanita phalloides ingestion was predictive of fatal outcome.

Management

The management of acute liver failure involves supportive care, complication management and specific treatment modalities where they exist. Therapy needs to be initiated in the ED prior to transfer to a paediatric intensive-care environment. The initial management issues are listed in Table 7.7.4. Intubation and ventilation may be required due to coma or respiratory failure. Respiratory failure itself is multifactorial: altered cardiac output; capillary leak; possible oliguria; and significant fluid requirements contribute. Fluid management may be complex in the face of renal failure and electrolyte imbalances. Vitamin K, fresh frozen plasma or cryoprecipitate may be required to correct symptomatic coagulopathy. Intravenous fluids containing 10% dextrose or more are usually required to correct hypoglycaemia and then maintain normoglycaemia. Lactulose is given in hepatic encephalopathy to reduce absorption of nitrogenous wastes. Neomycin and/or metronidazole, given enterally, reduce the enteric bacterial load and the production of nitrogenous wastes. Proton pump inhibitors, H₂-receptor blockers and/or sucralfate are given to limit the risk of gastric ulceration in the context of coagulopathy. Sepsis is a common and serious complication, and will exacerbate liver failure and requires aggressive antimicrobial management. Raised intracranial pressure and, more specifically, reduced cerebral perfusion pressure are important complications of ALF. Both these effects may be improved by therapeutic cooling. Therapeutic cooling (32–33°C) reduces brain energy metabolism, normalises cerebral blood flow, reduces ammonia delivery, reduces oxidative pressure on astrocytes and reduces brain glutamate.¹⁴

Management tasks Observation of: Vital signs
Pulse oximetry
Level of consciousness
Urine output (may need indwelling catheter) Monitoring of: ECG
Blood glucose
Acid/base status (blood gases)
Coagulation
Liver function tests
Serum electrolytes Insertion of: Vascular access (peripheral, central, intraosseous)
Nasogastric tube (for gastric drainage and administration of neomycin and lactulose) Supplementation of: Glucose
Potassium
Albumin
Coagulation factors (vitamin K, frozen plasma, cryoprecipitate, platelets)
Oxygen (may require endotracheal intubation)
Intravascular volume if required Identification of: Treatable cause if present (toxic, infectious, metabolic)
Evolving encephalopathy
Raised intracranial pressure

A bridge to liver transplantation may be created via the use of liver support devices. These have not undergone extensive testing as yet. Artificial systems using filtration, dialysis or ion exchange or bioartificial systems (human or non-human hepatocytes within an artificial framework) are available. Anecdotal reports of these systems include reduction in serum copper in Wilson’s disease-induced ALF that allowed stabilisation prior to transplantation.²⁰

The development of liver transplantation has allowed children with irreversible liver failure to survive. The paucity of available donors and contraindications to transplantation limit the number of children able to receive liver transplants in the acute setting. Contraindications to transplantation include: uncontrolled systemic infection; extrahepatic metastasis in liver tumours, irreversible neurological injury; and multiorgan failure. Living donor transplantation has increased the number of liver transplants in children. Auxiliary partial orthotopic transplantation allows the transplanted liver segment to function while a diseased native liver recovers and regenerates. This technique also may allow for the discontinuity of antirejection medication once the native liver recovers.²¹ Disease-specific treatment is available for paracetamol toxicity. Intravenous N-acetylcysteine (NAC) is given in addition to supportive measures. Herpesvirus-induced fulminant hepatitis may respond to aciclovir. Children with Wilson’s disease may respond to chelation therapy pending transplantation. Certain metabolic diseases can be managed through dietary manipulation or metabolic pathway manipulation.

Disposition

Management of the child with ALF requires a multidisciplinary team of physicians, nursing staff and allied health personnel in an intensive-care environment. The invasive nature of monitoring and maintaining such patients will necessitate transport to a paediatric intensive-care unit. Transportation will require stabilisation and continued monitoring of the above parameters, with intervention occurring en route if necessary. Liver transplantation will require the involvement of surgeons and anaesthetists in addition to those already involved within the paediatric intensive care unit. The transplant service should be consulted early in such cases.

Prognosis

The mortality of ALF is approximately 60%. Of children with Stage 4 hepatic encephalopathy, 80% will die. Sepsis is the cause of death in approximately 10% of children with ALF. The King’s College criteria (Table 7.7.5), based on multivariate analysis of 588 patients with fulminant hepatic failure, provide clinical and laboratory parameters predictive of mortality. A single adverse factor was associated with 80% mortality; three adverse factors were associated with 95% mortality. Paracetamol toxicity was associated with a better prognosis. If paracetamol toxicity was the reason for ALF then the presence of a single adverse risk factor places mortality risk at 55%. It is important to compare these figures with the 20–30% mortality rate of all children undergoing liver transplantation.