ACUTE LIVER FAILURE

DR D A KELLY

BIRMINGHAM CHILDREN’S HOSPITAL NHS TRUST

AETIOLOGY
CLINICAL PRESENTATION
DIAGNOSIS
MANAGEMENT
SELECTION FOR LIVER TRANSPLANTATION

Acute liver failure or fulminant hepatitis is a rare but potentially fatal disease. Mortality without supportive management and/or liver transplantation is in excess of 70%. Adult definitions of fulminant hepatic failure, which include the development of hepatic necrosis and encephalopathy within 8 weeks of onset of liver disease do not apply to acute liver failure, in children particularly if secondary to autoimmune or metabolic liver disease (1).

Acute hepatic necrosis leading to hepatic encephalopathy and coagulopathy develops secondary to a virus, toxin or immune mediated attack. It is associated with failure of hepatic regeneration. The processes leading to such profound hepatic damage are unknown, but are multifactorial and depend on the age and susceptibility of the host and the extent of hepatic injury.

The aetiology of acute liver failure varies with the age of the child (Table 1). In neonates, infection or an inborn error of metabolism are common, while viral hepatitis and drug induced liver failure are more likely in older children.

Many neonates develop acute liver failure secondary to septicaemia. Specific causes of hepatitis include hepatitis B, adenovirus, echovirus and Coxsackie virus. Hepatitis A is rare in neonates.

Hepatitis B is vertically transmitted during pregnancy with an overall transmission rate of 70%, depending on the hepatitis B surface antigen or e-antigen status of the mother. Although the majority of infected infants become asymptomatic carriers, infants born to hepatitis
e-antibody positive or hepatitis e-antigen negative and hepatitis e-antibody negative mothers may develop fulminant hepatitis within the first 12 weeks of life (2). It is possible that the increased incidence of fulminant hepatitis B at this age is due either to partial immunity (as the mother may have circulating anti-e antibodies) or due to vaccine failure. However, it is now well established that the majority of cases are associated with the transmission of a pre-core mutant virus from mother to child (3). Although fulminant hepatitis B may be effectively prevented by vaccination of all infants of hepatitis B carrier mothers, this depends on ante-natal screening.

This rare disorder is the commonest cause of acute liver failure in infancy. It is associated with intense iron accumulation in liver, pancreas, heart and brain. It is not clear whether the disease is due to an inherited or an acquired defect of iron handling . Infants present within hours or weeks of birth with jaundice, hypoglycaemia and severe coagulopathy. Encephalopathy may not be obvious. The diagnosis is made by identifying a high serum iron with hypersaturation of iron binding capacity (95-105%) and grossly elevated ferritin levels (2,000 – 3,000 ug/l), transferrin may be normal. Liver biopsy is rarely feasible in life, but extrahepatic siderosis may be demonstrated in salivary glands obtained by biopsy.

Management includes supportive management for liver failure and use of an anti-oxidant cocktail. Response is variable, as it is more effective if begun within 24-48 hours of birth and in infants with a less severe phenotype. Liver transplantation is the definitive treatment for children who do not respond to medical therapy(4).

This rare autosomally recessive disorder is due to a defect in the metabolism of tyrosine, which leads to the development of toxic metabolites. Acute liver failure is a common presentation in infants between 1 and 6 months of age, who present with mild jaundice, hypoglycaemia, coagulopathy, encephalopathy and occasionally ascites. The diagnosis is established by demonstrating increased plasma tyrosine, phenylalanine, methionine and urinary succinyl acetone. Management of this condition has been transformed by treatment with NTBC (2-nitrotrifluoromethylbenzoyl-1, 3-cyclohexenedione) which prevents the formation of toxic metabolites and restores hepatic function(5). Liver transplantation is now only required for those children who fail to respond to NTBC.

This rare group of disorders presents with acute liver failure and multiorgan disease. There is a wide range of acute clinical phenotypes with different modes of inheritance, including transmission through maternal DNA. These disorders include deficiencies of the electron transport chain enzymes or mitochondrial DNA depletion. Infants present with jaundice, coagulopathy and prominent neurological features which may be difficult to differentiate from hepatic encephalopathy. The diagnosis may be suspected by demonstrating an increased plasma and CSF lactate or the detection of specific organic acids such as urinary

3-methylglutaconic acid. Muscle biopsy may indicate abnormal mitochondria or fat storage. Liver histology, usually only possible at hepatectomy or post-mortem , demonstrates microvesicular fatty infiltration with hepatocyte degeneration and micronodular cirrhosis. There is no treatment and liver transplantation is contraindicated because of multiorgan failure (6).

This rare disease may be secondary to an autosomal recessive disorder or virally induced. There is multiorgan failure with jaundice, hepatosplenomegaly, relapsing fever, skin rash. The diagnosis is suggested by a pancytopenia, elevated plasma triglycerides, increased serum ferritin and the demonstration of erythrophagocytosis in bone marrow, liver or occasionally CSF. Treatment is supportive, although etopside and steroids may induce remission. Liver transplantation is contraindicated but bone marrow transplantation is a potential possibility (7).

Viral hepatitis is the commonest cause of fulminant hepatic failure in children of all age groups, accounting for 80% of fulminant hepatic failure. Acute hepatitis A is more common than hepatitis B and has a better prognosis. Sporadic non A-G virus represents 50% of virally induced hepatic failure in older children with a spontaneous recovery rate of only 30% without transplantation (8). Autoimmune hepatitis, particularly autoimmune hepatitis type II may present with hepatic failure which is non-responsive to Prednisolone. Wilson’s disease is the commonest metabolic cause of fulminant hepatic failure in the older child and may present with haemolysis.

Clinical presentation is variable depending on the age and aetiology. In neonates, jaundice and coagulopathy may be obvious, but encephalopathy may be sub-clinical. Infants may be irritable and have reversal of day/night sleep patterns, while older children may present with aggressive behaviour. Vomiting and poor feeding may be an early presentation of encephalopathy in metabolic liver disease.

It is important to screen for infection, drugs and to exclude metabolic liver disease. Biochemical features demonstrate marked conjugated hyperbilirubinaemia; elevated aminotransferase (>10,000 IU/l), raised plasma ammonia (> 100 IU/L), coagulopathy (prothrombin > 40 seconds). Liver histology is usually impossible to obtain because of the abnormal coagulation.

The management of acute liver failure includes:

1. Assessment of prognosis for liver transplantation
2. Prevention of complications while awaiting hepatic regeneration or a donor liver.
3. Hepatic support

The complications of acute liver failure are numerous and include: sepsis, gastro-intestinal bleeding, cerebral oedema, renal and cardiac failure. Baseline management includes fluid restriction to 75% of maintenance using either Dextrose or high calorie enteral feeds. It is essential to maintain glucose levels >4 mmol/l. Gastrointestinal bleeding is frequent and may be prevented using H₂ antagonists and Sucralfate. The role of broad spectrum antibiotics in prevention of infection is controversial, but anti-fungal agents, such as Fluconazole, should be utilised pre-transplant. The use of N-acetyl-cysteine, which is particularly useful in paracetamol poisoning, has anecdotal success in the management of acute liver failure.

In the early stages of establishing the prognosis and requirement for liver transplantation, coagulation support is not recommended. If coagulation is severe (prothrombin time > 60 seconds) and/or the decision for liver transplantation has been taken, then coagulation support using fresh frozen plasma, cryoprecipitate and Vitamin K is essential.

The management of cerebral oedema is critical for survival. Fluid restriction (50% maintenance), and the use of intravenous Mannitol (0.5 g/kg over 4-6 hours) may be helpful in the short-term. Elective ventilation should be performed if Grade II or III hepatic coma develop or when cerebral oedema is suspected. Convulsions should be promptly treated and may respond to Thiopentone infusion. Monitoring of intracranial pressure is controversial, but may improve selection for liver transplantation.

There is no good way to provide hepatic support in this difficult situation. Attempts to remove potentially neuroactive toxins, which include double volume exchange transfusion, plasmaphoresis, charcoal haemoperfusion, liver assist devices containing cultured hepatocytes and extracorporeal perfusion through a human or animal liver, have generally been ineffective. Artificial liver support using either porcine hepatocytes or hepatoma cell-lines have improved coagulopathy and reduced encephalopathy in both adults and children. Although useful as a "bridge to transplantation", long-term outcome and survival were not affected in a recent controlled trial ( 9). Current research using bioreactors containing human hepatocytes and the use of isolated hepatocyte cell transplantation is at an experimental stage.

Selection for liver transplantation depends on the aetiology of the disease, prognostic factors, the presence or absence of multisystem disease and/or reversible brain damage.

In paediatric acute liver failure, patients with Paracetamol poisoning or hepatitis A have the best prognosis for spontaneous recovery compared to infants or children with metabolic liver disease. Prognostic factors for survival are less well established in children than in adults, but children with metabolic liver disease or severe coagulopathy (prothrombin time > 50 seconds) are less likely to recover (10). In general, poor prognostic features indicating the immediate necessity for liver transplantation in infants include persistent prolonged coagulopathy (PT > 50 seconds), rising bilirubin and falling transaminases. In older children, in whom encephalopathy is easier to detect, grade II or III hepatic coma indicates a poor prognosis.

It is important to exclude multisystem disease and to diagnose a mitochondrial disorder (plasma CSF, lactate, muscle biopsy) or erythrophagocytosis (bone marrow aspirate). It is less easy to demonstrate irreversible cerebral damage because the cerebral sutures will not have fused in many neonates and infants and the classical signs of cerebral oedema may not be present. The best guide to irreversible cerebral damage is the development of grey/white reversion on CT scan secondary to cerebral ischaemia or the development of convulsions.

Early consideration for liver transplantation is essential in order to expedite the search for a donor liver. Although age and size are no longer contraindications to liver transplantation the shortage of age and size matched organs for transplantation means that most children will receive a reduced or split liver graft. Auxiliary liver transplantation, in which part of the recipient liver is left in situ to regenerate is still controversial treatment for fulminant hepatic failure, but recent studies have suggested that the graft may be removed if the original liver regenerates(11). It is not suitable for transplantation for acute liver failure secondary to metabolic liver disease, as these livers are unlikely to recover and there may be a risk of hepatoma in the cirrhotic liver.

Living related donation for acute liver failure is carried out by some centres, but has the disadvantage that families and potential donors have little time for preparation and counselling.

Survival post-liver transplantation for acute liver failure has improvedand most recipients can expect a 70% 5 year survival. Survivors of liver transplantation for acute liver failure face psychological sequelae and thus preparation both of the family and the child (post-transplant) is mandatory.

Acute liver failure in childhood is a rare but fatal disease which may develop secondary to metabolic liver disease or infection. The prognosis has been improved by the development of effective medical therapy for certain metabolic disorders and the success of liver transplantation, but is dependent on the presence of multisystem disease and reversible cerebral damage.

Neonate/Infant

Infection:

• Septicaemia
• Hepatitis B
• Adenovirus
  
• Parvovirus B19
• Echovirus
• Coxsackie
• Non A-G

Metabolic - Neonatal haemochromatosis

• Tyrosinaemia type I
• Mitochondrial disorders
• Fatty acid oxidation defects

Poisoning - Paracetamol
Erythrophagocytic Syndrome

Older Children

Viral Hepatitis A-G
Paracetamol
Auto-immune
Metabolic : Wilson’s disease

N-acetyl cysteine (140 mg/kg; 70 mg/kg 6 h)
Selenium (2-3 ugm/kg/day)
Alpha-tocopherol polyethylene glycol succinate (20-30 IU/kg/day)
Prostaglandin E1 (0.4-0.6 ugm/kg/hour)
Dexferrioxamine (30 mg/kg/day)

TABLE 3 DIAGNOSTIC INVESTIGATION IN FULMINANT HEPATITIS

Serum:

Paracetamol levels
Cu, caeruloplasmin (> 3 years)
Autoantibodies
Immunoglobulins
Amino acids
Hepatitis A, B, C, E
EBV, CMV, HSV
Leptospira (if clinically relevant)
Other viruses

Urine

Drug metabolites
Amino acids, succinyl acetone
Organic acids
Reducing sugars

EBV = Epstein Barr Virus; CMV = cytomegalovirus; HSV = Herpes Simplex Virus;

PT = Prothrombin Time; PTT = Partial Thromboplastin Time

Encephalopathy and cerebral oedema
Sepsis
Gastrointestinal Bleeding
Renal Failure
Haemodynamic Complications

No sedation except for procedures

Monitor

Neurological observations
Gastric pH (> 5)
Blood glucose (> 4 mmol/l)
Acid-base/Electrolytes
PT, PTT

Fluid balance 75% maintenance

Maintain circulating volume with colloid/FFP

Coagulation support only if required

Drugs

Vitamin K
H₂ antagonist, Antacids
Lactulose
N-acetylcysteine
+/- Broad spectrum antibiotics & Antifungals

Nutrition

Enteral feeding (1-2 gm protein/day)
PN if ventilated

FFP = fresh frozen plasma; PN = parenteral nutrition

REFERENCES

1. Kelly DA. Fulminant hepatitis and acute liver failure. Management of Digestive and Liver Disorders in Infants and Children. Eds, JP Buts and EM Sokal. Elsevier Science: 1993; 577-593
2. Beath SV, Boxall EH, Watson RM, Tarlow MJ, Kelly D. Fulminant hepatitis B in infants born to anti-Hbe hepatitis B carrier mothers. Brit Med J, 1992; 304:1169-1170
3. Hawkins AE, Gilson RJC, Beath SV, Boxall EH, Kelly DA, Tedder RS, Weller IVD. Novel application of a point mutation assay: Evidence for transmission of hepatitis B virus with precore mutations and their detection in infants with fulminant hepatitis B. J Med Virol, 1994; 44:13-21.
4. Sigurdsson L, Reyes J, Kocoshis SA, Hansen TW, Rosh J, Knisely AS. Neonatal hemochromatosis: outcome of pharmacologic and surgical techniques. J Pediatr Gastroenterol Nutr, 1998; 26(1): 85-9
5. Lindstetd S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet, 1992; 340(8823):813-7
6. Thomson M, McKiernan P, Buckels J, Mayer D, Kelly D. Generalised mitochondrial cytopathy is an absolute contraindication to orthotopic liver transplantation in childhood. J Ped Gastro Nut, 1998; 26:478-481
7. Jabado N, de Graeff-Meeder ER, Cavazzana-Calvo M, Haddad E, Le Deist F, Benkerrou M, Dufourcq R, Caillat S, Blanche S, Fischer A. Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors. Blood, 1997; 90(12):4743-8
8. Whittington PF. Fulminant hepatic failure in children. Liver disease in children, F J Suchy, ed, Mosby, St Louis, 1993; 180-213

9 Ellis AJ, Hughes RD, Wendon JA, Dunne J, Langley PG, Kelly JH, Gislason GT, Sussman NL, Williams R. Pilot-Controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatol, 1996; 6:1557

10 Bhaduri BR, Mieli-Vergani G. Fulminant hepatic failure: pediatric aspects. Sem LivDis, 1996; 16: 349-55

11 Sudan DL, Shaw BW jr. Fox IJ, Langnas AN. Long-term follow up of auxiliary orthotopic liver transplantation for the treatment of fulminant hepatic failure. Surgery, 1997; 122(4):777-778.