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Acute liver failure in neonates

Anil Dhawan, Giorgina Mieli-Vergani *

Paediatric Liver Centre, Institute of Liver Studies, Variety Club Children’s Hospital,King’s College School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK

0378-3782/$ - see front matter D 200doi:10.1016/j.earlhumdev.2005.10.003

* Corresponding author. Paediatric LChildren’s Hospital, King’s CollegeHospSE5 9RS, UK. Tel.: +44 20 7346 4643; fa

E-mail address: giorgina.vergani@k(G. Mieli-Vergani).

KEYWORDSNeonatal acute liverfailure;Coagulopathy;Herpes simplex virus;Metabolic disease;Neonatalhaemochromatosis;Liver transplant

Abstract Acute liver failure (ALF) in neonates is a rare but often fatal event.Though in adults and older children, a main symptom of ALF is hepaticencephalopathy, this is very difficult to diagnose and prove in infants. Causes ofALF in neonates encompass metabolic, infectious and haematological disorders,congenital vascular/heart abnormalities, and drugs. Infants with ALF should only betreated in specialised paediatric hepatology centres with facilities for livertransplantation, since for many liver transplant, with a long term survival of over60%, is the only therapeutic option.D 2005 Elsevier Ireland Ltd. All rights reserved.

Acute liver failure (ALF) is a rare but mainly fataldisorder in neonates, the mortality for which is 70%without liver transplantation. Managementrequires a multidisciplinary approach involvinghepatologists, neonatologists and transplant sur-geons, to support the child until liver regenerationor liver transplantation takes place. The mostcommon aetiologies are liver based metabolicdisorders and perinatally acquired infections. Liverdamage can be reversed in certain metabolicconditions by altering the diet and in someinfections by appropriate antimicrobial treatment,but when it is advanced, liver transplantation is theonly life saving option.

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iver Centre, Variety Clubital, DenmarkHill, Londonx: +44 20 7346 4224.cl.ac.uk

1. Definition

The definition of ALF in children and neonates is asubject of controversy. In adults, in 1970, Trey andDavidson defined ALF as ba potentially reversiblecondition, the consequence of severe liver injury,in which the onset of hepatic encephalopathy iswithin eight weeks of the first symptoms of illness,in the absence of pre-existing liver diseaseQ [1].This definition is unsatisfactory for children, espe-cially during infancy, not only because it is verydifficult to identify signs of encephalopathy in thisage group, but also because encephalopathy can bea very late event in the course of the disease.Moreover, children presenting with ALF often dohave an underlying unrecognized liver disease.Bhaduri and Mieli-Vergani have addressed this issueand proposed the following definition of ALF inchildren: ba rare multisystem disorder in whichsevere impairment of liver function, with or

Early Human Development (2005) 81, 1005—1010

s reserved.

A. Dhawan, G. Mieli-Vergani1006

without encephalopathy, occurs in association withhepatocellular necrosis in a patient with no recog-nised underlying chronic liver diseaseQ [2].

1.1. Aetiology

Causes of ALF during the newborn period are listedin Table 1 [3,4] and include inborn errors ofmetabolism, perinatal infections, hypotension/shock, and haematological conditions like haemo-phagocytic lymphohistiocytosis. Identifying thecause of ALF not only provides indication ofprognosis but also dictates specific managementoptions.

1.2. Viral infections

Perinatal infection with viruses of the herpesfamily, adenovirus, parvovirus and hepatitis B cancause ALF in newborn babies [5,6]. Herpes simplexvirus (HSV) induced ALF is the most commonamong viral aetiologies, carries a high mortalityand is rarely accompanied by skin lesions, hence itshould be considered in all sick babies withcoagulopathy and raised transaminases. Infantswith this presentation should be promptly startedon intravenous aciclovir. We have analysed retro-spectively the case notes of 11 patients with HSVinduced ALF. A history of possible herpes infectionwas elicited in 5 parents, but HSV had not beensuspected clinically. All patients were asymptom-atic when discharged from postnatal units, andpresented with non-specific symptoms of poorfeeding and lethargy within 2 weeks from birth.All had grossly deranged liver function and coagul-opathy at presentation. Seven of the 11 patientshad HSV-1 infection, 4 HSV-2. Only two patients,both of whom received early treatment withintravenous aciclovir survived. These findingsindicate that it is important to recognise HSV

Table 1 Common causes of acute liver failure in neonate

Disease entity

GalactosemiaTyrosinemiaNeonatal haemochromatosisHaemophagocytic lymphohistiocytosis and congenital leukaemiaSepticemia and shockGiant cell hepatitis with hemolytic anemiaHHV-6, Hepatitis B, Adenovirus, ParvovirusMitochondrial hepatopathy

Vascular malformations and congenital heart diseaseMaternal overdose (paracetamol) [3]Hypocortisolism [4]

infection in women of childbearing age and theirsexual partners and to treat the infected baby assoon as possible.

1.3. Metabolic diseases

Inherited disorders of metabolism are an importantcause of ALF in the neonatal period, and must bepromptly investigated because dietary manipula-tion or disease specific treatment may be lifesaving. The most common metabolic diseases tobe considered are galactosaemia, hereditary fruc-tose intolerance, and tyrosinaemia [3—9]. For thefirst two, withdrawal of the offending dietarycomponent is usually life saving. The managementof tyrosinaemia has changed dramatically since theintroduction of 2(2-nitro-4-trifluoromethylben-zoyl)-1,3-cyclohexenedione (NTBC), which pre-vents the formation of toxic metabolites andproduces rapid clinical and biochemical improve-ment [7]. Recently, mitochondrial respiratory chaindefects have been implicated as an etiologicalfactor for ALF in infants. They usually present withhypoglycemia, vomiting, coagulopathy, acidosisand raised lactate with or without neurologicalsymptoms [10]. Rarely fatty acid oxidation defectsand inborn errors of bile acid synthesis present withALF. Neonatal haemochromatosis (NH) is usuallylisted under the metabolic disorders associatedwith ALF in infancy, though its aetiopathogenesisis unknown. It is a rare disease, but the mostcommon cause of ALF in the neonatal period. In NH,liver injury of fetal onset is associated with massiveintra and extra hepatic iron deposition sparing thereticulo-endothelial system. It presents with acuteliver failure around birth. It has been suggestedthat it may be the ultimate phenotype of differentaetiologies. There is an 80% recurrence rate withinfamilies of affected children. The description of NHin half siblings born to the same mother has led to

s and diagnostic investigations

Diagnostic test

Red cell galactose-1-phosphate uridyl transferaseUrine succinyl acetoneRaised ferritin, extrahepatic iron depositionBone marrow examinationPositive cultures, clinical scenarioCoombs positive haemolytic anemiaViral serology and PCRMitochondrial DNA, muscle and liver biopsy (open,if coagulopathy permits) for quantitative respiratorychain enzyme determinationEchocardiographyHistory and drug levelsCortisol levels, short synacthen test

Acute liver failure in neonates 1007

the suggestion that the disease could be due toincomplete penetrance or gonadal mosaicism for adominant disorder or a mitochondrial defect,rather than be autosomal recessive, but the precisepattern of inheritance is unknown. Other proposedcauses of NH are intrauterine infection and mater-nal alloimmune antibodies. There is often a historyof maternal anaemia, oligohydramnios or mega-placenta. There are no specific diagnostic tests forNH, but hypersaturation of transferrin with elevat-ed ferritin levels are useful biochemical clues in ababy with ALF. The diagnosis can only be confirmedby the demonstration of extra hepatic iron depositssparing the reticuloendothelial system, which invivo can be sought by performing a biopsy of lipsalivary glands. Intra-hepatic iron deposition on itsown is not diagnostic, because the neonatal liver isphysiologically iron overloaded and high hepaticiron content is observed in any form of severe liverdisease in this age group. Magnetic resonanceimaging of the abdomen may demonstrate ironstorage in the pancreas, but iron storage is typicallyabsent in the spleen. The prognosis of NH has beenuniversally reported as poor. Chelation treatmentalone is ineffective in altering the course of thedisease. Specific management includes the use ofan antioxidant cocktail [11,12] (Table 2), but itsefficacy has not been tested in controlled trials andin our own series of 19 patients it has not modifiedthe outcome [11]. Liver transplantation is the onlytherapeutic option for severely affected babies andis performed successfully even during the first fewdays of life, though the waiting period for a suitablesize donor is usually long, given the small size of therecipient. While waiting for transplantation, singlevolume whole blood exchange transfusion may behelpful to manage symptomatic coagulopathy, andpossibly to remove maternal alloantibodies thathave been recently suggested to play a significantrole in the pathogenesis of this condition. Thesurvival after liver transplantation for NH in ourcenter is 50% (median follow up 7.8 years, range 3—10 years) [11]. Antenatal administration of intra-venous immunoglobulins weekly from the 18 weekof gestation until term has been shown to reducethe severity of the illness in the newborn in a series

Table 2 Anti oxidant cocktail for neonatal haemo-chromatosis

Vitamin E 25 IU/kg/day orallyN-acetylcysteine 100 mg/kg/day i.v.Prostaglandin—E1 0.4 Ag/kg/h i.v. for a maximum

of 2 weeksSelenium 3 mg/kg/day i.v.Desferioxamine 30 mg/kg/day i.v. until ferritin

b500 ng/ml

of 15 pregnant mothers who previously had anaffected baby [13].

1.4. Ischemic injury

Shock liver can occur after cardiac arrest, a periodof hypotension/hypovolaemia or in the setting ofcongestive cardiac failure, even when hypotensionis not clearly documented. Serum transaminaselevels are markedly elevated but they do normalizerapidly once the circulatory problem is stabilized[5].

1.5. Vascular causes

Congestive heart failure of any aetiology canpresent as liver failure. Conditions that we haveseen in our unit presenting as ALF include hypo-plastic left heart, coarctation of the aorta andright heart failure. Ascites, significant hepatomeg-aly, coagulopathy and hypoalbuminemia are oftenpresent [5].

1.6. Hematological malignancies

Haemophagocytic lymphohistiocytosis (HLH)presents with fever, hepatosplenomegaly, pancy-topaenia and, in severe cases, with ALF. Biochem-ically, there are high serum triglycerides and lowfibrinogen. Usually, these patients bleed severelyfrom venepuncture sites, in contrast to infantswith other forms of ALF. Bone marrow aspiration orcytospin from body fluids (ascites, cerebrospinalfluid) usually demonstrate haemophagocytosis.When HLH presents with ALF, mortality is highdespite aggressive supportive treatment, chemo-therapy and bone marrow transplantation [14].Haematologic malignancies, e.g., congenital leu-kemia, can present with ALF due to massiveinfiltration of the liver. The presence of high feverwith hepatosplenomegaly, high alkaline phospha-tase, high lactate dehydrogenase and abnormali-ties of the peripheral blood film suggest thediagnosis and bone marrow examination confirmsit [15,16].

2. Management

2.1. General measures

Patients with ALF should be nursed in a quietenvironment with as little stimulation as possible tominimize acute increases in intra-cranial pressure.

A. Dhawan, G. Mieli-Vergani1008

Babies with encephalopathy and those withoutencephalopathy, but an international normalizedprothrombin ratio (INR) greater than 4 should beadmitted to the intensive care unit for continuousmonitoring. Patients should be carefully monitoredin respect of haemodynamics and fluid manage-ment (blood pressure, urine output), metabolicparameters (electrolytes, blood sugar) and neuro-logical status (presence of encephalopathy). Seda-tion should be avoided unless the patient is to bemechanically ventilated, as it can interfere withthe monitoring of the neurological status. Coagu-lation and metabolic parameters, full blood countand arterial blood gases in ventilated patientsshould be regularly checked. Controlled trials inadults have failed to substantiate any beneficialeffect of corticosteroids, interferon, insulin andglucose, prostaglandin E1, bowel decontamination,and charcoal hemoperfusion in patients with ALF.Maintenance of nutrition is crucial and hypoglyce-mia should be avoided by use of intravenousglucose infusion or by ensuring adequate enteralintake. Total fluid intake is restricted to two-thirdsof the maintenance if the patient is not dehy-drated. The concept of protein intake aggravatingor precipitating hepatic encephalopathy has nowbeen discarded, and adequate calories should beprovided using oral or nasogastric feeding. Inves-tigations to elucidate the cause of ALF should beperformed urgently to start appropriate treatment.Liver biopsy is only rarely useful and usuallycontraindicated because of severe coagulopathy[5].

3. Complications

3.1. Encephalopathy

The most serious complications of ALF are cerebraloedema with resultant intracranial hypertensionand hepatic encephalopathy. Encephalopathy usu-ally presents late in the course of the illness, andwhen present carries a bad prognosis. The conven-tional grading system for encephalopathy (grade I—IV) used for adults and older children is notapplicable to babies. Signs of early encephalopathyin babies are inconsolable crying and sleep distur-bance, which can progress to somnolence orirritability and later to frank coma more or lessresponsive to painful stimuli. The infant should beelectively ventilated and sedated at the first signsof encephalopathy. Mannitol, an osmotic diureticthat remains the mainstay of treatment for in-creased ICP in adults and older children, is not

often used in babies, for whom we prefer usingexchange transfusions.

3.2. Infection

Patients with ALF have impaired immune function.About 60% of deaths in ALF have been attributed tosepsis. An active uncontrolled infection is also arelative contraindication for liver transplantation.The risk factors for infections include coexistingrenal failure, cholestasis and treatment with thio-pental. In adults, the presence of encephalopathy(grade II or above) has been shown to be associatedwith bacterial infection in about 80% of cases andfungal infections in about 32% of cases. The mostcommon bacterial infection is due to Staphylococ-cus aureus, but streptococci or gram negativeorganisms such as coliforms are also isolated.Prophylactic intravenous antibiotics have beenshown to reduce the incidence of culture-positivebacterial infection from 61.3% to 32.1% in adultpatients. Candida species are the most commonfungal isolates which are often unrecognized andmay be ominous. Deterioration of encephalopathyafter an initial improvement, a markedly raisedleukocyte count, pyrexia unresponsive to antibi-otics, and established renal failure are strongindicators of fungal infection [17,18]. In our unit,neonates with ALF are treated from admission withbroad spectrum antibiotics (usually third genera-tion cephalosporin and an aminoglycoside), acyclo-vir and fluconazole.

3.3. Coagulopathy

The prothrombin time, expressed as INR, is used asan indicator of the severity of liver damage and todecide when to list for transplantation. An INRz4is associated with more than 90% mortality and isthe main parameter used in our centre fortransplant listing. Thus, correction of coagulop-athy is indicated only if the patient is alreadylisted for transplant or prior to invasive proce-dures. Significant disseminated intravascular co-agulation is unusual in ALF. The risk of hemorrhagedoes not correlate with INR but with thrombocy-topenia which can develop rapidly. A plateletcount of less than 100�109/L has been reportedin about two-thirds of adults with ALF. Commonsites of internal haemorrhage include the gastro-intestinal tract, nasopharynx, lungs, and retroper-itoneum. Intracranial hemorrhage is uncommon.The presence of significant disseminated intravas-cular coagulation usually indicates sepsis or sec-ondary HLH. Prophylactic ranitidine or proton

Acute liver failure in neonates 1009

pump inhibitors have been shown to decrease theincidence of gastric bleeding [19].

3.4. Haemodynamic complication

The early haemodynamic changes in ALF patientsare similar to those seen in the systemic inflam-matory response syndrome and reflect a state ofhyperdynamic circulation with decreased systemicperipheral vascular resistance and increased cardi-ac output. Circulatory failure is a common mode ofdeath in patients with ALF, often complicatingsepsis or multiorgan failure. Invasive haemody-namic monitoring like arterial blood pressure,central venous pressure or lately use of PICCO andoesophageal echocardiography in adults may pro-vide early evidence of circulatory failure and ishelpful in deciding fluid management, but may bedifficult in small infants. In the presence ofpersistent hypotension despite normal filling, nor-adrenaline is the inotropic agent of choice. N-acetylcysteine has been shown to improve param-eters of oxygen metabolism. A combination ofprostacycline and N-acetylcysteine has been foundto be more beneficial for oxygen metabolism thaneither drug alone [20,21].

3.5. Renal failure

Renal failure with severe oliguria often develops inALF, especially in later stages. In the pediatricpopulation, the incidence of renal failure is lower(10—15%) than in the adult population (30%) butthere are no studies in neonates [21]. Renal failurecould be due either to a direct toxic effect on thekidneys, as in paracetamol overdose, or to acomplex mechanism such as hepatorenal syndromeor acute tubular necrosis secondary to complica-tions of ALF (sepsis, bleeding, and/or hypoten-sion). Although the mechanism of renal failure isnot clear, it is essential to correct intravascularhypovolemia. Continuous filtration or dialysis sys-tems are associated with less haemodynamicinstability and consequently less risk of aggravatinglatent or established encephalopathy than inter-mittent haemodialysis.

3.6. Metabolic derangement

Hypoglycaemia is present in some 40% of patientswith ALF. The classic signs and symptoms ofhypoglycemia are often masked, especially in thepresence of encephalopathy, hence regular bloodglucose monitoring is mandatory as hypoglycemiacan worsen the encephalopathy and cause rapid

neurologic deterioration. Acid—base imbalance iscommon. Metabolic acidosis is present in about 5%of patients with ALF and is associated with pooroutcome. Lactic acidosis is related to inadequatetissue perfusion. Sometimes respiratory alkalosis oracidosis may complicate the clinical picture.

3.7. Liver transplantation

Advances in surgical techniques have made itpossible to perform liver transplantation in new-born babies. The availability of liver transplanta-tion for this age group has significantly improvedsurvival, but the procedure is contraindicated inpatients with advanced complications of ALF, suchas fixed and dilated pupils, uncontrolled sepsis, andsevere respiratory failure (adult respiratory distresssyndrome) or conditions not treatable by liverreplacement, such as mitochondrial cytopathieswith neurological involvement, HLH, giant cellhepatitis with Coombs positive haemolytic anaemia(which recurs after transplant) and malignancies.Though worse than for older children, the outcomeof neonatal liver transplantation is acceptable,with a patient survival of about 65% in our centre,the downside being a life long need for immuno-suppressive medications [22,23].

4. Hepatocyte transplantation

Liver cells isolated from unused donor livers can beinfused in to the failing liver to provide a function-ing hepatic mass while the native liver regenerates.The procedure has shown some encouraging resultsas a bridge to transplant, however, the techniqueremains experimental [24].

5. Liver support systems

In ALF, there is impairment of synthetic, detoxify-ing, and biotransformatory activity resulting fromthe loss of functioning hepatocytes and Kupffercells. Theoretically a support device, which pro-vides all these functions would be ideal, either as abridge to liver transplant or, better, to obviate theneed for it, by supporting liver function while thenative liver regenerates. Liver support devicescould be either cleansing devices or bioartificialliver support systems. Cleansing devices performonly the detoxifying function of the liver, whereasbioartificial liver support systems have the theo-retical advantage of having synthetic and detoxi-

A. Dhawan, G. Mieli-Vergani1010

fying properties. None of these devices have beentried systematically in children or neonates hencetheir use outside research protocols is not recom-mended [25—27].

6. Conclusions

ALF is a multisystem disorder with a high mortalityrate, which should be managed in a specializedpaediatric liver centre with facilities for livertransplantation, since this procedure, despite im-provement in intensive care support, remains theonly effective mode of treatment for most infants.Liver assist devices and hepatocyte transplant holda great potential of providing a bridge to transplantor avoiding it while the native liver regenerates,but are still at the experimental stage.

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