etiology and prognosis of acute liver failure in children

AASLD/ILTS SYLLABUS

Etiology and Prognosis of Acute Liver Failurein ChildrenAnil DhawanPaediatric Liver Centre, King’s College London School of Medicine, King’s College Hospital,London, United Kingdom

Received July 24, 2008; accepted August 18, 2008.

Key Points

1. The etiology of acute liver failure in children differsfrom that in adults, with metabolic conditions beingcommoner in Europe and North America and hepa-titis A being the commonest cause in Asia and SouthAmerica.

2. Encephalopathy usually is a late feature and is notessential for the diagnosis.

3. Unlike adults, there are no good prognostic criteriathat can predict survival without liver transplantation.

4. It is important to exclude genetic multisystem disor-ders before liver transplantation is considered.Liver Transpl 14:S80-S84, 2008. © 2008 AASLD.

Acute liver failure (ALF) is the final common pathwayof a variety of insults to the liver. There is considerablevariation in the etiologies around the world, with acuteviral hepatitis and drugs accounting for the majority ofcases. In children, acute viral hepatitis is the mostcommon identified cause in most of the series, but thereis a lot of geographical variation, with hepatitis A beingthe most common cause in Asia, whereas in Europeand North America, the etiology in most stays indeter-minate.1 The etiologies of ALF, as seen in a tertiarypediatric liver center and in the multicenter PaediatricAcute Liver Failure Study, are shown in Table 1 and Fig.1. A list of causes responsible for ALF in children isshown in Tables 2 and 3.

INFECTIVE ETIOLOGY

Viruses

Infection with hepatotropic viruses is probably the mostidentifiable cause of ALF. Patients usually present with

icterus and markedly raised serum transaminase lev-els. The magnitude of transaminase elevation and therate of decline do not predict prognosis. In patients whospontaneously recover, serum bilirubin, the interna-tional normalized ratio (INR), and serum transaminasesgradually decline, whereas continued increases in bili-rubin levels and INR, despite declining serum transam-inase levels, indicate massive hepatocyte necrosis andpoor prognosis.

Hepatitis A virus (HAV) infection is the most commoncause of ALF in the Indian subcontinent and SouthAmerica.2-4 A higher incidence of ALF is suggestedwhen HAV infection occurs in patients with underlyingchronic liver disease. The diagnosis of acute hepatitis Ais made by the detection of the anti-HAV immunoglob-ulin M antibody in serum. In 95% of cases, the anti-HAV immunoglobulin M antibody is present at the timeof presentation, and the remaining 5% become positiveon repeat testing.

Hepatitis B virus as a cause of ALF is less common inchildren than in adults as the perinatal infection inmost of the babies leads to a chronic state; however,infants born to mothers positive for the antibody tohepatitis B e antigen are a special group that canpresent with ALF around 3 weeks to 3 months of age.5

Hepatitis E virus infection, a water-borne infectionlike hepatitis A and a well-recognized cause of ALF, iscommon in the Indian subcontinent and Africa. A studyfrom northern India reported 7 of 44 children with ALFhad isolated hepatitis E infection, and another 16 of 44had mixed hepatitis E and hepatitis A infection.5

Non–A-E hepatitis (seronegative hepatitis) is the mostcommon cause of ALF in the Western world. In ourseries, out of 100 cases of ALF, 45 were due to non–A-E

Abbreviations: ALF, acute liver failure; APAP, N-acetyl-p-aminophenol; HAV, hepatitis A virus; INR, international normalized ratio;PALFSG, Paediatric Acute Liver Failure Study Group; WCC, white cell count.Address reprint requests to Anil Dhawan, M.D., F.R.C.P.C.H., Paediatric Liver Centre, King’s College London School of Medicine, King’s CollegeHospital, London, United Kingdom SE 59RS. Telephone: 0044 203 299 3578; FAX: 0044 203 299 4228; E-mail: [email protected]

DOI 10.1002/lt.21641Published online in Wiley InterScience (www.interscience.wiley.com).

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hepatitis.6 A similar experience was reported from Chi-cago, with 26 of 42 children with ALF being diagnosedwith non–A-E hepatitis.7 The diagnosis is one of exclu-sion in which other causes of ALF are eliminated withappropriate laboratory investigations and clinical ex-amination. Non–A-E hepatitis is characterized by itspropensity to cause severe hepatitis, its high fatalityrate (low spontaneous remission) without liver trans-plantation, and its association with bone marrow fail-ure in up to 10% of patients.8 Bone marrow failure candevelop even after a few weeks of the onset of symptomsof ALF.

Other Hepatotropic Viruses

Herpes simplex virus, cytomegalovirus, Epstein-Barrvirus, and varicella zoster virus, members of the her-pesvirus family, can cause severe hepatic necrosis, par-ticularly in immunocompromised patients and neo-nates. Herpes simplex infection–induced ALF in theneonatal period has a very high case fatality ratio. Thediagnosis is suspected in an unwell neonate with orwithout a vesicular lesion along with remarkably raisedserum transaminases and coagulopathy. ParvovirusB19 infection can cause severe hepatitis, ALF, andrarely bone marrow failure in children. Echovirus, Cox-

sackieviruses, and adenoviruses are the other virusesthat can cause ALF, particularly in newborn babies.

DRUGS AND TOXINS

Drugs and toxins are well known to cause liver failurein children. In general, risk factors for drug-inducedhepatotoxicity are age (very young children or adoles-cents), abnormal renal function, concurrent use ofother hepatotoxic agents, drug interactions, and preex-isting liver diseases. Drug-induced hepatoxicity can bea dose-dependent response, an idiosyncratic reaction,or a synergistic reaction (Table 3).

Paracetamol (acetaminophen APAP), the most com-mon drug associated with ALF, is a safe drug whenused in therapeutic doses in healthy individuals. It isnormally a dose-dependent hepatotoxic agent. Conse-quently, even therapeutic doses of acetaminophen canlead to an accumulation of N-acetyl-para-benzoquinoneimide causing ALF. The inadvertent administration ofhigher doses of acetaminophen can lead to ALF in chil-dren.9 Serum acetaminophen levels after 4 hours ofingestion are useful in identifying high-risk patientsbut are not informative in patients in which toxicity issecondary to chronic administration.

AUTOIMMUNE HEPATITIS

Autoimmune hepatitis can present as ALF, most ofthese patients being liver/kidney microsome antibody–positive. The diagnosis may be difficult as some casesmay not show antibody response at presentation. In ourexperience, children with autoimmune hepatitis pre-senting with ALF along with encephalopathy do notrespond to any form of immunosuppression and needurgent liver transplantation.

METABOLIC DISEASES

Inherited disorders of metabolism merit special atten-tion in a differential diagnosis when ALF is being inves-tigated in pediatric patients, particularly newborn ba-bies. Although all these patients have variable degreesof liver damage before clinical presentation of ALF, overtsigns and stigmata of chronic liver disease are usuallyabsent. A high index of suspicion is important as urgentintervention such as dietary manipulation or diseasespecific treatment may be lifesaving. Conditions that

Figure 1. Three hundred thirty-one patients with acute liver fail-ure. Abbreviations: APAP, N-acetyl-p-aminophenol; PALFSG, Pae-diatric Acute Liver Failure Study Group.

TABLE 1. Etiologies of Acute Liver Failure in Neonates and Children (King’s College Hospital, London, England)

Neonates n � 31 Children n � 100

Neonatal hemochromatosis 15 Non–A-E hepatitis 45Hemophagocytic lymphohistiocytosis 4 Hepatitis A/B 7Disseminated herpes simplex virus 5 Other viral infection 3Metabolic 4 Metabolic 18Transplacental acetaminophen toxicity 1 Paracetamol toxicity 8Endocrine (isolated cortisol deficiency) Other drug/toxin 5Sepsis/shock 1 Sepsis/hypoxia 3

1 Miscellaneous 3

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LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

are common to the neonatal age group are listed inTable 3.

Galactosemia is usually associated with hypoglyce-mia and gram-negative septicemia. Immediate exclu-sion of galactose (from the diet and medications) usu-ally leads to a quick recovery, but some cases doprogress to liver failure. Tyrosinemia presents with se-vere coagulopathy, mild jaundice, and rickets. Heredi-tary fructose intolerance is rare, but a history of admin-istration of fructose as in fruits, sugar, or honey maycoincide with clinical symptoms.

Neonatal hemochromatosis is a disorder of iron han-dling of antenatal onset with excess iron deposition inthe nonreticuloendothelial system. Liver failure usuallypresents in the first few days of life, but liver disease isgenerally present at birth. Maternal viral infection inthe antenatal period or metabolic disease in the fetushas been suggested as an underlying cause. Althoughan underlying genetic basis for neonatal hemochroma-tosis has been suspected, no test is available for pre-dictive analysis in at-risk pregnancies. The diagnosisshould be considered in every case of neonatal liverfailure. Commonly used as a diagnostic test, ferritinelevation is sensitive but not specific as ferritin eleva-tion in sick babies is usually observed. A laboratory testof value is hypersaturation of transferrin with relativehypotransferrinemia. Magnetic resonance imaging ofthe liver or pancreas to demonstrate iron is not usuallyrewarding, but a punch biopsy specimen of buccal mu-cosa is a useful diagnostic tool. Documentation of ironin salivary glands in buccal mucosa is diagnostic ofneonatal hemochromatosis. To ensure the presence ofsalivary glands in the buccal mucosal biopsy specimen,a frozen-section examination is advisable. The treat-ment with high-dose immunoglobulin of pregnantmothers (with a previous history) with suspected neo-natal hemochromatosis has been shown to modify thecourse of the illness in the affected baby.10

Wilson’s disease, an autosomal recessive disorder,may present as ALF in an older child. The acutehepatic presentation is characterized by the presenceof liver failure, Coomb’s negative hemolytic anemia,and low alkaline phosphatase. The demonstration ofKayser-Fleisher rings is diagnostic of Wilson’s dis-ease in a patient who presents with ALF. Serum cer-uloplasmin is usually but not invariably low, and theserum free copper concentration can be increased ornormal. A serum alkaline phosphatase to total biliru-

TABLE 2. Causes of Acute Liver Failure

InfectiveViral

Viral hepatitis (A, B, B�D, and E)Non–A-E hepatitisAdenovirus, Epstein-Barr virus, and cytomegalovirusEchovirusVaricella and measlesYellow feverRarely Lassa, Ebola, Marburg, dengue, and Toga virus

BacterialSalmonellosisTuberculosisSepticemia

OthersMalariaBartonellaLeptospirosis

DrugsDose-dependent

AcetaminophenHalothane

Idiosyncratic reactionIsoniazidNonsteroidal anti-inflammatory drugsPhenytoinSodium valproateCarbamazepineEcstasyTroglitazoneAntibiotics (penicillin, erythromycin, tetracyclines,

sulfonamides, and quinolones)AllopurinolPropylthiouracilAmiodaroneKetoconazoleAntiretroviral drugs

Synergistic drug interactionsIsoniazid � rifampicinTrimethoprim � sulfamethoxazoleBarbiturates � acetaminophenAmoxycillin � clavulinic acid

ToxinsAmanita phalloides (mushroom poisoning)Herbal medicinesCarbon tetrachloride (CCl4)Yellow phosphorusIndustrial solventsChlorobenzenes

MetabolicGalactosemiaTyrosinemiaHereditary fructose intoleranceNeonatal hemochromatosisNiemann-Pick disease type CWilson’s diseaseMitochondrial cytopathiesCongenital disorder of glycosylationAcute fatty liver of pregnancy

AutoimmuneType 1 autoimmune hepatitisType 2 autoimmune hepatitisGiant cell hepatitis with Coomb’s positive hemolytic anemia

Vascular/ischemicBudd-Chiari syndromeAcute circulatory failureHeat strokeAcute cardiac failureCardiomyopathies

InfiltrativeLeukemiaLymphomaHemophagocytic lymphohistiocytosis

TABLE 3. Causes of Neonatal Liver Failure

Perinatal herpes simplex virus infectionNeonatal hemochromatosisGalactosemiaTyrosinemiaHemophagocytic lymphohistiocytosisSepticemiaMitochondrial cytopathiesCongenital disorder of glycosylationSevere birth asphyxia

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bin ratio of �2.0 has also been suggested as a diag-nostic tool to discriminate Wilson’s disease fromother causes of ALF.

In recent years, mitochondrial respiratory chain dis-orders have been implicated in the etiology of ALF inchildren. This group of disorders encompasses a widevariety of diseases, including Pearson syndrome, mito-chondrial DNA depletion syndrome, nuclear DNA de-fects, Alper disease, and intestinal pseudo-obstructionwith liver disease. Presenting symptoms can be hypo-glycemia, vomiting, coagulopathy, acidosis, and in-creased lactate with or without neurological symptoms.The presence of high serum lactate in the mother and ahistory of sibling deaths are suggestive of this condi-tion. Diagnosis involves a quantitative assessment ofthe respiratory chain enzyme complexes in the affectedtissues (muscle, liver, and skin fibroblast culture). Iso-lated hepatic involvement with successful liver trans-plantation has been reported; however, the follow-up ofthese patients is not long enough to rule out futureneurological deterioration.

Rarely, fatty acid oxidation defects and inborn errorsof bile acid synthesis, especially �4-3-oxosteroid 5�-reductase enzyme deficiency, can present as ALF.

MALIGNANCIES

Hemophagocytic lymphohistiocytosis is a spectrum ofinherited and acquired conditions with disturbed im-mune regulation, and it encompasses 2 main condi-tions that have common clinical and pathobiologicalcharacteristics: familial (primary) hemophagocytic lym-phohistiocytosis and secondary hemophagocytic lym-phohistiocytosis. Familial (primary) hemophagocyticlymphohistiocytosis is an invariably fatal inherited dis-ease seen mostly in infancy and early childhood, butsecondary hemophagocytic lymphohistiocytosis can af-fect any age and may subside spontaneously. Variousforms of hematological malignancies, such as leukemiaand lymphoma, can present with ALF. Diagnostic cluesinclude high fever, hepatosplenomegaly, high alkalinephosphatase, lactate dehydrogenase, and abnormali-ties on peripheral blood film. A bone marrow examina-tion is diagnostic.

PROGNOSIS

The prognosis of ALF varies greatly with the underlyingetiology. In an adult series from King’s College Hospital

(London, England), 50% of patients survived after anacetaminophen overdose, whereas the survival rate wasonly 12.5% after halothane-induced ALF, 66% for hep-atitis A, and 39% for hepatitis B.11

The prothrombin time is the best indicator of surviv-al.12 Bhaduri and Mieli-Vergani12 showed that themaximum INR reached during the course of illness wasthe most sensitive predictor of the outcome, with 73% ofchildren with an INR � 4 surviving versus only 4 of 24(16.6%) with an INR � 4.

In children, a factor V concentration of �25% of nor-mal suggests a poor outcome, and in France, this cri-terion is used for listing for liver transplantation.13

Liver biopsy is rarely helpful in ALF and is usuallycontraindicated because of the presence of coagulopa-thy.14

Wilson’s disease presenting with encephalopathy isinvariably fatal and can be treated only by liver trans-plantation, but the decision to list a child with Wilson’sdisease without encephalopathy is very difficult. In ourexperience, a prognostic score (Table 4) has been usefulin identifying the patients who carry a high risk ofmortality without liver transplantation.15 It incorpo-rates bilirubin, INR, aspartate aminotransferase, whiteblood count, and albumin at presentation. A score of 11or more indicates high mortality with 93% sensitivityand 96% specificity. Survival depends on the ability ofthe liver to recover from the ensuing insult, but it is verydifficult to predict the potential for recovery. There is nosingle criterion that can predict the outcome with ab-solute certainty and be universally applicable to allpatients with ALF with different etiologies. However, theprediction of a low level of survival (chance � 20%) isclinically useful in deciding to list the patient for ortho-topic liver transplantation, which has a 1-year survivalrate of 75%.

REFERENCES

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TABLE 4. Revised King’s Wilson’s Index

Score Bilirubin (�mol/L) INR AST (IU/L) WCC (109/L) Albumin (g/L)

0 0-100 0-1.29 0-100 0-6.7 �451 101-150 1.3-1.6 101-150 6.8-8.3 34-442 151-200 1.7-1.9 151-200 8.4-10.3 25-333 201-300 2.0-2.4 201-300 10.4-15.3 21-244 �301 �2.5 �301 �15.4 0-20

NOTE: This table was adapted from Dhawan et al.15

Abbreviations: AST, aspartate aminotransferase; INR, international normalized ratio; WCC, white cell count.

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4. Shah U, Habib Z, Kleinman RE. Liver failure attributableto hepatitis A virus infection in a developing country. Pe-diatrics 2000;105:436-438.

5. Arora NK, Nanda SK, Gulati S, Ansari IH, Chawla MK,Gupta SD, et al. Acute viral hepatitis types E, A, and Bsingly and in combination in acute liver failure in childrenin north India. J Med Virol 1996;48:215-221.

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11. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Earlyindicators of prognosis in fulminant hepatic failure [com-ment]. Gastroenterology 1989;97:439-445.

12. Bhaduri BR, Mieli-Vergani G. Fulminant hepatic failure:pediatric aspects. Semin Liver Dis 1996;16:349-355.

13. Devictor D, Desplanques L, Debray D, Ozier Y, DuboussetAM, Valayer J, et al. Emergency liver transplantation forfulminant liver failure in infants and children. Hepatology1992;16:1156-1162.

14. Hind J, Quaglia A, Dhawan A. Role of liver biopsy in acuteliver failure. Hepatology 2007;46(4):728A.

15. Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiy-iannakis L, Mieli-Vergani G. Wilson’s disease in children:37-year experience and revised King’s score for liver trans-plantation. Liver Transpl 2005;11:441-448.

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etiology and prognosis of acute liver failure in children

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