Orthotopic liver transplantation for acuteliver failure secondary to autoimmunehepatitis in a child with autoimmunepolyglandular syndrome type 1

Smith D, Stringer MD, Wyatt J, O’Meara M, Davison S, Cheetham TD,McClean P. Orthotopic liver transplantation for acute liver failuresecondary to autoimmune hepatitis in a child with autoimmunepolyglandular syndrome type 1.Pediatr Transplantation 2002: 6: 166–170. # 2002 Blackwell Munksgaard

Autoimmune polyglandular syndrome type 1 (APS-1) is anautosomal-recessive condition characterized by hypoparathyroidism,autoimmune Addison’s disease, and chronic mucocutaneous candidiasis.Autoimmune hepatitis develops in 10–20% of affected patients and has avariable course ranging from asymptomatic chronic liver disease to lethalfulminant hepatic failure. Liver transplantation has been documentedpreviously in only two patients. We report a 14-yr-old boy with APS-1 whodeveloped acute liver failure secondary to associated autoimmunehepatitis. He did not respond to corticosteroid therapy and wassuccessfully treated with an orthotopic liver transplant.

Dominic Smith1, Mark D. Stringer1,Judy Wyatt2, Moira O’Meara3,Suzanne Davison1, Tim D. Cheetham4

and Patricia McClean11Children’s Liver Unit and Departments of2Histopathology and 3Anaesthesia, St. James’sUniversity Hospital, Leeds, UK, 4Department ofChild Health, University of Newcastle upon Tyne,Newcastle, UK

Key words: autoimmune polyglandular syndrome –

autoimmune hepatitis – liver transplantation

P McClean, Children’s Liver Unit, St. James’s

University Hospital, Leeds LS9 7TF, UK

Tel.: +44 113 206 6880Fax: +44 113 206 6691E-mail: patricia.mcclean@leedsth.nhs.uk

Accepted for publication 27 August 2001

APS-1 is an autosomal-recessive condition char-acterized by a variable combination of multi-organautoimmune endocrinopathy, chronic mucocuta-neous candidiasis, and ectodermal dystrophy (1).The condition has also been termed APECED (2).

Autoimmune hepatitis develops in 10–20% ofpatients with APS-1 (3–5) and has a variable sev-erity ranging from a subclinical chronic activehepatitis to acute hepatic failure (3, 4), which maybe fatal (4–8). There are only two previous reportsof LTx for APS-1-associated autoimmune hepa-titis (6, 7). We report a child with APS-1 and acute

liver failure who was successfully treated with anOLTx.

Case report

A 14-yr-old boy was transferred to our unit for themanagement of acute liver failure. He was one offour children of non-consanguinous parents.There was no family history of autoimmune dis-ease. APS-1 had been suspected 4 yr previouslyafter the patient had presented with symptomatichypoparathyroidism. He had enamel hypoplasiaand dystrophic fingernails, although repeated nailscrapings did not demonstrate Candida infection.He had no evidence of additional endocrinopathy.Subsequent genetic analysis for the common 13-bp deletion (964del13) of the AIRE-1 gene in UKkindreds demonstrated one abnormal allele (9).Three years later he developed chronic diarrheaand steatorrhea, together with benign intra-cranial hypertension. The latter was determined

Abbreviations: AADC, aromatic L-amino acid decarboxylase; AIRE-

1, autoimmune regulator gene; ALP, alkaline phosphatase; ALT,

alanine aminotransferase; APECED, autoimmune polyendocrino-

pathy–candidiasis–ectodermal dystrophy; APS-1, autoimmune poly-

glandular syndrome type 1; CMV, cytomegalovirus; CT, computer-

ized tomography; CYP2D6, cytochrome P450 2D6; INR, interna-

tional normalized ratio; LTx, liver transplantation; MMF, myco-

phenolate mofetil; OLTx, orthotopic liver transplantation.

Pediatr Transplantation 2002: 6: 166–170

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Pediatric TransplantationISSN 1397-3142

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by the finding of bilateral papilledema at routineophthalmic review, an elevated cerebrospinal fluidpressure, and a CT brain scan which showed smallventricles and calcification of the basal ganglia.He was treated with acetazolamide.

Six months prior to referral, the patientdeveloped asymptomatic liver disease character-ized by a mildly elevated ALT level (approxi-mately twice the upper limit of normal) and aslightly prolonged prothrombin time (INR51.4).An autoantibody screen, including liver, kidney,microsomal, smooth muscle, and adrenal anti-bodies, was negative. Acetazolamide was discon-tinued but his ALT remained elevated and a liverbiopsy was planned. However, 1 week prior totransfer he developed jaundice and was admittedto his local hospital. His liver function deterio-rated rapidly and, despite commencing intrave-nous corticosteroids, he continued to deteriorateand developed grade 3 encephalopathy requiringsedation and ventilation. He was transferred toour unit to be assessed for LTx.

On examination he appeared jaundiced but hadno stigmata of chronic liver disease and nohepatosplenomegaly. Ophthalmic examinationrevealed no Kayser-Fleischer rings and normalfundi.

Investigation results were as follows: prothrom-bin time, 37 s (INR 3.1); bilirubin, 118 mmol/L(normal range 3–15 mmol/L); ALT, 1,181 IU/L(normal range 0–35 IU/L); ALP, 1002 IU/L(normal range 70–300 IU/L); albumin, 31 g/L(normal range 37–49 IU/L); calcium, 2.16 mmol/L (normal range 2.2–2.6 mmol/L); and phos-phate, 1.0 mmol/L (normal range 0.8–1.3 IU/L).The patient’s blood group was B positive. Viralserology was negative for hepatitis A, B, and C,and for CMV, Epstein–Barr virus, herpes simplexvirus, and human immunodeficiency virus. Serumimmunoglobulin concentrations were within thenormal range. An autoantibody screen, whichincluded anti-nuclear, anti-mitochondrial, andliver, kidney, microsomal antibodies was nega-tive; anti-smooth muscle antibodies were negativeon one occasion and weakly positive (1 : 20) onanother. Serum ceruloplasmin and a1-anti-tryp-sin levels had previously been recorded as normal.

A CT brain scan showed no signs of raisedintracranial pressure and this was confirmed afterinsertion of an intracranial pressure monitor.However, in view of grade 3 encephalopathy, theextremely poor prognosis for acute liver failure inAPS-1, and his rapidly deteriorating liver func-tion, he was listed for LTx and received a full-sizedgraft from a group O positive, CMV-positivedonor, 2 days later. Primary immunosuppression

was with corticosteroids and tacrolimus, andCMV prophylaxis was with gancyclovir.

The immediate post-operative course wascomplicated by the development of hepaticarterial anastomotic stenosis on the fifth post-operative day. The anastomosis was reviseduneventfully and an intra-operative liver biopsydemonstrated moderately severe acute cellularrejection, which was treated with pulsed high-doseintravenous methylprednisolone (10 mg/kg). Onpost-operative day 28, a repeat liver biopsy wasperformed following a rise in plasma ALT. Thisdemonstrated mild ongoing acute cellular rejec-tion and no features suggestive of diseaserecurrence. MMF was added to his maintenanceimmunosuppression.

The patient was discharged home 32 days aftertransplantation. Eight weeks later he was re-admitted with an episode of febrile neutropeniaassociated with a serologically proven parvovirusinfection. MMF and gancyclovir were discontin-ued and he made a rapid and complete sponta-neous recovery. Ten months later he is fully activeand well, with normal liver function tests. Hiscurrent immunosuppressive regimen comprisesprednisolone 0.1 mg/kg/day and tacrolimus0.06 mg/kg/day (therapeutic levels 5–10 ng/mL).He has been maintained on a prophylactic doseof fluconazole because of the risk of develop-ing mucocutaneous candidiasis associated withAPS-1.

Histology

The explanted liver weighed 530 g and appearedpale and shrunken with several areas of confluentnecrosis, and elsewhere a nutmeg appearance ofsurviving parenchyma, without regenerativenodules. Gallstones were present in the gallblad-der. Histologic examination confirmed extensiveareas of confluent multi-acinar necrosis withcollapse and ductular proliferation (Fig. 1a).Elsewhere there was peri-venular and bridgingnecrosis with minimal portal tract inflammationbut variable mild-to-moderate interface hepatitis(Fig. 1b). There were scanty plasma cells in theinflammatory cell infiltrate and no rosetting ofhepatocytes. The bile ducts were not affected bythe inflammation. Stains for iron, copper-asso-ciated protein, and evidence of a1-anti-trypsindeficiency were negative. Hepatocytes showedoccasional acidophil bodies but without anylobular inflammation; there was evidence ofregeneration with extensive twinning of liver cellplates and canalicular cholestasis.

The histology was of a sub-acute hepatitis, con-sistent with autoimmune hepatitis; the relatively

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mild inflammatory cell infiltrate may have beenthe result of suppression by intravenous corticos-teroids in the week preceding the transplant.

Discussion

The autoimmune endocrinopathies are character-ized by autoimmune-mediated destruction of en-docrine tissues (1). APS-1 is a rare autosomal-recessive condition caused by a defect in theAIRE-1 or APECED gene, located on the longarm of chromosome 21 (10). This gene encodes theAIRE protein, which is expressed in the thymus,lymph nodes, spleen, and fetal liver, probablyfunctioning as a transcription regulator. At least30 different mutations in the AIRE-1 gene havenow been described in patients with APS-1 (11,12). APS-1 typically includes the triad of hypo-parathyroidism, autoimmune Addison’s disease,and chronic mucocutaneous candidiasis. Onset isusually in childhood and multiple autoimmunemanifestations gradually develop throughout life

(3). These include hypergonadotropic hypogon-adism, insulin-dependent diabetes mellitus, auto-immune thyroid disease, hypopituitarism, chron-ic atrophic gastritis, hepatitis, and vitiligo (3, 4).Gastrointestinal fat malabsorption occurs in< 20% of patients and has been linked to adeficiency of cholecystokinin-producing entero-endocrine cells in the mucosa of the proximalsmall intestine (13). Associated non-endocrineconditions include ectodermal dystrophy, enamelhypoplasia, and keratoconjunctivitis. The numberof disease components in affected individualsvaries from one to eight with a mean of four. Thediagnosis of APS-1 in our case was based on thecombination of hypoparathyroidism, dystrophicnail changes, hypoplasia of the dental enamel,chronic diarrhea and steatorrhea, and the findingof one abnormal AIRE-1 allele.

Autoimmune hepatitis develops in 10–20% ofpatients with APS-1 (3–5). In a series of 41patients from Italy, eight had hepatitis, one ofwhom died at 11 yr of age from acute liver failure(4). In another series of 68 patients from Finland,12 had hepatitis and there were two deaths fromacute liver failure in patients aged 7 and 17 yr (3).Both of the latter patients had normal plasmatransaminase levels shortly before the onset ofacute liver failure. In patients with APS-1,periodic determination of liver enzymes andautoantibodies and a high index of suspicionmay allow early diagnosis and treatment ofhepatic complications.

The autoimmune nature of hepatitis is con-firmed by the demonstration of autoantibodies,histological features, and exclusion of alternativecauses. The diagnostic criteria for autoimmunehepatitis (as defined by the InternationalAutoimmune Hepatitis Group) include clinical,serological, and immunological parameters. Ourpatient would be defined as having probableautoimmune hepatitis by these criteria (14). Therewas no evidence of other causes of liver disease, hehad other autoimmune features, and his liverhistology was consistent with autoimmune hepa-titis. The histological appearances of APS-1-asso-ciated autoimmune hepatitis are an inflammatoryinfiltrate of predominantly lymphocytes andplasma cells with a variable degree of piecemealnecrosis (6, 7).

In previous reports, the liver disease associatedwith APS-1 has often been poorly characterized.It has not always fulfilled the criteria forautoimmune hepatitis, and frequently hypergam-maglobulinemia and serological evidence ofautoantibodies have been absent (4, 6, 7). Liver–kidney–microsomal antibodies have been found

(a)

(b)

Fig. 1. (a) An area of confluent, multi-acinar necrosis show-ing collapse of reticulin, complete absence of hepatocytes, andprominent ductular proliferation around portal areas (arrow-ed) (hematoxylin and eosin staining; 320 magnification). (b)High-power view of a periportal area showing moderateinterface hepatitis and swelling of hepatocytes (hematoxylinand eosin staining; 3200 magnification.)

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in some, but not all, APS-1 patients with hepatitis,and may predate biochemical evidence of liverdisease (4, 8, 15). Sera from APS-1 patients do notreact with CYP2D6, the major hepatic autoanti-gen in idiopathic autoimmune hepatitis type 2 (1,8, 16). Recent studies in patients with APS-1-associated hepatitis have shown that the targetantigens are the cytochromes CYP1A2 andCYP2A6 in the liver microsomes (8, 15, 16).Autoantibodies to these antigens have not yetbeen found in patients with other varieties ofautoimmune liver disease (8, 15). Anotherenzyme, AADC, present in neuroendocrinetissue and kidney as well as in liver, has alsobeen identified as an autoantigen in APS-1, but isnot specific for liver disease (15). In a study ofeight Scandinavian patients, autoantibodies toAADC were detected in all, but CYP1A2 auto-antibodies were only found in the three patientswith APS-1 and autoimmune hepatitis (15).

There is a paucity of information in theliterature regarding the treatment and outcomeof patients with APS-1-associated autoimmunehepatitis. Treatment with prednisolone, with orwithout azathioprine, can reduce inflammationand improve liver function in affected children (6).Untreated cases progress to hepatic fibrosis andcirrhosis (7, 17). To our knowledge, there are onlytwo published reports of OLTx for APS-1-asso-ciated autoimmune hepatitis. A 10-yr-old girl withAPS-1 developed acute hepatic decompensation4 yr after first developing symptoms of liverdisease; she died despite an emergency livertransplant but the cause of death was not specified(6). In the second case, a liver transplant wasperformed electively for cirrhosis secondary tochronic active hepatitis ina 20-yr-old man whofirstdeveloped abnormal liver function tests at the ageof 10 yr (7). The patient was well 4 yr later. There iscurrently no information on the risk of recurrentautoimmune hepatitis after transplantation inpatients with APS-1. However, some features ofthe syndrome (gastrointestinal dysfunction, alo-pecia, keratoconjunctivitis, and possibly diabetesmellitus) have shown a dramatic response toimmunosuppressive therapy (10, 18). It is interest-ing to note that our patient’s diarrhea appears tohave resolved and his hypocalcemia has beenrelatively easy to control in the period since histransplant.

Our case is the first report of successful OLTxfor acute liver failure in APS-1-associated auto-immune hepatitis. Early detection and treatmentof autoimmune hepatitis in APS-1 may preventthis complication. It is known that aggressiveimmunosuppressive therapy may avoid the need

for transplant in children with early acute liverfailure secondary to type 2 autoimmune hepatitis(19). Nevertheless, LTx appears to be an effectivetherapy for patients with acute liver failureassociated with APS-1.

Acknowledgments

We wish to thank our colleagues at St James’s University Hospital in

Leeds for their assistance with the pediatric liver transplant program

and Professor Giorgina Mieli-Vergani for her helpful advice when

considering this patient for transplantation.

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