--->

The Turkish Journal of Pediatrics 2005; 47: 63-66 Case

Neonatal lupus erythematosus presenting with cholestatichepatitis: a case report and review of the literature

Fatih Erbey1, Abdullah Çuhacý2, Faruk Ýncecik1, Aytül Noyan1, Derya Ufuk Altýntaþ1

Ýlhan Tuncer3, Figen Duran3

Departments of 1Pediatrics, 2Family Health, and 3Pathology, Çukurova University Faculty of Medicine, Adana, Turkey

SUMMARY: Erbey F, Çuhacý A, Ýncecik F, Noyan A, Altýntaþ DU, Tuncer Ý,Doran F. Neonatal lupus erythematosus presenting with cholestatic hepatitis:a case report and review of the literature. Turk J Pediatr 2005; 47: 63-66.

Neonatal lupus erythematosus (NLE) is a disease primarily characterized bycardiac and/or cutaneous involvement. Hepatic, hematological, neurological andpulmonary involvement are rare manifestations and normally considered asmild and transient complications. But recent studies have shown more frequenthepatic involvement in NLE. We report a two month-old male infant, born toa clinically asymptomatic mother, presenting with significant hepaticinvolvement and annular, erythematous plaques with hyperkeratotic bordersat the eyebrow region and anterior surface of trunk. Both the infant and hismother were positive for anti-Ro (SS-A) and anti-La (SS-B).

Key words: neonatal lupus erythematosus, cholestatic hepatitis.

Neonatal lupus erythematosus (NLE) is a diseaseprimarily characterized by cardiac and/orcutaneous involvement. Hepatic, hematological,neurological and pulmonary involvement are raremanifestations and normally considered as mildand transient complications. These children havemothers with systemic lupus erythematosus(SLE), Sjögren�s syndrome (SS), other systemicrheumatic diseases, or their mothers areasymptomatic. NLE is characterized by thetransplacental passage of auto antibodies, inparticular anti-Ro (SS-A), and anti-La (SS-B), orboth, from the mother to the fetus1. We reporta case of NLE who presented with cholestatichepatitis.

Case Report

A two-month-old male infant, 15 days after birth,presented with annular, erythematous plaquesof several millimeters in diameter with sharp,hyperkeratotic borders at the eyebrow region andanterior surface of trunk (Fig. 1). Physicalexamination revealed hepatosplenomegaly andjaundice. Liver function studies revealed a mildincrease of aspartate aminotransferase(AST: 403 U/L), alanine aminotransferase(ALT: 155 U/L), and gamma glutamyl

Fig. 1. A two-month-old male infant presented withannular, erythematous plaques of several millimeters in

diameter with sharp, hyperkeratotic borders at theeyebrow region and on the anterior surface of the trunk.

transpeptidase (GGT: 358 U/L). His bilirubinlevels, with a predominance of direct billirubin(9.1 mg/dl), were also increased. A hepatobiliaryscintigraphy showed a decreased hepatic uptakewith no passage through the intrahepatic bile

<---

Fig. 2. Epidermal hyperkeratosis, basal cell liquefaction,and dermal perivascular and periadneal lymphocyte and

plasmocyte infiltration are seen; degeneration atdermal collagen is also noted (HE X 200).

Fig. 3. Nodular regenerative hyperplasia andmicrovesicular fatty degeneration in the liver (HE X 100).

ducts. His complete blood count, electro-cardiogram and echocardiography were normal.No proteinuria was seen in urine analysis.Histopathological examinations of the skinbiopsy showed hyperkeratosis in epidermis, basalcell liquefaction, a mild perivascular andperiadneal mononuclear infiltration, minimaledema, and dermal collagen degeneration indermis (Fig. 2). Immunohistochemical stainingof the skin specimen showed IgG deposition atthe dermoepidermal junction, and granulardeposition of IgG, IgA and IgM at the vascularwall. Both the infant and his mother werepositive for anti-Ro (SS-A) and anti-LA (SS-B).In addition, the mother had positive antinuclearantibodies (ANA). He was treated with topicalsteroid creams.

When the patient was four months old, AST,ALT and, direct bilirubin levels were 179 U/L,104 U/L and 3.8 g/dl, respectively.Hepatosplenomegaly and milder skin lesionswere still present. Systemic steroid treatmentwas started with a dose of 2 mg/kg/day. Onemonth after beginning systemic steroid therapy,direct bilirubin level had decreased to 0.65 g/dland hepatosplenomegaly regressed, but AST andALT levels were still high. At the 2nd month ofsystemic steroid therapy, due to developmentof pneumonia and cushingoid appearance.Systemic steroid treatment was stopped until

control of infection was achieved. At 4th monthof therapy anti-La (SS-B) was negative, andsplenomegaly and skin lesions had resolved.Hepatomegaly and high levels of AST and ALTwere still present. Systemic steroid dose washalved to 1 mg/kg/day and two weeks latercontinued with a dose of 1 mg/kg every twodays. Because of persistent hepatomegaly andelevated AST and ALT levels, liver biopsy wasdone, and histopathological examinations of theliver biopsy showed nodular regenerativehyperplasia and microvesicular fattydegeneration (Fig. 3). At 10th month oftreatment (age: 14 months), (Fig. 4), anti-Ro(SS-A) was negative, and AST and ALT levels hadregressed to 60 U/L, respectively. Tapering ofsystemic steroid therapy was started. Duringfollow-up of the patient, no cardiac, hematologicalor any other abnormal findings was observed.

His mother had only a positive ANA test as asign of SLE. She is currently being followed forSS and/or SLE/SS due to positive anti-Ro (SS-A)and anti-La (SS-B).

Fig. 4. A picture of the patient at 10th month oftreatment (aged 14 months), showing complete

resolution of the skin lesions.

64 Erbey F, et al The Turkish Journal of Pediatrics � January - March 2005

--->

Discussion

Neonatal lupus erythematosus is a rare diseaseof cutaneous lupus, congenital complete heartblock (CHB), or both, and/or other systemicmanifestations, which appear in children ofwomen with SLE, SS, other systemic rheumaticdiseases, or in children of asymptomatic mothers1.NLE is characterized by the transplacental passageof auto antibodies, in particular anti-Ro (SS-A)and anti-La (SS-B), or both, from mother to fetus.In our case, the mother was asymptomatic andboth the boy and his mother were positive foranti-Ro (SS-A) and anti-La (SS-B).

Almost half of NLE patients have CHB, andtwo-thirds of these habies are females. TheCHB is complete in most reported cases. Otherdescribed rare cardiac inflammatory forms arepericarditis, myocarditis, cardiomyopathy andLibman-Sacks endocarditis1. CHB carries asignificant mortality (15-30%) and morbidity:two-thirds of children require permanentpacing2.

Approximately 40-50% of patients with NLEhave cutaneous findings, and three-fourths arefemales. The skin rashes consist of annular,erythematous, scaly, hyperkeratotic, macular,papular or plaque-like lesions with centralclearing on mostly sun-exposed areas, such asface, scalp, trunk and extremities. These rashesare similar to those seen in SLE and/or discoidlupus erythematosus. Cutaneous manifestationof NLE usually does not require muchtreatment beyond the avoidance of sunexposure and use of sunblock and topicalhydrocortisone cream. They typically last for 2-6 months and disappear without leaving a scar;sometimes minimal atrophy, telangiectasis, orhyperpigmentation is reported. The skin biopsyof rashes reveals findings of hyperkeratosis,follicular plugging, acanthosis, atrophy, andliquefactive degeneration of keratinocytes1,3,4.

In our case, skin lesions were annular,hyperkeratotic with sharp borders and locatedon face and trunk, and appeared in the firstmonth of life. The skin biopsy examination withhistopathological and immunohistochemicalstudies confirmed the diagnosis of NLE. Skinlesions repond to moderate-to-potent topicalsteroid treatment.

In previous studies, liver involvement in NLE hasbeen mentioned as a rare condition. A total of294 babies with NLE had been described by the

end of the 1991. Of these babies, 54.4% had CHB,37.1% had cutaneous NLE, 7.1% had both, andonly 1.4% had other manifestations. Hepaticinvolvement was seen in 7.8% of patients havingcardiac and/or cutaneous involvement1. In recentstudies it has been reported that at least 10% ofNLE cases have liver involvement5. Rosh et al6.reported hepatomegaly and elevation oftransaminases in 20-40% of infants with NLE. Leeet al7. found hepatic disease in 4 of 35 (114%)NLE patients. Laxer et al8. reported that the liverinvolvement is more frequent than previouslydescribed. Especially in prospective studies,mothers of infants with idiopathic neonatalhepatitis should be explored for auto antibodies8.In hepatic involvement, hepatomegaly,splenomegaly, elevations of transaminases,jaundice, cholestasis, cirrhosis and seriousgastrointestinal bleedings can be seen. But themajor clinical picture is cholestasis5,7. The liverbiopsy shows non-infectious hepatitis, neonatalgiant cell hepatitis, intra and extracellularcholestasis, ductal and ductular hyperplasia, portalseptal fibrosis, cirrhosis, excessive extramedullaryhematopoiesis, and IgG deposits1,7.

Lee et al.5 described three clinical variants ofhepatobiliary disease in their recent series:1- severe liver failure presenting duringgestation or in the neonatal period, often withthe phenotype of neonatal iron storage disease;2- conjugated hyperbilirubinemia with mild orno elevations of aminotranferases, occurring inthe first few weeks of life; and 3- mildelevations of aminotransferases occurring atapproximately two to three months of life. Theyreported that the prognosis for children in thelatter two categories is excellent, and frequentlythey do not need treatment5. Evans et al9.reported that patients with hepatic involvementheal spontaneously in six months9. The liverbiopsy revealed nodular regenerativehyperplasia and microvesicular fattydegeneration. Nodular regenerative hyperplasiais a rare liver biopsy finding of SLE patients.Matsumota et al10. found nodular regenerativehyperplasia in liver biopsy materials taken from3 of 52 SLE patients. Colina et al.11 definedautoimmune disease in 5 (20.8%) of 24 patientswho had liver pathology findings of nodulardegenerative hyperplasia. Liver biopsy findingsof our case were compatible with NLE, butthere was no sign of cholestasis. We shouldkeep in mind that the liver biopsy of the case

Volume 47 � Number 1 Neonatal Lupus with Cholestatic Hepatitis 65

<---

was performed during steroid treatment andelevated direct bilirubin level had decreased tonormal before the biopsy.The literature on long-term follow-up ofchildren with NLE is limited. Fox et al12.described a patient with cutaneous lupus as aneonate who developed SLE at19 years of age.Jackson and Gulliver13 reported an infant withNLE who developed SLE at 13 years of age.Neiman et al3. followed up affected children fora mean period of 77 months (range, 1-204months). In four children, signs or symptomsof autoimmune disease were noted. One childdeveloped Hashimoto�s thyroiditis at sevenyears of age. Two developed juvenile rheumatoidarthritis (at 2 years and 5 years). Anotherdeveloped Raynaud�s phenomenon.Buyon et al14. reported that in 37 (71%) of52 subsequent pregnancies, no signs of NLE werereported in the children. Ten (19%) pregnanciesresulted in a second child with a skin rash. In threeadditional families, the next younger siblingshaving cutaneous manifestation of NLE was seenin 25%. Twenty of the 47 mothers became pregnantafter the birth of the child with cutaneous NLE.Seven (35%) children had no manifestations ofNLE. Notably, six (30%) subsequent children hadCHB, two in isolation and four in association witha skin rash. Seven (35%) of the subsequentchildren had cutaneous manifestations alone3.Julkunen et al15. reported that the risk of havinga child with CHB after a previous birth of anaffected child (with CHB) was 8%.Both this case and his mother are beingfollowed for development of possible disorders.

REFERENCES

1. Kitridou RC. The neonatal lupus syndrome. In: WallaceDJ, Hahn BH (eds). Dubois�Lupus Erythematosus(5th ed). USA: Williams and Wilkins; 1997: 1023-1935.

2. Buyon JP. Neonatal lupus: bedside to bench and back.Scand J Rheumatol 1996; 25: 271-276.

3. Neiman AR, Lee LAA, Weston WL, Buyon JP.Cutaneous manifestations of neonatal lupus withoutheart block: characteristics of mothers and childrenenrolled in a national registry. J Pediatr 2000;137: 674-680.

4. Corona R, Angelo C, Cacciaguerra MG, et al. Neonatallupus erythematosus. Cutis 2000; 65: 379-381.

5. Lee LA, Sokol RJ, Buyon JP. Hepatobiliary disease inneonatal lupus: prevalence and clinical characteristicsin cases enrolled in a national registry. Pediatrics 2002;109: e11.

6. Rosh JR, Silverman ED, Groisman G, Dolgin S, LeLeikoNS. Intrahepatic cholestasis in neonatal lupuserythematosus. J Pediatr Gastroenterol Nutr 1993;17: 310-312.

7. Lee LA,Reichlin M, Ruyle SZ, Weston WL. Neonatallupus liver disease. Lupus 1993; 2: 333-338.

8. Laxer RM, Roberts EA, Gross KR, et al. Liver diseasein neonatal lupus erythematosus. J Pediatr 1990;116: 238-242.

9. Evans N, Gaskin K. Liver disease in association withneonatal lupus erythematosus. J Pediatr Child Helath1993; 29: 478-480.

10. Matsumota T, Yoshmine T, Shimouchi K, et al. Theliver in systemic lupus erythematosus: pathologicanalysis of 52 cases and review of Japanese autopsyregistry data. Hum Pathol 1992; 23: 1151-1158.

11. Colina F, Alberti N, Solis JA, Martinez-Tello FJ. Diffusenodular regenerative ehyperplasia of the liver. Aclinicopathologic study of 24 cases. Liver 1989;9: 253-265.

12. Fox RJ, McCuistion CH, Schoch EP. Systemic lupuserythematosus. Association with previous neonatallupus erythematosus. Arch Dermatol 1979; 115: 340.

13. Jackson R, Gulliver M. Neonatal lupus erythematosusprogressing in to systemic lupus erythematosus. A 15year follow-up. Br J Dermatol 1979; 101: 81-86.

14. Buyon IP, Hiebert R, Copel J, et al. Autoimmune-associated congenital heart block: demographics,mortality, morbidity and recurrence rates obtained froma national neonatal lupus registry. J Am Coll Cardiol1998; 31: 1658-1666.

15. Julkenen H, Kaaja R, Wallgren E, Teramo K. Isolatedcongenital heart block: fetal and infant outcome andfamilial incidence of heart block. Obstet Gynecol 1993;82: 11-16.

66 Erbey F, et al The Turkish Journal of Pediatrics � January - March 2005