Successful liver transplantation in a childwith Caroli�s disease

CD is a rare autosomal recessive disease, char-acterized by multifocal cystic dilatation of intra-hepatic bile ducts caused by a congenital walldysplasia of bile ducts. The disease is frequentlyaccompanied by pancreatic cysts and cystic renaldisease, specifically renal tubular ectasia ormedullary sponge kidney (1). The disease man-ifests at any age with recurrent fever, abdominalpain, and variable jaundice (2). The course of thedisease is characterized by intrahepatic choleli-thiasis, recurrent episodes of cholangitis, becauseof cholelithiasis, intrahepatic abscesses and oftenending in death as the result of uncontrolledinfection. Endoscopic drainage of the bile duct ispalliative and ineffective (3). OLT appears to be

the treatment of choice in bilobar CD. Inmonolobar cases, partial liver resection has beenshown to be a curative therapeutic option (2–4).

Case report

We report on a Turkish girl, who presented forthe first time in our clinic when she was 4.5 yrold. At the age of three wk, after normalpregnancy and birth, she developed hepato-megaly and recurrent fever. Sonographic andcomputertomographic imaging had shownremarkable saccular dilatation of the intrahepaticbile ducts suspicious for CD. At the age of fourmonths polycystic renal dysplasia of the rightkidney had been found and at the age of ninemonths polycystic renal dysplasia of both kid-neys had been diagnosed by ultrasound. Anti-biotic prophylaxis was started, but givenirregularly. In the course, the girl showed recur-rent septicemia and hepatomegaly. The episodeswere interpreted as cholangitis and treated with

Meier C, Deutscher J, Muller S, Haluany K, Fangmann J, SiekmeyerW, Richter T, Kiess W. Successful liver transplantation in a child withCaroli�s disease.PediatrTransplantation2008:12:483–486.�2008BlackwellMunksgaard

Abstract: CD is a rare autosomal recessive disease, characterized bymultifocal cystic dilatation of intrahepatic bile ducts. The course of thedisease is characterized by intrahepatic cholelithiasis, recurrent episodesof cholangitis, because of cholelithiasis, hepatic abscesses often endingin death caused by uncontrolled infection. Other conditions such ascholedochal cyst and renal cystic disease are frequently associated, andpatients have a higher risk for the development of cholangiocarcinoma.Endoscopic drainage of the bile duct is palliative and ineffective. OLTappears to be the treatment of choice. In monolobar cases partial liverresection has been shown to be a curative therapeutic option. We reporton the course of disease in a Turkish girl who was diagnosed with CD inthe neonatal period. At the age of 8.2 yr, she received OLT and is ingood health 57 months post-transplantation.

Constance Meier1, Jens Deutscher1,Susanna M�ller2, Karin Haluany3,Josef Fangmann4, Werner Siekmeyer1,Thomas Richter5 and Wieland Kiess1

1Hospital of Children and Adolescents, University ofLeipzig Medical Centre, Leipzig, Germany, 2Instituteof Pathology, University of Leipzig Medical Centre,Leipzig, Germany, 3Curatorium for Dialysis and KidneyTransplantation; Centre for Kidney Disease ofChildren and Adolescents, Staedtisches Klinikum "St.Georg," Leipzig, Germany, 4Department of Visceral-and Transplant-Surgery, University of Leipzig MedicalCentre, Leipzig, Germany, 5Department for Childrenand Adolescents, Staedtisches Klinikum "St. Georg,"Leipzig, Germany

Key words: children – chronic renal failure –congenital liver disease – pediatric – livertransplantation

Constance Meier, Hospital for Children andAdolescents, University of Leipzig, Oststrasse 21-25,04317 Leipzig, GermanyTel.: +49 341 972 6093Fax: +49 341 972 6099E-mail: constance.meier@medizin.uni-leipzig.de

Accepted for publication 20 November 2007

Abbreviations: BW, body weight; CD, Caroli�s disease;CKD, chronic kidney disease; CNI, calcineurin inhibitors;GFR, glomerular filtration rate; MCL, medioclavicularline; OLT, orthotopic liver transplantation; PTLD, post-transplantation lymphoproliferative disorders.

Pediatr Transplantation 2008: 12: 483–486 Copyright � 2008 Blackwell Munksgaard

Pediatric TransplantationDOI: 10.1111/j.1399-3046.2007.00879.x

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metronidazol. Only with the beginning of along-term treatment with trimetoprime (5 mg/kgBW) the girl felt well and was asymptomatic.At the initial presentation in our clinic the girl

was in good clinical condition, with abdominaldistension, palpable hepatosplenomegaly (4 cmMCL) and multiple palpable, various sizedtumors in the area of the left kidney. There wereno signs of infection. In the abdominal sonogra-phy and computertomography cystic dilatationof the intrahepatic bile ducts, partly with calci-fications, was found, especially in the righthepatic lobe, as well as hepatic fibrosis and anenlarged gall bladder with small concrements(Fig. 1a). Both kidneys were enlarged and isohe-patic echogenic with lost corticomedullar differ-entiation and numerous minute cysts. Spleen andpancreas appeared normal. During gastroscopyvarices (stages II–III according Denck) were

found in the distal esophagus, highly temptingto bleed. Supportive therapy with ursodesoxy-cholic acid, propranolol, iron and again antibi-otic long-term therapy with trimetoprime (5 mg/kg BW) was started. Regular outpatient visitsduring the next two yr showed no progressionand the patient was well.At the age of seven yr, the girl presented with

hypersplenic syndrome, severe arterial hyperten-sion (150/120 mmHg) and a progression of theesophageal varices (stage III acc. Denck, stage IVacc. Dagradi). Some of the varicous veins wereligated. A month later, severe bleeding of fundusvarices had to be treated by endoscopic injectionof histoacryl. At this time 13C-aminopyrinebreath test [0.49% dosis · kg BW · (mmolCO2)]showed impaired liver function. Other laboratoryvalues, except a decreased creatinine clearance,were within the normal range.The girl was presented to the transplantation

unit of the department of surgery/University ofLeipzig. To bridge the acute complication ofvaricous bleeding and to avoid progression ofportal hypertension a distal splenorenal shunt(Warren-shunt) was established. During thisprocedure a liver biopsy was taken and electiveappendectomy was performed. Histopathologicalevaluation of the liver biopsy showed broadconfluent portal fibrosis with proliferation anddilatation of bile ducts with marked cholestasis(Fig. 2a). All members of the caring teamincluding pediatric gastroenterologist and hepa-tologist as well as pediatric nephrologist, trans-plant surgeons and psychologists discussed thiscase carefully considering all effects of a possibleliver transplantation especially the impact ofimmunosuppressive therapy on renal functionthat was already affected by CD. In addition, thepossibility of a combined liver and renal trans-plantation from the same donor later in thecourse of the disease was considered, knowingthat the long-term renal outcome might be better.Also the immense psychological impact of trans-plantation was discussed since there had beenpsychosocial problems earlier in the course andsince so far professional psychological supportwas refused by the patient and her family.However, the girl already showed manifest livercirrhosis with impaired liver function for exampleas assessed by 13C-aminopyrine breath test. Overthe years liver function had declined, multiplesepticemic episodes because of cholangitis andseveral varicous bleedings had been life-threat-ening. On the other hand having a patient instable clinical condition prior to transplantationthe post-transplant outcome is known to bebetter. In summary, after this reasoning, the

(a)

(b)

Fig. 1. Computed tomography showing hepatic fibrosis,cystic dilatation of the intrahepatic bile ducts, partly withcalcifications, especially in the right hepatic lobe and anenlarged gall bladder with small concrements (a) and in-traoperative picture of the explanted enlarged liver in a girlwith Caroli�s disease (b).

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decision for liver transplantation was agreedupon by the caring pediatric gastroenterologistand hepatologist, pediatric nephrologist, thetransplant surgeons, and our psychologists.At the age of 8.2 yr, when the girl was in good

clinical condition without any infectious signs,OLT was performed. The patient received a fullsize pediatric organ. Intraoperatively an impres-sive picture of the affected organ was found(Fig. 1b) with dilatation of bile ducts and severeintrahepatic purulent foci (Fig. 2b), althoughpreoperatively laboratory inflammatory signswere only slightly elevated. Postoperative coursewas complicated by a perihepatic hematoma,pleural and pericardial effusions and the devel-opment of temporary insulin dependent diabetesmellitus. Immunosuppressive therapy was startedwith triple therapy consisting of tacrolimus,mycophenolate mofetil and prednisolone. Anti-hypertensive therapy was routinely applied.Recurrent varicella developed and was treated

with i.v. acyclovir. Renal function declined froma GFR of 122 to at present 85 mL/min/1.73 m2,while liver function remained stable except forvitamin K (10 mg/wk) dependent decrease ofthromboplastin time.The course over the 57 months follow-up was

complicated by repeated minor psychologicaland psychosocial problems. Professional psycho-logical support again was refused. However, thepatient and her family show fair compliance/adherence. At present the girl is in good clinicalcondition, shows good liver function, no venouscongestion and no signs of chronic rejection.

Discussion

Septicemia because of recurrent cholangitiscaused by cholestasis is a common complicationof CD. The antibiotic therapy is complicated bybacterial resistance, intrahepatic cysts and lithi-asis, which allow microbial persistence. Becauseof chronic inflammation and epithelial dysplasiaof bile ducts patients with CD have an increasedrisk of developing cholangiocarcinoma. In theliterature the coincidence of CD and this malig-nant disease is 5–10% (5). In patients with adiffuse form of CD, associated with complica-tions, OLT is treatment of choice with prospectof long-term survival and prevention of cholan-giocarcinoma (3, 4). Liver transplantation inchildren has become an accepted modality oftreatment in end-stage liver disease and irrevers-ible acute liver failure. Today an excellent qualityof life with complete rehabilitation can beachieved in most children after liver transplan-tation. Biliary atresia is the most commonindication requiring liver transplantation inchildhood. The most serious, life-threateningearly and late complications are bacterial infec-tions and PTLD (6). Especially in patients withCD liver transplantation should be proposed as adefinitive therapeutic option once severe cholan-gitis or (suspicion of) malignant transformationis present. The frequently used radiological,endoscopical or surgical biliary drainage proce-dures carry a high morbidity and mortality rate.Liver transplantation in pediatric patients withCD has been reported rarely. So far the youngestpatient reported in detail in respect to clinicalfollow-up and history of disease was 11 yr old attime of transplantation (7). In our patient livertransplantation was performed after a course ofthe disease of eight yr. During the pretransplantcourse, several complications like septicemicepisodes, esophageal and fundus varices withlife-threatening bleeding and hypersplenismoccurred. In the explanted liver severe

(b)

(a)

Fig. 2. Liver biopsy of a girl with Caroli�s disease showingbroad confluent portal fibrosis with proliferation and dila-tation of bile ducts. Goldner, 16· (a) and intraoperativepicture of the explanted enlarged liver with dilatation of bileducts and intrahepatic purulent foci (b).

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intrahepatic purulent foci were found, thoughpreoperatively the girl had no clinical signs ofinfection and in addition laboratory inflamma-tory signs had only slightly been elevated.Significant CKD is a known problem follow-

ing OLT. In parts the prolonged use of CNI,cyclosporin A or tacrolimus is associated withthe development of CKD resulting from thenephrotoxic side effects of these drugs. Initially,these effects are reversible; however, there is arisk of structural damage such as glomerularsclerosis and tubular atrophy after chronicexposure. CKD management should be startedas early as six months after transplantation toinfluence outcomes of OLT recipients. To protectthe kidney after OLT CNI levels should bereduced to as low as possible and use ofalternative drugs should be considered. Themedian blood pressure should be within the50th percentile. Controls of GFR and bloodlevels of immunosuppressive agents as well asrenal sonography should be done regularly. Ourpatient received prednisolone, tacrolimus andmycophenolate mofetil as immunosuppressivetherapy directly post-transplantation, later onprednisolone was weaned. Sixteen months post-transplantation the patient showed chronic renalinsufficiency stage 2. However, although the girlhad still normal renal function, she showedpolycystic renal dysplasia of both kidneys witharterial hypertension because of CD alreadybefore OLT.At present, 57 months of follow-up after OLT

the girl is in excellent clinical condition with

stable renal function, normal growth and devel-opment, shows good liver function, no venouscongestion and no signs of an acute or chronicrejection.Our case shows that if liver transplantation in

a patient with bilobar CD at an early age isnecessary it can be successful. One has toconsider carefully and has to keep in mind thepossible side effects, especially the impact ofimmunosuppressive therapy on renal function.The long-term renal outcome might be betterwith a combined liver and kidney transplantationfrom the same donor. Psychological support ofthe patient and his/her family throughout thecourse is of high importance.

References

1. Taylor AC, Palmer KR. Caroli�s disease. Eur J Gastroenterol

Hepatol 1998: 10: 105–108.

2. Kassahun WT, Kahn T, Wittekind C, et al. Caroli�s disease:

Liver resection and liver transplantation. Experience in 33 pa-

tients. Surgery 2005: 138: 888–898.

3. Waechter FL, Sampaio JA, Pinto RD, et al. The role of liver

transplantation in patients with Caroli�s disease. Hepatogas-

troenterology 2001: 48: 672–674.

4. Ulrich F, Steinmuller T, Settmacher U, et al. Therapy of

Caroli�s disease by orthotopic liver transplantation. Transplant

Proc 2002: 34: 2279–2280.

5. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann

Oncol 1999: 10: 308–311.

6. Goss JA, Shackleton CR, McDiarmid SV, et al. Long-term

results of pediatric liver transplantation. An analysis of 569

transplants. Ann Surg 1996: 228: 411–420.

7. De Kerckhove L, De Meyer M, Verbaandert C, et al. The

place of liver transplantation in Caroli�s disease and syndrome.

Transpl Int 2006: 19: 381–388.

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