EDITORIAL

Caroli’s Disease and Liver TransplantationShahid Habib and Obaid S. Shaikh2

1Center for Liver Diseases, Iowa Health–Des Moines, Des Moines, IA; and 2Division of Gastroenterology,Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA

Received October 1, 2007; accepted October 3, 2007.

See Article on Page 11

Caroli’s disease is a rare indication for liver transplan-tation that accounts for 0.13% of all liver transplantsperformed in the United States.1 It was first describedin 1958 by the French physician Jacques Caroli (1902-1979).2 The disease is characterized by segmental dila-tation of the intrahepatic biliary tree, and it has anautosomal recessive inheritance pattern. In patientswith coexistent congenital hepatic fibrosis, it is termedCaroli’s syndrome. The disease often develops in asso-ciation with autosomal recessive polycystic kidney dis-ease.

Caroli’s disease belongs to the group of fibrocysticliver diseases that develop as a result of biliary ductalplate malformation. In the human embryo, liver devel-opment begins in the third week of gestation in the formof a hollow endodermal outgrowth from the ventral fo-regut or future duodenum into the mesodermal septumtransversum.3 The progenitor hepatic parenchymalcells or hepatoblasts soon align themselves as double-layered sheets in proximity with the vitelline capillaryplexus to create what is termed the ductal plate. At 12weeks of gestation, the ductal plate starts to remodel toform tubular and cylindrical structures accompaniedby resorption of excess epithelial cells. The ductal plateremodeling persists throughout the fetal life, with agradient directed from the hepatic hilum to the periph-ery that results in the formation of a network of bileducts within the portal tracts. The gallbladder, cysticduct, and extrahepatic biliary tree develop from thecaudal part of the embryonic endodermal projection.3

Defective ductal plate remodeling may involve all levelsof the intrahepatic biliary tree, with large duct involve-ment in Caroli’s disease and smaller portal bile ductmalformation in congenital hepatic fibrosis.4

The clinical course of Caroli’s disease is determinedby the underlying pathologic abnormalities. Biliary cys-tic dilatation and narrowing predispose patients to cho-lestasis and recurrent bouts of acute cholangitis thatmay become complicated with intrahepatic biliarystones, septicemia, liver abscesses, and cholangiocar-cinoma. With associated hepatic fibrosis, as seen inCaroli’s syndrome, portal hypertension develops thatmay lead to varices, ascites, and liver failure. Treatmentof such patients is therefore directed to alleviation ofcholestasis with ursodeoxycholic acid, management ofacute cholangitis with analgesia and antibiotics, andmanagement of complications related to portal hyper-tension. In the case of biliary obstruction, radiologic orendoscopic drainage procedures or laparoscopic or sur-gical deroofing is needed. In some patients with severe,localized, monolobar disease, hepatic resection may behelpful.5 However, for patients with extensive bilobardisease and/or recurrent bouts of cholangitis and thosewith complications related to portal hypertension, med-ical therapy and localized resection may not provide acure. Such patients may require liver transplantation.

Until recently, only small case series were availableregarding the application of liver transplantation amongpatients with Caroli’s disease.6,7 We published our single-center experience of 33 patients and noted graft and pa-tient survival comparable to the survival of patients whounderwent transplantation for other etiologies.8 Most ofour patients had clinical and/or histologic evidence ofrecurrent cholangitis and complications related to portalhypertension as indications for liver transplantation. Areport from the European Liver Transplant Registry pro-vided a limited description of 110 recipients with Caroli’sdisease. Several patients had pretransplant septic com-plications, and posttransplant cumulative graft and pa-tient survival was 68% and 76%, respectively.9

Abbreviation: MELD, Model for End-Stage Liver Disease.Address reprint requests to Obaid S. Shaikh, M.D., F.R.C.P., Division of Gastroenterology, Hepatology, and Nutrition, Center for Liver Diseases,University of Pittsburgh Medical Center, Kaufmann Medical Building, Suite 916, 3471 Fifth Avenue, Pittsburgh, PA 15213. Telephone: 412-802-3162; FAX: 412-647-9268; E-mail: obaid@pitt.edu

DOI 10.1002/lt.21379Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 14:2-3, 2008

© 2007 American Association for the Study of Liver Diseases.

In this issue of Liver Transplantation, Millwala et al.10

describe the outcome of 104 patients with Caroli’s dis-ease who were identified to have undergone liver trans-plantation over a 19-year period in the United Networkof Organ Sharing database. Ninety-six patients receivedliver allografts alone, whereas 8 patients underwentcombined liver and kidney transplantation. Data weredeficient regarding the indications for liver transplan-tation, but it was noted that 39% were hospitalized and8% were on life support at the time of transplantation.The Model for End-Stage Liver Disease (MELD) scorewas unavailable for most of the patients, but the meanserum level of bilirubin was 7.4 mg/dL, that of creati-nine was 1.3 mg/dL, and that of albumin was 3.3 g/dL.These data suggest that many patients likely had cho-lestasis and probably septicemia before transplanta-tion. Graft and patient survival was similar to that re-ported for transplantation for other etiologies, althoughno direct comparison is provided. It appears that sickerpatients with higher serum bilirubin levels and thosehospitalized or on life support were more likely to havepoor outcome after transplantation.

So, what shall we make of these findings? A follow-upstudy of patients with Caroli’s disease indicated that atleast 46% died over a period of 21 years, mainly fromsepticemia, liver abscesses, and liver failure.11 The cur-rent study does not provide adequate information re-garding indications for liver transplantation mainly be-cause of its retrospective nature and the limitedavailable information in the database. In our ownstudy, patients underwent transplantation either be-cause of recurrent episodes of cholangitis and sepsis orbecause of progressive liver failure and portal hyperten-sion.8 It is therefore reasonable to conclude that livertransplantation should be considered once medical op-tions are deemed ineffective and if liver resection is notapplicable. The authors propose a management algo-rithm for patients with Caroli’s disease that is based onsimilar principles. It is also apparent that many suchpatients are not likely to have a MELD score that willenable them to have high prioritization for organ allo-cation. Transplant centers will therefore need to re-quest exceptions to their regional review boards in or-der to get a higher MELD score as is applicable to otherconditions that do not cause marked abnormalities ofthe components of MELD. One striking feature of thisstudy is 100% 1-year survival in patients with com-bined liver and kidney transplantation. The reason forthis difference is not clear, but perhaps it is related tobetter liver functions among combined organ recipientsas they had normal mean serum bilirubin before trans-plant. Liver transplantation in such patients may bedriven by the availability of a renal allograft. Liver re-cipients with low pretransplant MELD scores have beenshown to have better outcome following transplantcompared to those with high MELD scores.12

Thus, Caroli’s disease is an important but infrequentindication for liver transplantation. Patients who developrecurrent episodes of acute cholangitis, liver abscesses, orcomplications related to portal hypertension and liver fail-

ure are appropriate transplant candidates. Patients withcholangiocarcinoma are unlikely to benefit from the pro-cedure.13 The reported success of liver transplantationcombined with neo-adjuvant chemoradiation applied to aselect group of patients with hilar cholangiocarcinomaneeds to be validated.14 Among patients with both liverdisease and renal failure, the decision regarding com-bined liver and kidney transplant versus liver transplan-tation alone is the subject of much debate, and a clearconsensus has not yet emerged.15

REFERENCES

1. Organ Procurement and Transplantation Network. Avail-able at: http://www.optn.org. Accessed September 2007.

2. Caroli J, Soupault R, Kossakowski J, Plocker L, Parad-owska. Congenital polycystic dilation of the intrahepaticbile ducts; attempt at classification [in French]. Sem Hop1958;34:488-495/SP.

3. MacSween RNM, Desmet VJ, Roskams T, Scothorne RJ.Developmental anatomy and normal structure. In: Mac-Sween RNM, Burt AD, Portmann BC, Ishak KG, ScheuerPJ, Anthony PP, eds. Pathology of the Liver. 4th ed. Lon-don: Churchill Livingstone; 2002:1-66.

4. Desmet VJ. Congenital diseases of intrahepatic bile ducts:variations on the theme “ductal plate malformation”.Hepatology 1992;16:1069-1083.

5. Kassahun WT, Kahn T, Wittekind C, Mossner J, Caca K,Hauss J, et al. Caroli’s disease: liver resection and livertransplantation: experience in 33 patients. Surgery 2005;138:888-898.

6. Sans M, Rimola A, Navasa M, Grande L, Garcia-Valdeca-sas JC, Andreu H, et al. Liver transplantation in patientswith Caroli’s disease and recurrent cholangitis. TransplInt 1997;10:241-244.

7. Waechter FL, Sampaio JA, Pinto RD, Alvares-da-Silva MR,Cardoso FG, Francisconi C, et al. The role of liver trans-plantation in patients with Caroli’s disease. Hepatogastro-enterology 2001;48:672-674.

8. Habib S, Shakil O, Couto OF, Demetris AJ, Fung JJ, Mar-cos A, et al. Caroli’s disease and orthotopic liver transplan-tation. Liver Transpl 2006;12:416-421.

9. De Kerckhove L, De Meyer M, Verbaandert C, Mourad M,Sokal E, Goffette P, et al. The place of liver transplantationin Caroli’s disease and syndrome. Transpl Int 2006;19:381-388.

10. Millwala F, Seger DL, Thulurath PJ. Caroli’s Disease andoutcomes after liver transplantation. Liver Transpl 2008;14:11-17.

11. Tsuchida Y, Sato T, Sanjo K, Etoh T, Hata K, Terawaki K,et al. Evaluation of long-term results of Caroli’s disease:21 years’ observation of a family with autosomal “domi-nant” inheritance, and review of the literature. Hepatogas-troenterology 1995;42:175-181.

12. Habib S, Berk B, Chang CC, Demetris AJ, Fontes P,Dvorchik I, et al. MELD and prediction of post-liver trans-plantation survival. Liver Transpl 2006;12:440-447.

13. Meyer CG, Penn I, James L. Liver transplantation for chol-angiocarcinoma: results in 207 patients. Transplantation2000;69:1633-1637.

14. Rea DJ, Heimbach JK, Rosen CB, Haddock MG, AlbertsSR, Kremers WK, et al. Liver transplantation with neoad-juvant chemoradiation is more effective than resection forhilar cholangiocarcinoma. Ann Surg 2005;242:451-458.

15. Davis CL, Feng S, Sung R, Wong F, Goodrich NP, MeltonLB, et al. Simultaneous liver-kidney transplantation: eval-uation to decision making. Am J Transplant 2007;7:1702-1709.

EDITORIAL 3

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