Caroli's disease and orthotopic liver transplantation

ORIGINAL ARTICLE

Caroli’s Disease and Orthotopic LiverTransplantationShahid Habib,1 Obaid Shakil,1 Osvaldo F. Couto,1 Anthony J. Demetris,2 John J. Fung,3

Amadeo Marcos,3 and Kapil Chopra1

Divisions of 1Gastroenterology, Hepatology & Nutrition, 2Transplant Pathology, and 3Transplantation Surgeryand Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA

Caroli’s disease is a rare congenital hepatic disease, characterized by segmental dilatation of the biliary tree. Patients whohave recurrent bouts of biliary infection, particularly those with complications related to portal hypertension, may requireorthotopic liver transplantation (OLT). Few case reports have described the outcome of OLT in patients with Caroli’s diseaseand to date there is no large series reported in the literature. We retrospectively analyzed the outcome of OLT in patients withCaroli’s disease who underwent OLT between 1982 and 2002 at Starzl Transplantation Institute, University of Pittsburgh.Patients were identified and data was collected by computerized search of the electronic database system. All patients hadconfirmation of diagnosis by histopathology of explanted liver. A total of 33 patients with Caroli’s disease were listed for livertransplantation, 3 of whom were excluded, as they were not transplanted. A total of 90% had signs of hepatic decompensationat the time of OLT. Median posttransplantation follow-up was 7.7 yr. Short-term graft and patient survival at 1 month was 83%and 86%, whereas overall long-term graft survival rates at 1, 5, and 10 yr were 73%, 62%, and 53%, respectively, and patientsurvival rates were 76%, 65%, and 56%, respectively. Long-term outcome in patients who survived the first year aftertransplantation was significantly better. Their survival rate at 5 and 10 yr was 90% and 78%. On univariable analysis, recipientage, donor male gender, coexistent congenital hepatic fibrosis, and re-OLT were associated with poor patient survival. Eightpatients were retransplanted, 3 of whom had primary nonfunction. A total of 13 patients died; the most common cause of deathbeing sepsis and cardiovascular complications. Patients who died of sepsis had cholangitis pre-OLT. In conclusion, OLT is aform of curative and life-saving therapy in patients with Caroli’s disease, especially in those with decompensated liver disease.Overall survival is better with liver transplantation and is comparable with the survival of recipients who undergo OLT for otheretiologies of chronic liver disease. Survival was poor in patients with congenital hepatic fibrosis (Caroli’s syndrome) and inthose who had cholangitis at the time OLT. Liver Transpl 12:416-421, 2006. © 2006 AASLD.

Received March 29, 2005; accepted September 8, 2005.

Caroli’s disease is a rare congenital hepatic disease,characterized by gross segmental dilation of the intra-hepatic bile ducts (Fig. 1). It was first described in19061 and named after Caroli in 1958.2 The disease hasbeen included in the classification of choledochal cysts(type IVa and V).3 It may occur in association witheither autosomal recessive and dominant polycystickidney disease (in 60%-80% of patients) or congenitalhepatic fibrosis.4,5 When it is associated with congeni-tal hepatic fibrosis it is named Caroli’s syndrome. BothCaroli’s disease and Caroli’s syndrome were describedas distinct entities in 1964.6 Other associations are

Laurence-Moon Beidle syndrome, amyloidosis, andneurofibromatosis.7–9 Caroli’s disease is believed to becaused by an intrauterine event that arrests ductalplate remodeling at the level of the larger intrahepaticbile ducts.10 The resulting bile duct ectasia may bediffuse or localized. Both autosomal recessive and dom-inant modes of inheritance have been proposed.4,5

Caroli’s disease affects men and women equally andusually becomes symptomatic in early adulthood (morethan 80% of patients present with symptoms before theage of 30 yr). The clinical manifestations of Caroli’ssyndrome such as ascites and esophageal variceal

Abbreviations: OLT, orthotopic liver transplantation; CTP, Child-Turcotte-Pugh.Address reprint requests to Shahid Habib, MD, MRCP, Center for Liver Diseases, Iowa Methodist Medical Center, 1215 Pleasant Street, Suite 506,Des Moines, IA 50309. Telephone: 515-241-4044; FAX: 515-241-4100; E-mail: [email protected]

DOI 10.1002/lt.20719Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 12:416-421, 2006

© 2006 American Association for the Study of Liver Diseases.

hemorrhage are related both to the biliary abnormali-ties and to the portal hypertension from hepatic fibro-sis.11 Other patients present only with intermittent ab-dominal pain or pruritus. Hepatic synthetic function isinitially well preserved, but may be affected by progres-sive liver damage resulting from recurrent cholangitisand biliary obstruction leading to secondary biliary cir-rhosis. Diagnosis can be established with imaging (Fig.2).12 Sometimes other studies like endoscopic retro-grade cholangiopancreatography, percutaneous trans-hepatic cholangiography, or hepatobiliary iminodiace-tic acid scan are required to establish the continuitywith the remaining biliary system. Liver biopsy is con-firmatory (Fig. 3).

Treatment is mainly supportive, consisting of analge-sia, antibiotics for cholangitis, ursodeoxycholic acid todissolve intrahepatic calculi and management of portalhypertension.13 In the case of biliary obstruction, inter-nal or external drainage is required. The mostcommonly used surgical options include radiologic orendoscopic drainage and laparoscopic or surgical de-

roofing.14,15 Endoscopic intervention should beavoided in view of the risk of cholangitis. Hepatic resec-tion is indicated only when disease is extensive andlocalized to 1 lobe only.

Patients with extensive bilobar disease or recurrentbouts of biliary infection, particularly those also exhib-iting complications related to portal hypertension, mayrequire orthotopic liver transplantation (OLT). Few casereports have described experience of OLT in patientswith Caroli’s disease.15–22 To date there are no largeseries reported in the literature. We designed this ret-rospective study in order to analyze the outcome oforthotopic liver transplantation in patients with Caro-li’s disease.

PATIENTS AND METHODS

Study Population and Data Collection

All patients with Caroli’s disease who were listed forOLT between 1982 and 2002 at Thomas E. StarzlTransplantation Institute, University of Pittsburgh(Pittsburgh, PA) were identified through the electronicdata base system and included in the study. All clinicaland lab data, including donor information, were col-lected by computerized search of the electronic database system. No exclusion criteria were based on race,ethnicity, gender, or human immunodeficiency virusstatus.

The institutional review board approved the study.Data was also collected for patients with other etiologiesof chronic liver disease, for the same study period, inorder to compare post transplant outcome.

In all cases, primary diagnosis of Caroli’s disease wasconfirmed by histopathology of explanted liver. We cal-culated Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease scores at the time of liver transplan-tation retrospectively. Hepatic decompensation wasdefined by the presence of any of following at the time oftransplantation; ascites, encephalopathy, coagulopa-thy, portal hypertension (endoscopic/radiologic), syn-thetic dysfunction, or jaundice. Synthetic dysfunctionis characterized by prolongation of prothrombin time

Figure 1. Gross appearance of liver with Caroli’s disease.

Figure 2. CT findings in patient with Caroli’s disease.

Figure 3. Histology of liver in patient with Caroli’s disease.

CAROLI’S DISEASE AND POSTTRANSPLANT SURVIVAL 417

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

and/or hypoalbuminemia. Diagnosis of congenital he-patic fibrosis, secondary biliary cirrhosis, and cholan-gitis was based on histopathology of explanted liver.

Data Analysis

The variables analyzed included recipient age, donorage, recipient gender, donor gender, recipient race, do-nor race, cold ischemia time, re-OLT, serum creatinine,serum albumin, serum bilirubin, prothrombin time/international normalized ratio, CTP scores at OLT,Model for End-Stage Liver Disease score at OLT, pres-ence of decompensated disease, presence of congenitalhepatic fibrosis, and presence of cholangitis at OLT.CTP score was calculated and stratified on the basis ofmodified CTP classification. Primary end points weredeath or graft failure; graft failure being defined byretransplantation. Recipient age, donor age, and coldischemia time were analyzed, both as dichotomous andcontinuous variables. Recipient age was grouped as�21 yr or �21 yr based on median age of surviving.Donor age was analyzed as �50 yr or �50 yr and coldischemia time was divided into �12 or �12 hours. Eachpatient record was examined for the studied variables.For each variable analyzed, missing values were ex-cluded from analysis.

Statistical Analysis

The chi-squared test and Fisher’s exact test were usedto compare the basic characteristics. The Mann-Whit-ney U test was used to compare continuous variables.Kaplan-Meier analysis was used to estimate post trans-plant survival. The Breslow score and log-rank testwere used to compare short-term and long-term sur-vival. Multivariable analysis was not performed in viewof the small number in the study population per year ofpatient follow up. A P value of �0.05 was consideredsignificant.

RESULTS

A total of 33 patients were identified to have Caroli’sdisease and were listed at our center for OLT during thestudy period. Three patients were excluded. Of the ex-cluded patients, 1 did not have histopathologicalchanges consistent with Caroli’s disease and 2 werelisted, but did not get transplanted. One patient died onthe waiting list and 1 other was alive by the study enddate. All patients had deceased donor liver transplan-tation.

Clinical Features

Clinical features of both recipients and donors are de-scribed in Table 1. Median recipient and donor age was26 and 20 yr, respectively. Male to female ratio was 1:1for both recipient and donors. Among recipients, whiterace predominated (80%). Two patients had alcohol-related liver disease and 1 had chronic hepatitis C in-fection in addition to the features of Caroli’s disease.Associated conditions were congenital hepatic fibrosis

(Caroli’s syndrome � 9/30), and polycystic kidney dis-ease (3/19). Pancreatic cysts were found in 1 patientand required pancreatectomy. Features of secondarybiliary cirrhosis in the explanted liver were seen in morethan half (16/30) of recipients. One recipient (3%) hadcholangiocarcinoma in the explanted liver.

Prior surgical history was significant for cyst re-section (n � 1), right hepatic lobectomy (n � 1), pan-createctomy (n � 1), pancreatic cyst resection (n � 1),hepatojejunostomy (n � 1), transjugular intrahepaticportosystemic shunt (n � 1), and others (n � 4). Elevenpatients had comorbid conditions such as diabetesmellitus, hypertension, chronic renal insufficiency,portal vein thrombosis, seizure disorder, and Crohn’sdisease.

Indication or need for liver transplantation was de-termined by the presence of any of the signs of hepaticdecompensation as defined above. In patients withavailable data for decompensation (n � 22), 90% (20/22) had 1 or more complications to suggest hepaticdecompensation at OLT. Both of these patients wereCTP A at the time of transplantation. Two patients didnot have signs of hepatic decompensation. In 1 patientindication for liver transplantation was recurrentcholangitis and on histopathology of the explanted liverhe was diagnosed with cholangiocarcinoma. In the sec-ond patient (an 8-yr-old boy), extensive bilobar diseasewarranted liver transplantation. In the remaining 8 pa-tients, data was not clear about indication for trans-plantation because of incomplete record. Most of thosewith incomplete medical records had liver transplanta-tion in the early 1980s and had died. Therefore theyhave been purged from the medical record. The medianCTP score at time of OLT was 9.5 and the median Modelfor End-Stage Liver Disease score was 15. More than 1out of 3 (14/30) recipients had histological signs ofcholangitis in the explanted liver. A total of 81% (18/22)had features of portal hypertension on imaging studiesor endoscopic evaluation. Among them, 15 (83%) hadclinical or radiological evidence of ascites.

Transplant Course

Median follow up, post-liver transplantation, was 7.7yr. Median waiting time was greater than 3 months.Median graft and patient survival times were 6.19 and7.72 yr, respectively. Short-term graft and patient sur-vival at 1 month was 83% and 86%, whereas overalllong-term graft survival rates at 1, 5, and 10 yr were73%, 62%, and 53%, and patient survival rates were76%, 65%, and 56%, respectively (Fig. 4). Long-termoutcome in patients who survived for 1 yr after trans-plantation was significantly better. Their survival rateat 5 and 10 yr was 90% and 78%. On univariable anal-ysis, recipient age, donor male gender, and re-OLT wereassociated with poor patient survival. Patients withCaroli’s syndrome (Caroli’s disease associated withcongenital hepatic fibrosis) had significantly decreasedshort-term survival. There was no difference in long-term survival between Caroli’s disease and Caroli’s syn-drome patients. More recipients with Caroli’s syndrome

418 HABIB ET AL.


had evidence of perioperative cholangitis than recipi-ents with Caroli’s disease and some of these patientsdied shortly after transplantation. More patients withCaroli’s disease had evidence of hepatic lithiasis, as-cites, and encephalopathy as compared to patients withCaroli’s syndrome. Recipient gender, recipient and do-nor race, presence of features of secondary biliary cir-rhosis, portal hypertension, hepatic decompensation,CTP score, Model for End-Stage Liver Disease score,serum creatinine, serum bilirubin, serum albumin, in-ternational normalized ratio, cold ischemia time, anddonor age at OLT did not correlate with posttransplan-tation survival within the small group of patients. Acutecellular rejection episodes also did not correlate withsurvival. Recipients with perioperative cholangitis hada trend of higher mortality.

Overall, 13 patients died after a median follow up of10 months. The most common cause of death was sep-sis, both in immediate and late transplant phase.

Among them, 4 recipients died within 2 weeks of trans-plantation and 8 died by 1 yr after transplantation.Causes of death during the first year after transplanta-tion were: sepsis (n � 3), vascular complication (n � 3),graft failure (n � 1), and cardiac (n � 1). Vascularcomplications included hepatic artery thrombosis, gas-trointestinal hemorrhage, and stroke. All 3 patientswho died of sepsis had evidence of perioperative cholan-gitis. Two of them died within 2 weeks of transplanta-tion. Five recipients died after 1 yr of liver transplanta-tion, 4 of them died of sepsis at 2, 3.5, 8, and 12 yrposttransplantation and 1 died of malignancy (post-transplantation lymphoproliferative disease) more than12 yr posttransplantation. Two of the recipients withsepsis also had evidence of perioperative cholangitis.One recipient, who had cholangiocarcinoma at OLT,died almost 1 yr after transplantation as a result ofgastrointestinal hemorrhage.

Eight recipients underwent re-OLT. Indication for re-

TABLE 1. Clinical Features

Variables

Cases

analyzed Total Deceased Survived P value

Recipient age yr-median (range) 30 25.5 (66) 30 (60) 21 (52) 0.03Donor age yr-median (range) 26 20 (62) 20 (56) 18 (58) NSRecipient gender male-n (%) 30 16 (53) 9 (56) 7 (44) NSDonor gender male-n (%) 29 15 (50) 9 (60) 6 (40) 0.05Recipient race white-n (%) 30 24 (80) 11 (46) 13 (54) NSDonor race white-n (%) 27 17 (63) 8 (47) 9 (53) 0.04Bilirubin-median (range) 20 3.85 (21.8) 4 (21.2) 2.6 (21) NSALB-(G/dL)-median (range) 16 2.8 (1.9) 2.7 (0.9) 2.9 (1.9) NSCreatinine (mg/dL)-median (range) 20 0.85 (4.1) 1.05 (2.5) 0.7 (3.9) NSINR-median (range) 22 1.15 (3.9) 1.45 (3.7) 1.1 (1.1) NSAscites-n (%) 19 12 (63) 4 (33) 8 (67) NSEncephalopathy-n (%) 17 8 (47) 2 (25) 6 (75) NSPortal hypertension-n (%) 19 15 (78) 4 (27) 11 (73) NSHepatic decompensation-n (%) 22 20 (90) 7 (36) 13 (64) NSCo morbid conditions-n (%) 30 11 (37) 4 (36) 7 (64) NSPKD-n (%) 16 3 (19) 0 (0) 3 (100) NSCTP score-median (range) 14 9.5 (7) 10.5 (4) 9 (5) NSMELD score-median (range) 19 1527 23.527 1519 NSPathology of explanted liver

CHF-n (%) 30 9 (30) 5 (56) 4 (44) NSAlcohol-n (%) 30 2 (7) 2 (100) 0 (0) NSCholangitis-n (%) 30 12 (40) 5 (42) 7 (58) NSCholangiocarcinoma-n (%) 30 1 (3) 1 (100) 0 (0) NSHepatitis C-n (%) 30 1 (3) 1 (100) 0 (0) NSHepatic lithiasis-n (%) 30 3 (10) 2 (67) 1 (33) NSSecondary biliary cirrhosis-n (%) 30 16 (53) 8 (50) 8 (50) NS

CIT minutes-median (range) 28 629.5 (870) 627 (870) 641.5 (645) NSPatient with rejection episodes-

median (%)28 12 (43) 5 (42) 7 (58) NS

Patient with re-OLT-n (%) 30 8 (27) 8 (100) 0 (0) 0.00Patient follow-up days-median

(range)30 2782 (6625) 296 (4314) 4624 (6370) 0.000

Waiting time on listing-days-median (range)

23 94 (1318) 92 (346) 100 (1313) NS

Abbreviations: n, number; OLT, orthotopic liver transplantation; INR, international normalized ratio; Alb, Albumin; CTP score,Child-Turcotte-Pugh score; MELD, model for End-Stage Liver Disease; PKD, polycystic kidney disease; CHF, congenitalhepatic fibrosis; CIT, cold ischemia time; NS, not significant.



transplantation was primary nonfunction in 3 recipi-ents and unclear in the remaining 5. Recipients whohad evidence of sepsis at the time of first graft failure,were not considered for retransplantation. Median graftand patient survival in the second allograft was 45days. All of the recipients who underwent re-OLT diedafter a median survival of 11 months post first OLT.Causes of death after second allograft were primarynonfunction (n � 1), cardiovascular (n � 4) in first yr,and sepsis (n � 3) after the first year of transplantation.

Three recipients developed posttransplant lympho-proliferative disease. Two were treated successfully and1 died, as described above.

DISCUSSION

The prognosis of patients with Caroli’s disease is poor,especially in patients with extensive bilobar or compli-cated disease. Tsuchida et al.23 reviewed 50 well-docu-mented cases reported since 1968. At least 46% ofthese patients had died, primarily as a result of septi-cemia, liver abscess, liver failure, and portal hyperten-sion. The average time from diagnosis to death was 9months. In another series, 4 of 21 patients died duringa mean follow up period of 4.8 yr.24 Liver transplanta-tion has emerged as a curative option in these patients.To date there are only a few case reports describingexperience of OLT in Caroli’s disease. In 1 of the Euro-pean series, 5 patients underwent OLT, 2 of whom died(both cases were complicated by cholangiocarcinoma)and other 3 did well.15 In another report, 2 patients hadOLT and did well postoperatively.18

Our study showed that graft and patient survival isgood and is no different from patients who undergo OLTfor other etiologies of chronic liver disease (Fig. 5). Italso showed that higher mortality in the first year ofliver transplantation prevented better long-term sur-vival. Among the recipients who died, almost 2 of 3 diedduring the first year posttransplantation with the mostcommon cause of death being sepsis. All of these recip-ients who died of sepsis had perioperative cholangitis.Recipients who survived the first year post-liver trans-

plantation had good long-term survival. This indicatesthe need for early recognition and aggressive treatmentof cholangitis prior to liver transplantation. Episodes ofcholangitis were more prevalent in patients associatedwith congenital hepatic fibrosis (Caroli’s syndrome).Presence of congenital hepatic fibrosis, older recipientage, and retransplantation, emerged as predictors ofpoor survival posttransplantation. Therefore, there is aneed for histological diagnosis to differentiate betweenpatients with Caroli’s disease and Caroli’s syndromeprior to liver transplantation to better determine theposttransplantation course. However, portal hyperten-sion, renal failure, encephalopathy, CTP score, orModel for End-Stage Liver Disease score at transplan-tation did not correlate with posttransplantation mor-tality.

The exact pathophysiological basis for high mortalityin recipients associated with congenital hepatic fibrosisremains unknown. Poor prognosis in recipients associ-ated with congenital hepatic fibrosis appears to be re-lated to the presence of perioperative cholangitis. Thepresence of perioperative cholangitis also predicted

Figure 4. Survival in patients with Caroli’s disease and Caro-li’s syndrome. Breslow test, P � 0.03; log-rank test, P � 0.1.

Figure 5. Survival in patients with Caroli’s disease. (A) Graftsurvival in patients with Caroli’s disease in comparison withother (non-Caroli’s disease) patients. Log-rank test, P � 0.96.(B) Patient survival in patients with Caroli’s disease in com-parison with other (non-Caroli’s disease) patients. Log-ranktest, P � 0.66.

420 HABIB ET AL.


poor short-term outcome. However, the presence ofportal hypertension at transplantation (which is asso-ciated with congenital hepatic fibrosis ) did not corre-late with posttransplantation mortality. In 1 report, itwas shown that patients with Caroli’s disease and poly-cystic kidney disease had poor outcomes. Our study didnot show any correlation between renal failure andposttransplantation outcome. Patients who were trans-planted at an earlier age did well as compared to olderpatients. This could be attributed to less advanced oruncomplicated disease and fewer posttransplantationcomplications. It has been shown in other studies thatyounger recipients have better outcomes as comparedto older recipients. Re-OLT also significantly predictedincreased post-OLT mortality. Other reports have alsoshown similar results in patients with other etiologies.In our study, the recipient who had cholangiocarci-noma at the time of OLT, did not do well. A similarfinding has been reported in the literature.15

In conclusion, no definitive guidelines exist at presentregarding liver transplantation in Caroli’s disease.Based on our study and recent literature review, OLT isindicated in decompensated liver disease, bilobar dis-ease, recurrent episodes of cholangitis, and secondarybiliary cirrhosis. OLT is a curative therapy in this groupof patients and their posttransplantation survival iscomparable to those who had liver transplantation forother etiologies. An early and aggressive approach toprevent, diagnose, and treat cholangitis and sepsis,both pre- and post-liver transplantation, is warrantedin order to improve post-OLT survival. Further studiesare required to confirm these findings.

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Caroli's disease and orthotopic liver transplantation