History

The mode of presentation depends on the age of onset and the predominance of renal or hepatic involvement. Children with Caroli syndrome usually have an earlier onset of symptoms and a more progressive disease, given of the effects of both cholangitis and portal hypertension.

Patients with Caroli disease or Caroli syndrome may have a history of intermittent abdominal pain, which reflects episodes of bile stasis or the passage of bile stones. Patients may report pruritus secondary to cholestasis. Patients with cholangitis may report fever and pain in the right upper quadrant.

In Caroli syndrome, portal hypertension may result in hematemesis or melena secondary to bleeding varices. Patients may also develop ascites in association with portal hypertension. Most (64%) patients who have portal hypertension have autosomal recessive polycystic kidney disease (ARPKD).^[3]

Because Caroli syndrome is associated with ARPKD and is inherited in an autosomal recessive manner, the patient may have a family history of kidney or liver disease.

Physical

The following may be observed:

Hepatomegaly may be present.
Splenomegaly may be present if portal hypertension occurs.
Tenderness of the right upper quadrant is occasionally present.
Abdominal mass or masses occur if large polycystic kidneys are present.
Jaundice is rarely present.

Causes

A genetic cause is likely, given the association with ARPKD. Mutations in PKHD1 on chromosome 6p21, which is the gene linked to ARPKD, have been identified in patients with Caroli syndrome.

PKHD1 encodes the protein fibrocystin, which is expressed in cortical and medullary ducts in the kidney as well as biliary and pancreatic ducts in a pattern consistent with the histologic patterns seen in ARPKD.

Fibrocystin is one of a larger family of proteins that are present in the primary cilium.

Recent research supports a mechanistic link between ciliary dysfunction and polycystic kidney disease, although this remains controversial. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) in a rat model appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation.^[4]

The number of cases of Caroli syndrome caused by PKHD1 mutations is not known.

Caroli syndrome is inherited in an autosomal recessive manner.

Differential Diagnoses

Nakanuma Y, Harada K, Sato Y, Ikeda H. Recent progress in the etiopathogenesis of pediatric biliary disease, particularly Caroli's disease with congenital hepatic fibrosis and biliary atresia. Histol Histopathol. 2010 Feb. 25 (2):223-35. [QxMD MEDLINE Link].
Wang ZX, Li YG, Wang RL, et al. Clinical classification of Caroli's disease: an analysis of 30 patients. HPB (Oxford). 2015 Mar. 17 (3):278-83. [QxMD MEDLINE Link].
Srinath A, Shneider BL. Congenital Hepatic Fibrosis and Autosomal Recessive Polycystic Kidney Disease. J Pediatr Gastroenterol Nutr. 2012 May. 54(5):580-7. [QxMD MEDLINE Link].
Sato Y, Ren XS, Nakanuma Y. Caroli’s Disease: Current Knowledge of Its Biliary Pathogenesis Obtained from an Orthologous Rat Model. Int J Hepat. July 2012. doi:10.1155/2012/107945. [QxMD MEDLINE Link].
Leelawat K, Sakchinabut S, Narong S, Wannaprasert J. Detection of serum MMP-7 and MMP-9 in cholangiocarcinoma patients: evaluation of diagnostic accuracy. BMC Gastroenterol. 2009 Apr 30. 9:30. [QxMD MEDLINE Link].
Rawat D, Kelly DA, Milford DV, et al. Phenotypic Variation and Long-Term Outcome in Children With Congenital Hepatic Fibrosis. J Pediatr Gastroenterol Nutr. August 2013. 57 (2):161-6. [QxMD MEDLINE Link].
[Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005 Jun. 41(6):1407-32. [QxMD MEDLINE Link].
Lai Q, Lerut J. Proposal for an algorithm for liver transplantation in Caroli's disease and syndrome: putting an uncommon effort into a common task. Clin Transplant. 2016 Jan. 30 (1):3-9. [QxMD MEDLINE Link].
Biliary Atresia and Neonatal Disorders of the Bile Ducts. Robert Wyllie, Jeffrey Hyams and Marsha Kay. Pediatric Gastrointestinal and Liver Disease. Fifth Edition. Elsevier; 2016. 1172-1173.
Millwala F, Segev DL, Thuluvath PJ. Caroli's disease and outcomes after liver transplantation. Liver Transpl. 2008 Jan. 14(1):11-7. [QxMD MEDLINE Link].
Wang ZX, Yan LN, Li B, Zeng Y, Wen TF, Wang WT. Orthotopic liver transplantation for patients with Caroli's disease. Hepatobiliary Pancreat Dis Int. 2008 Feb. 7(1):97-100. [QxMD MEDLINE Link].
Alvarez F, Bernard O, Brunelle F, et al. Congenital hepatic fibrosis in children. J Pediatr. 1981 Sep. 99(3):370-5. [QxMD MEDLINE Link].
Bockhorn M, Malago M, Lang H, et al. The role of surgery in Caroli's disease. J Am Coll Surg. 2006 Jun. 202(6):928-32. [QxMD MEDLINE Link].
D'Agata ID, Jonas MM, Perez-Atayde AR, Guay-Woodford LM. Combined cystic disease of the liver and kidney. Semin Liver Dis. 1994 Aug. 14(3):215-28. [QxMD MEDLINE Link].
Guy F, Cognet F, Dranssart M, et al. Caroli's disease: magnetic resonance imaging features. Eur Radiol. 2002 Nov. 12(11):2730-6. [QxMD MEDLINE Link].
Habib S, Shakil O, Couto OF, et al. Caroli's disease and orthotopic liver transplantation. Liver Transpl. 2006 Mar. 12(3):416-21. [QxMD MEDLINE Link].
Hunter FM, Akdamar K, Sparks RD, et al. Congenital dilation of the intrahepatic bile ducts. Am J Med. 1966 Feb. 40(2):188-94. [QxMD MEDLINE Link].
Ibraghimov-Beskrovnaya O, Bukanov N. Polycystic kidney diseases: from molecular discoveries to targeted therapeutic strategies. Cell Mol Life Sci. 2008 Feb. 65(4):605-19. [QxMD MEDLINE Link].
Kassahun WT, Kahn T, Wittekind C, et al. Caroli's disease: liver resection and liver transplantation. Experience in 33 patients. Surgery. 2005 Nov. 138(5):888-98. [QxMD MEDLINE Link].
Lacy CF, Armstrong LL, Goldman MP. Drug Information Handbook. Available at: www.lexi.com/web. 2000-2001. [Full Text].
Madjov R, Chervenkov P, Madjova V, Balev B. Caroli's disease. Report of 5 cases and review of literature. Hepatogastroenterology. 2005 Mar-Apr. 52(62):606-9. [QxMD MEDLINE Link].
Mall JC, Ghahremani GG, Boyer JL. Caroli's disease associated with congenital hepatic fibrosis and renal tubular ectasia. A case report. Gastroenterology. 1974 May. 66(5):1029-35. [QxMD MEDLINE Link].
Miller WJ, Sechtin AG, Campbell WL, Pieters PC. Imaging findings in Caroli's disease. AJR Am J Roentgenol. 1995 Aug. 165(2):333-7. [QxMD MEDLINE Link].
Nakanuma Y, Terada T, Ohta G, Kurachi M, Matsubara F. Caroli's disease in congenital hepatic fibrosis and infantile polycystic disease. Liver. 1982 Dec. 2(4):346-54. [QxMD MEDLINE Link].
Piccoli DA, Witzleben CL. Disorders of the intrahepatic bile ducts. Pediatric Gastrointestinal Disease. Philadelphia, Pa: WB Saunders Co; 2000. 1124-40.
Ros E, Navarro S, Bru C, et al. Ursodeoxycholic acid treatment of primary hepatolithiasis in Caroli's syndrome. Lancet. 1993 Aug 14. 342(8868):404-6. [QxMD MEDLINE Link].
Sanzen T, Harada K, Yasoshima M, et al. Polycystic kidney rat is a novel animal model of Caroli's disease associated with congenital hepatic fibrosis. Am J Pathol. 2001 May. 158(5):1605-12. [QxMD MEDLINE Link]. [Full Text].
Senyuz OF, Yesildag E, Kuruoglu S, Yeker Y, Emir H. Caroli's disease in children: is it commonly misdiagnosed?. Acta Paediatr. 2005 Jan. 94(1):117-20. [QxMD MEDLINE Link].
Sgro M, Rossetti S, Barozzino T, et al. Caroli's disease: prenatal diagnosis, postnatal outcome and genetic analysis. Ultrasound Obstet Gynecol. 2004 Jan. 23(1):73-6. [QxMD MEDLINE Link].
Sleisenger MH, Fordtran JS, Feldman M, et al. Anatomy, anomalies, and pediatric disorders of the biliary tract. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. WB Saunders Co; 1993. 917-927.
Suchy FJ. The cholangiopathies. Sokol RJ, Balistreri WF, eds. Liver Disease in Children. Philadelphia, Pa: Lippincott Williams & Wilkins; 1994. 153-65.
Summerfield JA, Nagafuchi Y, Sherlock S, et al. Hepatobiliary fibropolycystic diseases. A clinical and histological review of 51 patients. J Hepatol. 1986. 2(2):141-56. [QxMD MEDLINE Link].
Caroli J, CouinaudC, SoupaultR, et al. Une affection nouvelle, sans doute cong´enitale, des voies biliaires: la dilatation cystique unilobaire des canaux h´epatiques. Sem. Sem Hop Paris. 1958. 34:134-42.

Media Gallery

Hepatic ultrasonogram of a neonate with Caroli disease. Multiple dilated intrahepatic bile ducts are present. Courtesy of Richard Bellah, MD, The Children's Hospital of Philadelphia.

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Author

Mutaz I Sultan, MD, MBChB Assistant Professor and Chief of Pediatrics, Al-Quds University Medical College; Pediatric Gastroenterologist and Hepatologist, Division of Pediatrics, Makassed Hospital, Palestine

Mutaz I Sultan, MD, MBChB is a member of the following medical societies: European Society for Paediatric Gastroenterology, Hepatology and Nutrition, Palestine Medical Council

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Royal College of Physicians and Surgeons of Canada

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers' bureau.

Additional Contributors

Robert Baldassano, MD Director, Center for Pediatric Inflammatory Bowel Disease, Children's Hospital of Philadelphia; Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine

Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Received consulting fee from Abbott, Inc for consulting.

David A Piccoli, MD Chief of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine

David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Joshua R Friedman, MD, PhD Director and Head of Disease Biology, Janssen Research and Development

Joshua R Friedman, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Study of Liver Diseases, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Received salary from Johnson & Johnson for employment.

Melissa Kennedy, MD Attending Physician, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia

Melissa Kennedy, MD is a member of the following medical societies: American Academy of Pediatrics, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Sections Pediatric Caroli Disease
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- Physical
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Pediatric Caroli Disease Clinical Presentation

History

Physical

Causes

References

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