| Domain | Caroli disease (CD) summary | Caroli syndrome (CS) distinction | Ontology suggestions | Evidence |
|---|---|---|---|---|
| Definition / identifiers | Rare congenital malformation characterized by non-obstructive, segmental or diffuse saccular dilatation of the **large intrahepatic bile ducts**; incidence estimated at **~1:1,000,000**. MONDO provided by user: **MONDO:0010913**. Disease-level knowledge here is derived from aggregated literature/review and registry-style summaries, not individual EHRs. | CS = CD features **plus congenital hepatic fibrosis (CHF)** involving interlobular ducts and portal fibrosis. | MONDO:0010913; UBERON: liver / intrahepatic bile duct; HPO: Dilatation of the intrahepatic bile duct | (pqac-00000001, pqac-00000002, pqac-00000010) |
| Inheritance / gene | Reported as **autosomal recessive** in the gathered evidence; associated mainly with **PKHD1** mutations encoding **fibrocystin/polyductin**; Open Targets also lists disease-target evidence for **PKHD1**, with weaker associations for **CYS1** and **DZIP1L**. | CS shares the same AR/PKHD1 association in review evidence and is more often discussed within the ARPKD/CHF spectrum. | HGNC: PKHD1; CL/GO-linked ciliopathy context | (pqac-00000002, pqac-00000003, pqac-00000011) |
| Hallmark anatomy | Primary lesion localizes to **large intrahepatic bile ducts** with ductal ectasia; imaging may show diffuse involvement (**50%**) or localization to right lobe (**28.6%**) or left lobe (**21.4%**). | CS additionally includes **portal tracts/congenital hepatic fibrosis** and signs of portal hypertension. | UBERON: intrahepatic bile duct, liver; CL: cholangiocyte | (pqac-00000002, pqac-00000008, pqac-00000011) |
| Core phenotypes with frequencies | Acute cholangitis **64%**; intrahepatic cholelithiasis/choledocholithiasis **33%**; right upper quadrant pain **50%**; jaundice **35.7%**; fever **28.6%**; asymptomatic **14.3%**. Lab abnormalities reported: elevated GGT **64.3%**, alkaline phosphatase **35.7%**, bilirubin **28.6%**. Mean diagnosis age **42 years** (range **15–68**); no gender predominance in the cited series. | CS cohorts more often show portal-hypertension phenotypes: abdominal pain, fever, thrombocytopenia, prolonged PT, ascites, varices, splenomegaly. | HPO: Cholangitis, Hepatolithiasis, Abdominal pain, Jaundice, Fever, Elevated gamma-glutamyltransferase, Elevated alkaline phosphatase, Hyperbilirubinemia, Hepatomegaly, Splenomegaly, Ascites, Esophageal varices | (pqac-00000001, pqac-00000002, pqac-00000010, pqac-00000011) |
| Mechanism / pathophysiology | CD is a **cholangiociliopathy**. PKHD1 loss causes defective fibrocystin, altered ciliary/plasma-membrane signaling, reduced interaction with PC2/calcium signaling, activation of **cAMP**, **β-catenin**, **NF-κB**, **JAK/STAT**, chemokine production, macrophage recruitment, **TGF-β** activation, myofibroblast stimulation, ECM deposition, and fibrogenic remodeling. Review evidence also notes aberrant **NOTCH1-4** expression in biliary epithelial cells in CD. | CS lies further along the fibrocystic/fibrotic spectrum, with CHF/portal fibrosis clinically manifest. | GO: cilium organization; calcium ion signaling; inflammatory response; chemokine production; macrophage chemotaxis; extracellular matrix organization; fibrosis. CL: cholangiocyte, macrophage, portal myofibroblast | (pqac-00000004, pqac-00000005, pqac-00000006, pqac-00000011) |
| Diagnosis | Preferred modality: **MRCP**. Pathognomonic imaging sign: **central dot sign** on contrast CT/MRI. Additional modalities: ultrasound, hepatobiliary scintigraphy (beading of intrahepatic ducts). Histology: localized dilated non-obstructive ducts with patent vascular channels/intraluminal wall protrusions; fetal-type markers **CK7**, **MUC-1**, and **β-catenin** support congenital origin. | CS diagnosis additionally evaluates CHF/portal-hypertension features and associated renal disease. | HPO: Abnormality of the biliary tract morphology; UBERON: intrahepatic bile duct; NCIT-imaging terms not confidently assigned from gathered evidence | (pqac-00000001, pqac-00000007, pqac-00000009) |
| Differential diagnosis | Key differentials in gathered evidence: **primary sclerosing cholangitis** and **recurrent pyogenic cholangitis**; NCT04007575 specifically aimed to distinguish CD from **obstructive benign or malignant bile duct dilatation** by MRCP criteria. | CS may also overlap clinically with other causes of congenital hepatic fibrosis/portal hypertension. | — | (pqac-00000007, pqac-00000009) |
| Complications / cancer risk | Recurrent cholangitis, biliary stones, hepatic abscess, sepsis, poor quality of life from recurrent infections. Cholangiocarcinoma risk elevated: **6.3% CD**, **7.6% CS** in one multicenter dataset; systematic review of **561 CD patients** found **6.6%** cholangiocarcinoma incidence. | CS shares the cancer risk and adds portal-hypertension complications. | HPO: Cholangiocarcinoma, Hepatic abscess, Sepsis, Portal hypertension | (pqac-00000001, pqac-00000010) |
| Treatment | Medical/supportive: **antibiotics** for cholangitis; **ursodeoxycholic acid** for intrahepatic cholelithiasis; chronic suppressive antibiotics may be used while awaiting transplant. Procedural/surgical: **hepatectomy/resection** for localized disease; **liver transplantation** for diffuse disease; **simultaneous liver-kidney transplantation** may be required with renal involvement. Reported postoperative complications after hepatectomy include biliary leakage **26%**, surgical revision **16%**, pleural effusion **5.5%**, UTI **5.5%**. | CS often more likely to require transplant because of diffuse hepatobiliary and fibrotic/portal-hypertensive involvement. | NCIT: Antibiotic Therapy; Ursodeoxycholic Acid; Hepatectomy; Liver Transplantation; Kidney and Liver Transplantation | (pqac-00000007, pqac-00000008) |
| Prognosis / temporal course | Most patients are asymptomatic until **age 20**; **>80%** become symptomatic by **age 30**. Disease burden is chronic/episodic with recurrent cholangitis. Main mortality drivers reported in review evidence are **sepsis** and **hepatic abscesses**. Reported transplant outcomes are favorable: patient survival **99%**, **96.2%**, **94.6%** at 1, 3, 5 years; graft survival **94.9%**, **91.1%**, **89.6%**. | CS prognosis worsens with portal hypertension, fibrosis, renal disease, and infectious complications. | HPO: Recurrent fever, Recurrent cholangitis, Portal hypertension, Chronic kidney disease | (pqac-00000008, pqac-00000010) |
| Models / research applications | **PCK rat** (PKHD1 splicing mutation) shows progressive intrahepatic bile duct dilatation, cyst development, renal collecting-duct cysts, and mild portal fibrosis. **Pkhd1del4/del4 mouse** develops intrahepatic bile duct dysgenesis progressing to cyst-like lesions, peribiliary fibrogenesis after 3 months, and splenomegaly in **>50%** by 6 months. These models are used to study cholangiocyte cilia dysfunction, inflammatory-fibrotic signaling, and portal-fibrosis mechanisms. | Models largely represent the broader ARPKD/CHF/CD-CS spectrum rather than isolated adult CD alone. | CL: cholangiocyte, macrophage; GO: fibrogenesis, chemokine-mediated signaling, epithelial tube morphogenesis | (pqac-00000004) |


*Table: This table provides a compact knowledge-base style summary of Caroli disease, explicitly distinguishing it from Caroli syndrome and organizing the main supported facts across genetics, phenotype, mechanism, diagnosis, treatment, prognosis, and models. It is useful as a structured extraction layer from the gathered evidence.*