Caroli disease

Mendelian MONDO:0010913 Pathograph 16 Show in embeddings browser non-neoplastic bile duct disorder liver disorder

Caroli disease is a rare congenital disorder of the intrahepatic biliary tree in which segmental, non-obstructive saccular dilatations of the large intrahepatic bile ducts arise from a ductal plate malformation — a failure of the embryonic ductal plate to remodel normally. It belongs to the fibrocystic liver diseases, a group of cholangiociliopathies caused by dysfunction of proteins expressed in the primary cilium of cholangiocytes; the best-characterised gene is PKHD1, encoding fibrocystin/polyductin, which also causes autosomal recessive polycystic kidney disease. Two forms are distinguished by whether the small interlobular ducts are also affected: the simple (type I) form shows ductal ectasia alone, whereas Caroli syndrome (type II) combines the ductal dilatations with congenital hepatic fibrosis. Bile stasis within the dilated segments drives hepatolithiasis and recurrent bacterial cholangitis; peribiliary fibrosis produces presinusoidal portal hypertension with splenomegaly and variceal bleeding despite long-preserved hepatocellular synthetic function. Chronic biliary inflammation carries a substantially increased risk of cholangiocarcinoma. No targeted medical therapy exists; management controls complications, with hepatic resection for localised disease and liver (or combined liver-kidney) transplantation for diffuse disease or hepatic decompensation.

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Mappings
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Inheritance
10
Pathophys.
11
Phenotypes
2
Gaps
16
Pathograph
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Genes
6
Medical Actions
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Subtypes
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Models
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References
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Deep Research
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Mappings

MONDO
MONDO:0010913 Caroli disease
skos:exactMatch MONDO Orphanet:53035 xref
MONDO:0010913 is the primary anchor for this entry and carries Orphanet:53035 and OMIM:600643 as disease cross-references. The syndromic form (Caroli syndrome, MONDO:0018808) is modelled here as a subtype rather than a separate entry because it shares the same ductal plate malformation mechanism and differs only by additional involvement of the small interlobular ducts.
MONDO:0018808 Caroli syndrome Not Yet Curated
skos:narrowMatch
Caroli syndrome is the subset of Caroli disease that coexists with congenital hepatic fibrosis; it is curated as the `Caroli syndrome` subtype of this entry.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
The PKHD1-associated forms of Caroli disease — in particular Caroli syndrome with congenital hepatic fibrosis, which shares its genetic basis with autosomal recessive polycystic kidney disease — are inherited in an autosomal recessive pattern. Simple Caroli disease is frequently reported as sporadic, and the genetic basis of isolated large-duct disease is less completely defined.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33824930 SUPPORT Human Clinical
"CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (PKHD1), a gene that encodes for fibrocystin/polyductin"
Attributes congenital hepatic fibrosis, Caroli disease/syndrome and ARPKD to mutations in PKHD1; ARPKD is by definition autosomal recessive.
PMID:20301501 SUPPORT Human Clinical
"ARPKD-PKHD1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PKHD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected..."
GeneReviews states the autosomal recessive mode of inheritance for ARPKD-PKHD1 outright, with the 25% per-conception sib recurrence risk, rather than leaving it to be inferred from the ARPKD label.
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Subtypes

2
Simple (type I) Caroli disease — ductal ectasia without hepatic fibrosis
Segmental saccular dilatation of the large intrahepatic bile ducts without congenital hepatic fibrosis. Clinical disease is dominated by bile stasis complications — hepatolithiasis, recurrent bacterial cholangitis and biliary sepsis — rather than by portal hypertension. Frequently segmental or monolobar, which makes curative hepatic resection possible.
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"Congenital intrahepatic bile duct dilatation without fibrosis is called Caroli disease (CD), and is called Caroli syndrome (CS) when it has fibrotic and cirrhotic liver morphology."
Defines the simple form as intrahepatic bile duct dilatation occurring without hepatic fibrosis, distinguishing it from the syndromic form.
Caroli syndrome (type II) — ductal ectasia with congenital hepatic fibrosis MONDO:0018808
PKHD1 hgnc:9016 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PKHD1 (hgnc:9016). hgnc:9016 is a gene from the HUGO Gene Nomenclature Committee.
Caroli disease coexisting with congenital hepatic fibrosis, reflecting ductal plate malformation of the small interlobular ducts in addition to the large intrahepatic ducts. It is strongly associated with autosomal recessive polycystic kidney disease. Presinusoidal portal hypertension with splenomegaly, hypersplenism and variceal bleeding dominates the clinical course, and diffuse involvement usually makes resection impossible so that transplantation becomes the definitive option.
Show evidence (2 references)
PMID:33824930 SUPPORT Human Clinical
"The ductal dysgenesis may affect the biliary system at multiple levels, from the small intrahepatic bile ducts"
States that the ductal dysgenesis affects the biliary tree at multiple levels, the basis for distinguishing Caroli syndrome (large plus small ducts) from simple Caroli disease.
PMID:34294522 SUPPORT Human Clinical
"In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients."
In a 17-centre German surgical series the syndromic form outnumbered the simple form (119 vs 79). This is a surgical-referral cohort, so it does not establish the population-level ratio.
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Discussions and Knowledge Gaps

2
What is the true incidence of cholangiocarcinoma in Caroli disease and Caroli syndrome, and can any risk factor stratify which patients will develop it?
KNOWLEDGE GAP OPEN caroli_cca_incidence_uncertainty
Attached to
pathophysiology#Cholangiocarcinoma
Reported cholangiocarcinoma incidence ranges from 2.7% to 37.5% across studies, with pooled estimates of 6.6% (systematic review) and 7.1% (German multicentre series). All available series are retrospective and drawn from surgical cohorts, so they are subject to referral bias, and no predictor of malignant transformation has been identified. This matters clinically because malignancy risk is one of the arguments used to justify prophylactic resection, yet the tumours are almost always found incidentally in the specimen because preoperative imaging cannot detect them.
Proposed experiments
Prospective unselected-cohort cholangiocarcinoma incidence study
exp_caroli_prospective_cca_incidence
Registry-based prospective follow-up of an unselected (not surgically referred) Caroli disease and Caroli syndrome cohort with standardised imaging surveillance, to estimate cholangiocarcinoma incidence free of surgical referral bias.
Decision criterion
An incidence estimate with confidence intervals that exclude the extremes of the currently reported 2.7-37.5% range would settle whether prophylactic resection is justified by malignancy risk alone.
Nested case-control analysis of cholangiocarcinoma risk factors
exp_caroli_cca_risk_factor_case_control
Within such a cohort, compare patients who did and did not develop cholangiocarcinoma, testing candidate risk factors (disease extent, cholangitis frequency, hepatolithiasis burden, age, PKHD1 genotype).
Decision criterion
Identification of any factor that stratifies risk would convert a uniform resection recommendation into a targeted surveillance strategy.
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"The development of intrahepatic carcinoma is described in both conditions, but the reported incidence varies extensively. Potential risk factors for the malignant transformation were not described."
States both halves of this knowledge gap explicitly — the incidence varies extensively and no risk factors for malignant transformation are known.
Can the cholangiociliopathy mechanism be targeted therapeutically, rather than only managing the downstream biliary and portal complications?
KNOWLEDGE GAP OPEN caroli_no_targeted_therapy
Attached to
pathophysiology#Fibrocystin Loss from the Cholangiocyte Primary Cilium
Every treatment curated in this entry acts on a consequence — infection, portal pressure, variceal bleeding, or the malformed anatomy itself — and none acts on the ciliary defect or on peribiliary fibrogenesis. A contributing obstacle is that fibrocystin/polyductin's molecular function is still not established, so there is no well-defined pathway to drug.
Proposed experiments
Fibrocystin function in patient-derived cholangiocyte organoids
exp_caroli_fibrocystin_function_organoid
Define the molecular function of fibrocystin/polyductin in cholangiocyte cilia (interactome and ciliary signalling readouts) in human cholangiocyte organoids derived from PKHD1-mutant patients versus isogenic controls.
Decision criterion
Identification of a defined signalling axis downstream of ciliary fibrocystin would provide the first druggable target in this disease.
Antifibrotic intervention trial in the PCK rat
exp_caroli_antifibrotic_pck_rat
Test antifibrotic candidates against peribiliary fibrogenesis in the PCK rat, using portal pressure and periportal collagen deposition as endpoints.
Decision criterion
A reduction in portal pressure and periportal collagen relative to untreated PCK controls would justify translation toward a portal-hypertension-modifying therapy.
Show evidence (1 reference)
PMID:33824930 SUPPORT Human Clinical
"Targeted medical therapy is not available yet and thus the current treatment aims at controlling the complications."
States directly that no targeted medical therapy exists and that management is complication-directed.
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Pathophysiology

10
Fibrocystin Loss from the Cholangiocyte Primary Cilium
Biallelic PKHD1 variants reduce or abolish fibrocystin/polyductin, a large receptor-like protein that in normal biliary epithelium localises to the single primary cilium projecting from each cholangiocyte into the duct lumen. Loss of fibrocystin leaves the cilium structurally abnormal — shortened and with bulbous deformities — so the cholangiocyte can no longer transduce the ciliary signals that normally govern planar cell polarity and oriented growth of the developing duct. Because the same protein is required in renal tubular cilia, the biliary lesion is typically accompanied by the renal phenotype of autosomal recessive polycystic kidney disease.
intrahepatic cholangiocyte CL:0002538 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intrahepatic cholangiocyte (CL:0002538). CL:0002538 is a cell type from the Cell Ontology.
PKHD1 hgnc:9016 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PKHD1 (hgnc:9016). hgnc:9016 is a gene from the HUGO Gene Nomenclature Committee.
cilium assembly GO:0060271 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology. ↓ DECREASED establishment of planar polarity GO:0001736 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased establishment of planar polarity (GO:0001736). GO:0001736 is a biological process from the Gene Ontology. ↓ DECREASED
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ductal Plate Malformation of the Intrahepatic Biliary Tree Loss of ciliary signalling in the developing biliary epithelium prevents normal remodelling of the embryonic ductal plate.
Show evidence (3 references)
PMID:33824930 SUPPORT Human Clinical
"an abnormal development of the embryonic ductal plate caused by genetically-determined dysfunctions of proteins expressed in the primary cilia of cholangiocytes"
Places the fibrocystic liver diseases, Caroli disease among them, in the cholangiociliopathy class — the defect is in proteins of the cholangiocyte primary cilium.
PMID:33824930 SUPPORT Human Clinical
"a protein of unclear function, but supposedly involved in planar cell polarity and other fundamental cell functions"
Links fibrocystin/polyductin to planar cell polarity, the process annotated on this node, but the source explicitly hedges ("unclear function", "supposedly"), so this is PARTIAL rather than SUPPORT.
PMID:14598246 SUPPORT Model Organism
"In normal IBDUs, each cholangiocyte had a single cilium that expressed fibrocystin. In contrast, cilia in the PCK rat were abnormal with bulbous extensions and diminished length, and were devoid of fibrocystin."
The orthologous PCK rat Pkhd1 model demonstrates that fibrocystin is a cholangiocyte ciliary protein and that its loss produces the shortened, bulbous cilia described in this node.
Ductal Plate Malformation of the Intrahepatic Biliary Tree
The intrahepatic bile ducts form from the ductal plate, a cylindrical sleeve of biliary precursors around each portal vein branch that is normally remodelled into tubular ducts during fetal life. In the fibrocystic liver diseases this remodelling fails, leaving persistent, abnormally shaped embryonic duct structures. Which level of the biliary tree is affected determines the clinical entity: dysgenesis of the small interlobular ducts produces congenital hepatic fibrosis, dysgenesis of the larger intrahepatic ducts produces Caroli disease, and involvement of both produces Caroli syndrome.
intrahepatic cholangiocyte CL:0002538 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intrahepatic cholangiocyte (CL:0002538). CL:0002538 is a cell type from the Cell Ontology.
intrahepatic bile duct development GO:0035622 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal intrahepatic bile duct development (GO:0035622). GO:0035622 is a biological process from the Gene Ontology. ⚠ ABNORMAL
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts Persistent unremodelled ductal plate segments of the large intrahepatic ducts present as the saccular dilatations that define Caroli disease.
Progressive Peribiliary Fibrosis Ductal plate malformation of the small interlobular ducts is accompanied by deposition of dense peribiliary fibrous tissue — the congenital hepatic fibrosis component of Caroli syndrome.
Show evidence (1 reference)
PMID:33824930 SUPPORT Human Clinical
"leading to biliary microhamartomas and segmental bile duct dilations. Biliary changes are accompanied by progressive deposition of abundant peribiliary fibrosis."
Describes the two consequences of the ductal dysgenesis modelled as the downstream edges of this node: segmental duct dilatation and peribiliary fibrosis.
Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts
The anatomical lesion that defines Caroli disease: multifocal, non-obstructive saccular or fusiform dilatations of the large intrahepatic ducts that remain in continuity with the biliary tree. Involvement may be confined to one segment or lobe or be diffuse and bilobar, and this distribution — not the histology — is what determines whether resection is feasible. The dilated segments are demonstrated non-invasively by MR cholangiopancreatography or CT.
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Bile Stasis in the Dilated Segments Bile pools within the saccular outpouchings, where it drains poorly from the dilated segments.
Show evidence (2 references)
PMID:34294522 SUPPORT Human Clinical
"Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts."
Identifies intrahepatic bile duct dilatation as the defining presenting lesion of both forms.
PMID:25327281 SUPPORT Human Clinical
"Magnetic resonance cholangiopancreatography (MRCP) and computed tomography (CT) examinations were most useful in diagnosing CD."
Supports the statement that the dilated ducts are demonstrated by MRCP and CT.
Bile Stasis in the Dilated Segments
Bile drains poorly from the saccular dilatations and stagnates within them. Stasis is the shared proximate cause of the two downstream complications: it supersaturates bile so that intrahepatic pigment stones form, and it permits ascending bacterial colonisation of the stagnant segments.
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hepatolithiasis Stagnant bile supersaturates and precipitates intrahepatic pigment stones within the dilated segments.
Recurrent Bacterial Cholangitis Stagnant bile in segments that communicate with the biliary tree permits ascending bacterial colonisation and repeated infection.
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"the further progression of this destructive inflammatory state leads to recurrent episodes of cholangitis, the development of biliary stones and malignant transformation in some cases"
Places biliary stone formation and recurrent cholangitis together as consequences of the ongoing destructive biliary process, supporting stasis within the dilated segments as their shared proximate step.
Hepatolithiasis
Intrahepatic pigment stones form within the stagnant dilated segments. The stones are themselves obstructive, so they worsen the drainage failure that produced them and provide a nidus for bacterial colonisation, feeding the recurrent cholangitis.
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Recurrent Bacterial Cholangitis Intrahepatic stones further obstruct bile drainage and provide a nidus for bacterial colonisation, precipitating infective episodes.
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"the further progression of this destructive inflammatory state leads to recurrent episodes of cholangitis, the development of biliary stones and malignant transformation in some cases"
States directly that biliary stones develop as part of the disease course, the claim this node carries.
Recurrent Bacterial Cholangitis
Repeated ascending bacterial infection of the stagnant, stone-bearing segments produces the recurrent cholangitis that dominates the clinical course of the simple form — episodic fever, right upper quadrant pain and jaundice — and that can progress to biliary sepsis. Repeated infection also sustains the chronic inflammatory stimulus that underlies both the fibrotic and the neoplastic consequences below.
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Chronic Biliary Inflammation Repeated episodes of cholangitis maintain a chronic inflammatory microenvironment in the biliary epithelium.
Progressive Peribiliary Fibrosis Recurrent biliary inflammation contributes to periportal fibrogenesis in addition to the developmental fibrosis of the ductal plate malformation.
Show evidence (2 references)
PMID:32884228 SUPPORT Human Clinical
"Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."
Across 561 pooled patients, cholangitis, sepsis, fever and abdominal pain were the dominant clinical events, supporting recurrent cholangitis as a core node.
PMID:22197937 SUPPORT Human Clinical
"Cholangitis is a major issue and necessitates anticipatory guidance and awareness."
A systematic review of 1,230 patients concludes that cholangitis is a major clinical problem in this disease group.
Progressive Peribiliary Fibrosis
Abundant fibrous tissue accumulates in the portal and periportal space around the malformed ducts. In Caroli syndrome this is the congenital hepatic fibrosis component and is developmental in origin, present from the outset rather than acquired; recurrent cholangitis adds a secondary inflammatory fibrogenic stimulus. The fibrosis is periportal and bridging rather than a true cirrhotic regenerative-nodule architecture, which is why hepatocellular synthetic function is characteristically preserved long after portal hypertension has become severe.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Presinusoidal Portal Hypertension Periportal fibrous expansion obstructs portal venous inflow at a presinusoidal level, raising portal pressure while sinusoidal and hepatocellular function remain relatively spared.
Show evidence (1 reference)
PMID:33824930 SUPPORT Human Clinical
"Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs and are responsible for the main clinical manifestations, such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma."
Names peribiliary fibrosis as one of the two fundamental lesions and links it directly to portal hypertension, the downstream node.
Presinusoidal Portal Hypertension
Portal pressure rises because of the periportal fibrous obstruction, producing splenomegaly with hypersplenic cytopenias and portosystemic collaterals — principally oesophageal and gastric fundal varices that bleed recurrently. The presinusoidal site of obstruction explains the characteristic dissociation between severe portal hypertension and near-normal liver biochemistry early in the course. Over years, repeated decompensation and progressive cholestasis erode hepatic reserve, converting a compensated Child-Pugh class A patient into a transplant candidate.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (3 references)
PMID:42438734 SUPPORT Human Clinical
"At initial presentation in 2015, she had splenomegaly, severe esophagogastric fundal varices, preserved liver biochemistry, Child-Pugh class A disease, and a low model for end-stage liver disease score."
A worked single-patient example of the dissociation this node describes — severe portal hypertension (splenomegaly, fundal varices) with preserved liver biochemistry.
PMID:42438734 SUPPORT Human Clinical
"longitudinal follow-up showed persistent portal hypertension, recurrent gastrointestinal bleeding, and progressive impairment of hepatic reserve"
Documents the decade-long erosion of hepatic reserve described in this node.
PMID:22197937 SUPPORT Human Clinical
"The nature of the portal hypertension was similar to that in other pediatric conditions (164 with varices, 74 bleeding varices, 81 underwent portosystemic shunting)."
Quantifies the varices and variceal bleeding that constitute the clinical expression of portal hypertension in this disease group.
Chronic Biliary Inflammation
Decades of bile stasis and recurrent cholangitis expose the biliary epithelium to a sustained inflammatory and proliferative stimulus. The inflammatory state itself is well documented — it is the continuously destructive process that drives the clinical course — and it is separated here from the malignant transformation it is proposed to trigger, whose derivation is weaker.
intrahepatic cholangiocyte CL:0002538 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intrahepatic cholangiocyte (CL:0002538). CL:0002538 is a cell type from the Cell Ontology.
positive regulation of cholangiocyte proliferation GO:1904056 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of cholangiocyte proliferation (GO:1904056). GO:1904056 is a biological process from the Gene Ontology. ↑ INCREASED
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cholangiocarcinoma Chronic inflammation of the biliary epithelium with consecutive dysplasia is the postulated trigger for malignant transformation; the intervening steps are not established in Caroli tissue.
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"Due to focal inflammation, likely initiated by an intrauterine malformation of the bile ductal plate, the biliary tract is continuously destroyed over decades"
Establishes sustained inflammatory destruction of the biliary tract over decades as the process this node describes.
Cholangiocarcinoma
Cholangiocarcinoma arises at rates far above the general population. Age at diagnosis is nonetheless predominantly beyond 40 years (mean 60.1 years in Caroli syndrome and isolated congenital hepatic fibrosis), so the excess risk is one of incidence rather than of markedly earlier onset. Reported incidence varies widely between series — from under 3% to over a third in small cohorts — but the two largest systematic assessments converge on roughly 6-7%. Tumours are frequently found incidentally in the resection specimen because preoperative imaging cannot reliably distinguish malignancy from the underlying cystic architecture, and outcomes once malignancy is present are poor. The node is marked PROVISIONAL because the inflammation-to-carcinoma link is inferred from the epidemiological association and from the general biliary-inflammation carcinogenesis model rather than demonstrated directly in Caroli tissue.
intrahepatic bile duct UBERON:0003704 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in intrahepatic bile duct (UBERON:0003704). UBERON:0003704 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (4 references)
PMID:32884228 SUPPORT Human Clinical
"Depending on the size of the study population the incidence of cholangiocarcinoma varied from 2.7% to 37.5% with an overall incidence of 6.6%."
Provides the pooled cholangiocarcinoma incidence (6.6%) and the wide between-study range quoted in this node.
PMID:34294522 SUPPORT Human Clinical
"In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%)."
An independent 198-patient multicentre series gives 7.1% overall, closely matching the pooled systematic-review estimate.
PMID:32884228 SUPPORT Human Clinical
"Tumor detection was an incidental finding of the surgical specimen in most cases because it is currently often impossible to detect tumor manifestation during preoperative diagnostics."
Supports the statement that malignancy is usually found incidentally in the resection specimen rather than preoperatively.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Caroli disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Cardiovascular 2
Portal hypertension HP:0001409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Portal hypertension (HP:0001409), qualified as course progressive. HP:0001409 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:42438734 SUPPORT Human Clinical
"Caroli's disease is a rare congenital disorder of the intrahepatic bile ducts that may be complicated by congenital hepatic fibrosis, portal hypertension, and recurrent variceal bleeding."
States portal hypertension as a recognised complication of Caroli disease.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25327281 SUPPORT Human Clinical
"Anaemia, leucopoenia and thrombocytopoenia were more frequent in patients with type II than type I CD."
Documents the hypersplenic cytopenias and their preferential association with the type II (syndromic) form.
Digestive 2
Esophageal varices with recurrent bleeding Esophageal varix HP:0002040 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esophageal varix (HP:0002040). HP:0002040 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22197937 SUPPORT Human Clinical
"164 with varices, 74 bleeding varices"
Of 1,230 pooled patients with congenital hepatic fibrosis, 164 had varices and 74 had bleeding varices, documenting variceal haemorrhage as a core manifestation.
Cholelithiasis and hepatolithiasis HP:0001081 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholelithiasis (HP:0001081). HP:0001081 is a phenotype from the Human Phenotype Ontology.
The cited snippet supports the cholestatic complication set of the fibrocystic liver diseases rather than stone disease specifically; a hepatolithiasis-specific citation is a curation follow-up.
Show evidence (1 reference)
PMID:33824930 SUPPORT Human Clinical
"such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma"
Lists the biliary complications of the fibrocystic liver diseases including cholestasis, from which stone disease follows; the source does not name hepatolithiasis, hence PARTIAL.
Constitutional 1
Abdominal pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."
Abdominal pain is among the dominant presenting symptoms.
Other 6
Intrahepatic bile duct dilatation HP:0033149 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrahepatic bile duct dilatation (HP:0033149). HP:0033149 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34294522 SUPPORT Human Clinical
"Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts."
Identifies intrahepatic bile duct dilatation as the presenting lesion.
Intrahepatic bile duct cysts HP:0005209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrahepatic bile duct cysts (HP:0005209). HP:0005209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33824930 SUPPORT Human Clinical
"Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs"
Names biliary cysts as one of the two fundamental lesions of this disease group.
Recurrent cholangitis HP:0030151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholangitis (HP:0030151), qualified as temporality recurrent. HP:0030151 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."
Cholangitis was the dominant clinical event across 561 pooled patients.
Congenital hepatic fibrosis HP:0002612 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hepatic fibrosis (HP:0002612). HP:0002612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32884228 SUPPORT Human Clinical
"is called Caroli syndrome (CS) when it has fibrotic and cirrhotic liver morphology"
Fibrotic liver morphology is the defining feature of the syndromic form.
Cholangiocarcinoma HP:0030153 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholangiocarcinoma (HP:0030153). HP:0030153 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32884228 SUPPORT Human Clinical
"With a mean age of 41.6 years old (range 23 to 56 years old), patients were younger than other populations undergoing liver surgery."
Documents the young age of the affected surgical population relative to other liver-surgery cohorts. This is age at liver surgery for the whole cohort, not age at cholangiocarcinoma diagnosis.
PMID:22197937 SUPPORT Human Clinical
"Cholangiocarcinoma (CCA) was predominant in individuals older than 40 years with either Caroli syndrome or isolated CHF, not ARPKD (median and mean age at CCA diagnosis were 70.3 and 60.1 years, respectively; range 33-75 years)."
Establishes the actual age at cholangiocarcinoma diagnosis in Caroli syndrome, correcting the conflation with the surgical cohort's mean age.
Polycystic kidney disease Polycystic kidney dysplasia HP:0000113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycystic kidney dysplasia (HP:0000113). HP:0000113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33824930 SUPPORT Human Clinical
"Among them, the autosomal recessive polycystic kidney disease (ARPKD) is the most frequent, and the renal function impairment is central in disease progression."
ARPKD is the most frequent associated renal disorder and its renal impairment drives overall progression.
🧬

Genetic Associations

1
PKHD1
Gene: PKHD1 hgnc:9016 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PKHD1 (hgnc:9016). hgnc:9016 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33824930 SUPPORT Human Clinical
"CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (PKHD1), a gene that encodes for fibrocystin/polyductin"
Directly attributes Caroli disease and Caroli syndrome, alongside congenital hepatic fibrosis and ARPKD, to PKHD1 mutations.
PMID:14598246 SUPPORT Model Organism
"Our results indicate that fibrocystin is expressed in cholangiocyte cilia and that disruption of Pkhd1 by a germ line mutation in the PCK rat or by siRNA in IBDUs results in abnormalities in ciliary morphology and possibly biliary cystogenesis."
Orthologous rat model evidence that Pkhd1 disruption causes ciliary abnormalities and biliary cystogenesis.
💊

Medical Actions

6
Antibiotic Therapy for Cholangitis
Action: Antibiotic TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Antibiotic Therapy (NCIT:C15620). NCIT:C15620 is a clinical intervention from the NCI Thesaurus. NCIT:C15620
Antimicrobial treatment of the recurrent bacterial cholangitis that arises from bile stasis, with anticipatory guidance for patients and families given how often infection recurs. Treatment is directed at the complication, not at the underlying ductal plate malformation.
Mechanism Target:
INHIBITS Recurrent Bacterial Cholangitis — Antimicrobials clear the bacterial infection of the stagnant biliary segments but do not correct the underlying stasis.
Show evidence (1 reference)
PMID:22197937 SUPPORT Human Clinical
"Cholangitis is a major issue and necessitates anticipatory guidance and awareness."
Establishes cholangitis as a major complication requiring active clinical management and anticipatory guidance.
Nonselective Beta-Blocker Therapy for Portal Hypertension
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: propranolol CHEBI:8499 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses propranolol (CHEBI:8499). CHEBI:8499 is a therapeutic agent from Chemical Entities of Biological Interest. carvedilol CHEBI:3441 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carvedilol (CHEBI:3441). CHEBI:3441 is a therapeutic agent from Chemical Entities of Biological Interest.
Propranolol or carvedilol to lower portal pressure and reduce variceal bleeding risk. Symptomatically effective at first, but the reported long-term course shows persistent portal hypertension and recurrent bleeding despite therapy, including after conversion from propranolol to carvedilol.
Mechanism Target:
INHIBITS Presinusoidal Portal Hypertension — Nonselective beta-blockade reduces portal inflow and portal pressure, the mechanism targeted for variceal bleeding prophylaxis.
Show evidence (1 reference)
PMID:42438734 SUPPORT Human Clinical
"Symptoms improved after nonselective beta-blocker therapy; however, longitudinal follow-up showed persistent portal hypertension, recurrent gastrointestinal bleeding, and progressive impairment of hepatic reserve."
Single-patient evidence of initial symptomatic benefit followed by long-term failure to control portal hypertension — hence PARTIAL rather than SUPPORT.
Endoscopic Variceal Ligation
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
Endoscopic band ligation of bleeding oesophageal varices. Effective for acute haemorrhage control but, in the documented long-term course, did not prevent recurrent bleeding when applied sequentially over years.
Mechanism Target:
INHIBITS Presinusoidal Portal Hypertension — Obliterates the variceal collaterals through which portal hypertension causes haemorrhage, without altering portal pressure itself.
Show evidence (1 reference)
PMID:42438734 SUPPORT Human Clinical
"she experienced recurrent hematemesis and melena despite sequential endoscopic variceal ligation and beta-blocker therapy"
Documents recurrent bleeding despite sequential band ligation, supporting the described limitation of endoscopic therapy.
Hepatic Resection for Localised Disease
Action: HepatectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hepatectomy (NCIT:C15249). NCIT:C15249 is a clinical intervention from the NCI Thesaurus. NCIT:C15249
Segmental or lobar hepatectomy when the ductal dilatations are confined to a resectable part of the liver. Resection removes the stasis-and-infection focus, relieves symptoms, and eliminates the segment at risk of malignant transformation; occult cholangiocarcinoma is not infrequently found in the specimen.
Mechanism Target:
INHIBITS Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts — Removes the malformed duct segments, eliminating the anatomical substrate for stasis, infection and carcinogenesis in the resected territory.
Show evidence (1 reference)
PMID:34294522 SUPPORT Human Clinical
"There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised."
Multicentre surgical series concludes that resection is strongly advised, on grounds of both malignancy risk and symptom relief.
Liver Transplantation
Action: Liver TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver Transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. NCIT:C15271
The definitive option for diffuse bilobar disease that cannot be resected, for hepatic decompensation, and for portal hypertension refractory to endoscopic and pharmacological therapy. Combined liver-kidney transplantation is considered when ARPKD has produced concurrent renal failure. Referral before advanced decompensation is advocated, since hepatic reserve declines progressively while complications recur.
Mechanism Target:
INHIBITS Presinusoidal Portal Hypertension — Replacing the fibrotic, malformed liver removes the presinusoidal obstruction and with it the portal hypertension.
Show evidence (2 references)
PMID:42438734 SUPPORT Human Clinical
"This case demonstrates the limitations of long-term endoscopic and pharmacological therapy in Caroli's disease complicated by portal hypertension and supports timely transplant referral before advanced hepatic decompensation occurs."
Supports transplantation as the definitive option and argues for timely referral, the recommendation captured in this treatment.
PMID:33824930 SUPPORT Human Clinical
"Interventional radiology or surgical treatments, including liver transplantation, are used in selected cases."
Confirms liver transplantation as an accepted treatment in selected cases of fibrocystic liver disease.
Avoidance of Hepatotoxic and Nephrotoxic Agents
Action: avoidance of hepatotoxic and nephrotoxic agentsNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is avoidance of hepatotoxic and nephrotoxic agents, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Where Caroli disease occurs as the hepatobiliary presentation of ARPKD-PKHD1, GeneReviews advises minimising potentially hepatotoxic exposures — acetaminophen at doses above 30 mg/kg/day, herbal supplements and alcohol — alongside known nephrotoxic agents such as NSAIDs and aminoglycosides, on the rationale that hepatic and renal reserve are already committed by the underlying disease. Scope caveat: this guidance is written for ARPKD-PKHD1 and so applies to the PKHD1-associated Caroli syndrome form curated here; it should not be transferred wholesale to simple, frequently sporadic Caroli disease, whose genetic basis and renal involvement are not the same.
Show evidence (1 reference)
PMID:20301501 SUPPORT Human Clinical
"Minimizing use of known nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides (unless otherwise advised) and of potentially hepatotoxic agents (e.g., acetaminophen doses >30 mg/kg/day, herbal supplements, and alcohol) is advised."
The GeneReviews Agents/Circumstances to Avoid guidance for ARPKD-PKHD1, recorded verbatim as the exposure-avoidance advice for the PKHD1-associated form of this entry.
🔬

Diagnosis

1
MR cholangiopancreatography
MRCP demonstrates the saccular intrahepatic duct dilatations and their communication with the biliary tree, and is the mainstay of non-invasive diagnosis together with CT. No symptom, sign or laboratory value distinguishes Caroli disease from other biliary disorders.
Show evidence (1 reference)
PMID:25327281 SUPPORT Human Clinical
"No typical symptoms, signs or laboratory indicators are able to distinguish CD from other conditions. Both MRCP and CT were most valuable in diagnosis."
Establishes cross-sectional/MRCP imaging as the diagnostic modality and the absence of a discriminating clinical or laboratory feature.
🐁

Animal Models

1
PCK rat (Pkhd1 splicing mutant) Spontaneous orthologous mutant
The PCK rat carries a germline Pkhd1 mutation and is an orthologous model of ARPKD with biliary involvement. It reproduces the distorted, dilated biliary tree and established that fibrocystin is a cholangiocyte ciliary protein whose loss yields shortened, bulbous cilia — the ciliary lesion that anchors the root pathophysiology node of this entry.
Multiple intrahepatic bile duct dilatation Focal biliary budding Shortened, bulbous cholangiocyte cilia
Species
Rat (Rattus norvegicus)
Genotype
PCK rat, germline Pkhd1 splicing mutation (homozygous)
Genes
Pkhd1 hgnc:9016 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns Pkhd1 (hgnc:9016). hgnc:9016 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:14598246 SUPPORT Model Organism
"The biliary tree in the PCK rat was distorted markedly, showing multiple bile duct dilatation and focal budding."
The model reproduces the multiple intrahepatic bile duct dilatations that define the human disease.
{ }

Source YAML

click to show 
name: Caroli disease
creation_date: "2026-08-07T00:00:00Z"
category: Mendelian
description: >-
  Caroli disease is a rare congenital disorder of the intrahepatic biliary tree in
  which segmental, non-obstructive saccular dilatations of the large intrahepatic
  bile ducts arise from a ductal plate malformation — a failure of the embryonic
  ductal plate to remodel normally. It belongs to the fibrocystic liver diseases,
  a group of cholangiociliopathies caused by dysfunction of proteins expressed in
  the primary cilium of cholangiocytes; the best-characterised gene is PKHD1,
  encoding fibrocystin/polyductin, which also causes autosomal recessive polycystic
  kidney disease. Two forms are distinguished by whether the small interlobular
  ducts are also affected: the simple (type I) form shows ductal ectasia alone,
  whereas Caroli syndrome (type II) combines the ductal dilatations with congenital
  hepatic fibrosis. Bile stasis within the dilated segments drives hepatolithiasis
  and recurrent bacterial cholangitis; peribiliary fibrosis produces presinusoidal
  portal hypertension with splenomegaly and variceal bleeding despite long-preserved
  hepatocellular synthetic function. Chronic biliary inflammation carries a
  substantially increased risk of cholangiocarcinoma. No targeted medical therapy
  exists; management controls complications, with hepatic resection for localised
  disease and liver (or combined liver-kidney) transplantation for diffuse disease
  or hepatic decompensation.
synonyms:
- Caroli's disease
- Congenital dilatation of the intrahepatic bile ducts
- Congenital polycystic dilatation of intrahepatic bile ducts
- Cystic dilatation of the intrahepatic biliary tree
- Type V choledochal cyst
disease_term:
  preferred_term: Caroli disease
  term:
    id: MONDO:0010913
    label: Caroli disease
parents:
- non-neoplastic bile duct disorder
- liver disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010913
      label: Caroli disease
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO Orphanet:53035 xref
    mapping_justification: >-
      MONDO:0010913 is the primary anchor for this entry and carries Orphanet:53035
      and OMIM:600643 as disease cross-references. The syndromic form (Caroli
      syndrome, MONDO:0018808) is modelled here as a subtype rather than a separate
      entry because it shares the same ductal plate malformation mechanism and
      differs only by additional involvement of the small interlobular ducts.
  - term:
      id: MONDO:0018808
      label: Caroli syndrome
    mapping_predicate: skos:narrowMatch
    mapping_justification: >-
      Caroli syndrome is the subset of Caroli disease that coexists with congenital
      hepatic fibrosis; it is curated as the `Caroli syndrome` subtype of this entry.
has_subtypes:
- name: Simple Caroli disease
  display_name: Simple (type I) Caroli disease — ductal ectasia without hepatic fibrosis
  description: >-
    Segmental saccular dilatation of the large intrahepatic bile ducts without
    congenital hepatic fibrosis. Clinical disease is dominated by bile stasis
    complications — hepatolithiasis, recurrent bacterial cholangitis and biliary
    sepsis — rather than by portal hypertension. Frequently segmental or monolobar,
    which makes curative hepatic resection possible.
  review_notes: >-
    Intentionally has no `subtype_term`. MONDO has no separate term for the simple
    form — MONDO:0010913 (Caroli disease) *is* the term for ductal dilatation
    without hepatic fibrosis, and it is already the entry-level `disease_term`, so
    repeating it here would assert that the subtype and the whole entry are the same
    entity. Only the syndromic form has its own MONDO anchor (MONDO:0018808). The
    advisory `test_subtypes_have_disease_term` warning on this subtype is therefore
    expected, not an omission.
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital intrahepatic bile duct dilatation without fibrosis is called Caroli disease (CD), and is called Caroli syndrome (CS) when it has fibrotic and cirrhotic liver morphology."
    explanation: >-
      Defines the simple form as intrahepatic bile duct dilatation occurring without
      hepatic fibrosis, distinguishing it from the syndromic form.
- name: Caroli syndrome
  display_name: Caroli syndrome (type II) — ductal ectasia with congenital hepatic fibrosis
  subtype_term:
    preferred_term: Caroli syndrome
    term:
      id: MONDO:0018808
      label: Caroli syndrome
  description: >-
    Caroli disease coexisting with congenital hepatic fibrosis, reflecting ductal
    plate malformation of the small interlobular ducts in addition to the large
    intrahepatic ducts. It is strongly associated with autosomal recessive
    polycystic kidney disease. Presinusoidal portal hypertension with splenomegaly,
    hypersplenism and variceal bleeding dominates the clinical course, and diffuse
    involvement usually makes resection impossible so that transplantation becomes
    the definitive option.
  genes:
  - preferred_term: PKHD1
    term:
      id: hgnc:9016
      label: PKHD1
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ductal dysgenesis may affect the biliary system at multiple levels, from the small intrahepatic bile ducts"
    explanation: >-
      States that the ductal dysgenesis affects the biliary tree at multiple levels,
      the basis for distinguishing Caroli syndrome (large plus small ducts) from
      simple Caroli disease.
  - reference: PMID:34294522
    reference_title: "The rate of cholangiocarcinoma in Caroli Disease A German multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients."
    explanation: >-
      In a 17-centre German surgical series the syndromic form outnumbered the simple
      form (119 vs 79). This is a surgical-referral cohort, so it does not establish
      the population-level ratio.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    The PKHD1-associated forms of Caroli disease — in particular Caroli syndrome
    with congenital hepatic fibrosis, which shares its genetic basis with autosomal
    recessive polycystic kidney disease — are inherited in an autosomal recessive
    pattern. Simple Caroli disease is frequently reported as sporadic, and the
    genetic basis of isolated large-duct disease is less completely defined.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (PKHD1), a gene that encodes for fibrocystin/polyductin"
    explanation: >-
      Attributes congenital hepatic fibrosis, Caroli disease/syndrome and ARPKD to
      mutations in PKHD1; ARPKD is by definition autosomal recessive.
  - reference: PMID:20301501
    reference_title: "Autosomal Recessive Polycystic Kidney Disease - PKHD1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARPKD-PKHD1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PKHD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      GeneReviews states the autosomal recessive mode of inheritance for
      ARPKD-PKHD1 outright, with the 25% per-conception sib recurrence risk,
      rather than leaving it to be inferred from the ARPKD label.
pathophysiology:
- name: Fibrocystin Loss from the Cholangiocyte Primary Cilium
  role: root
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic PKHD1 variants reduce or abolish fibrocystin/polyductin, a large
    receptor-like protein that in normal biliary epithelium localises to the single
    primary cilium projecting from each cholangiocyte into the duct lumen. Loss of
    fibrocystin leaves the cilium structurally abnormal — shortened and with bulbous
    deformities — so the cholangiocyte can no longer transduce the ciliary signals
    that normally govern planar cell polarity and oriented growth of the developing
    duct. Because the same protein is required in renal tubular cilia, the biliary
    lesion is typically accompanied by the renal phenotype of autosomal recessive
    polycystic kidney disease.
  conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
  gene:
    preferred_term: PKHD1
    term:
      id: hgnc:9016
      label: PKHD1
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  - preferred_term: establishment of planar polarity
    term:
      id: GO:0001736
      label: establishment of planar polarity
    modifier: DECREASED
  downstream:
  - target: Ductal Plate Malformation of the Intrahepatic Biliary Tree
    causal_link_type: DIRECT
    description: >-
      Loss of ciliary signalling in the developing biliary epithelium prevents normal
      remodelling of the embryonic ductal plate.
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an abnormal development of the embryonic ductal plate caused by genetically-determined dysfunctions of proteins expressed in the primary cilia of cholangiocytes"
    explanation: >-
      Places the fibrocystic liver diseases, Caroli disease among them, in the
      cholangiociliopathy class — the defect is in proteins of the cholangiocyte
      primary cilium.
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a protein of unclear function, but supposedly involved in planar cell polarity and other fundamental cell functions"
    explanation: >-
      Links fibrocystin/polyductin to planar cell polarity, the process annotated on
      this node, but the source explicitly hedges ("unclear function", "supposedly"),
      so this is PARTIAL rather than SUPPORT.
  - reference: PMID:14598246
    reference_title: "Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In normal IBDUs, each cholangiocyte had a single cilium that expressed fibrocystin. In contrast, cilia in the PCK rat were abnormal with bulbous extensions and diminished length, and were devoid of fibrocystin."
    explanation: >-
      The orthologous PCK rat Pkhd1 model demonstrates that fibrocystin is a
      cholangiocyte ciliary protein and that its loss produces the shortened,
      bulbous cilia described in this node.
- name: Ductal Plate Malformation of the Intrahepatic Biliary Tree
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    The intrahepatic bile ducts form from the ductal plate, a cylindrical sleeve of
    biliary precursors around each portal vein branch that is normally remodelled
    into tubular ducts during fetal life. In the fibrocystic liver diseases this
    remodelling fails, leaving persistent, abnormally shaped embryonic duct
    structures. Which level of the biliary tree is affected determines the clinical
    entity: dysgenesis of the small interlobular ducts produces congenital hepatic
    fibrosis, dysgenesis of the larger intrahepatic ducts produces Caroli disease,
    and involvement of both produces Caroli syndrome.
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  biological_processes:
  - preferred_term: intrahepatic bile duct development
    term:
      id: GO:0035622
      label: intrahepatic bile duct development
    modifier: ABNORMAL
  downstream:
  - target: Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts
    causal_link_type: DIRECT
    description: >-
      Persistent unremodelled ductal plate segments of the large intrahepatic ducts
      present as the saccular dilatations that define Caroli disease.
  - target: Progressive Peribiliary Fibrosis
    causal_link_type: DIRECT
    description: >-
      Ductal plate malformation of the small interlobular ducts is accompanied by
      deposition of dense peribiliary fibrous tissue — the congenital hepatic
      fibrosis component of Caroli syndrome.
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "leading to biliary microhamartomas and segmental bile duct dilations. Biliary changes are accompanied by progressive deposition of abundant peribiliary fibrosis."
    explanation: >-
      Describes the two consequences of the ductal dysgenesis modelled as the
      downstream edges of this node: segmental duct dilatation and peribiliary
      fibrosis.
- name: Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    The anatomical lesion that defines Caroli disease: multifocal, non-obstructive
    saccular or fusiform dilatations of the large intrahepatic ducts that remain in
    continuity with the biliary tree. Involvement may be confined to one segment or
    lobe or be diffuse and bilobar, and this distribution — not the histology — is
    what determines whether resection is feasible. The dilated segments are
    demonstrated non-invasively by MR cholangiopancreatography or CT.
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  downstream:
  - target: Bile Stasis in the Dilated Segments
    causal_link_type: DIRECT
    description: >-
      Bile pools within the saccular outpouchings, where it drains poorly from the
      dilated segments.
  evidence:
  - reference: PMID:34294522
    reference_title: "The rate of cholangiocarcinoma in Caroli Disease A German multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts."
    explanation: >-
      Identifies intrahepatic bile duct dilatation as the defining presenting lesion
      of both forms.
  - reference: PMID:25327281
    reference_title: "Clinical classification of Caroli's disease: an analysis of 30 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance cholangiopancreatography (MRCP) and computed tomography (CT) examinations were most useful in diagnosing CD."
    explanation: >-
      Supports the statement that the dilated ducts are demonstrated by MRCP and CT.
- name: Bile Stasis in the Dilated Segments
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Bile drains poorly from the saccular dilatations and stagnates within them.
    Stasis is the shared proximate cause of the two downstream complications:
    it supersaturates bile so that intrahepatic pigment stones form, and it
    permits ascending bacterial colonisation of the stagnant segments.
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  downstream:
  - target: Hepatolithiasis
    causal_link_type: DIRECT
    description: >-
      Stagnant bile supersaturates and precipitates intrahepatic pigment stones
      within the dilated segments.
  - target: Recurrent Bacterial Cholangitis
    causal_link_type: DIRECT
    description: >-
      Stagnant bile in segments that communicate with the biliary tree permits
      ascending bacterial colonisation and repeated infection.
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the further progression of this destructive inflammatory state leads to recurrent episodes of cholangitis, the development of biliary stones and malignant transformation in some cases"
    explanation: >-
      Places biliary stone formation and recurrent cholangitis together as
      consequences of the ongoing destructive biliary process, supporting stasis
      within the dilated segments as their shared proximate step.
- name: Hepatolithiasis
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Intrahepatic pigment stones form within the stagnant dilated segments. The
    stones are themselves obstructive, so they worsen the drainage failure that
    produced them and provide a nidus for bacterial colonisation, feeding the
    recurrent cholangitis.
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  downstream:
  - target: Recurrent Bacterial Cholangitis
    causal_link_type: DIRECT
    description: >-
      Intrahepatic stones further obstruct bile drainage and provide a nidus for
      bacterial colonisation, precipitating infective episodes.
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the further progression of this destructive inflammatory state leads to recurrent episodes of cholangitis, the development of biliary stones and malignant transformation in some cases"
    explanation: >-
      States directly that biliary stones develop as part of the disease course,
      the claim this node carries.
- name: Recurrent Bacterial Cholangitis
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Repeated ascending bacterial infection of the stagnant, stone-bearing segments
    produces the recurrent cholangitis that dominates the clinical course of the
    simple form — episodic fever, right upper quadrant pain and jaundice — and that
    can progress to biliary sepsis. Repeated infection also sustains the chronic
    inflammatory stimulus that underlies both the fibrotic and the neoplastic
    consequences below.
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  downstream:
  - target: Chronic Biliary Inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Repeated episodes of cholangitis maintain a chronic inflammatory
      microenvironment in the biliary epithelium.
  - target: Progressive Peribiliary Fibrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Recurrent biliary inflammation contributes to periportal fibrogenesis in
      addition to the developmental fibrosis of the ductal plate malformation.
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."
    explanation: >-
      Across 561 pooled patients, cholangitis, sepsis, fever and abdominal pain were
      the dominant clinical events, supporting recurrent cholangitis as a core node.
  - reference: PMID:22197937
    reference_title: "Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cholangitis is a major issue and necessitates anticipatory guidance and awareness."
    explanation: >-
      A systematic review of 1,230 patients concludes that cholangitis is a major
      clinical problem in this disease group.
- name: Progressive Peribiliary Fibrosis
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Abundant fibrous tissue accumulates in the portal and periportal space around
    the malformed ducts. In Caroli syndrome this is the congenital hepatic fibrosis
    component and is developmental in origin, present from the outset rather than
    acquired; recurrent cholangitis adds a secondary inflammatory fibrogenic
    stimulus. The fibrosis is periportal and bridging rather than a true cirrhotic
    regenerative-nodule architecture, which is why hepatocellular synthetic function
    is characteristically preserved long after portal hypertension has become severe.
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  downstream:
  - target: Presinusoidal Portal Hypertension
    causal_link_type: DIRECT
    description: >-
      Periportal fibrous expansion obstructs portal venous inflow at a presinusoidal
      level, raising portal pressure while sinusoidal and hepatocellular function
      remain relatively spared.
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs and are responsible for the main clinical manifestations, such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma."
    explanation: >-
      Names peribiliary fibrosis as one of the two fundamental lesions and links it
      directly to portal hypertension, the downstream node.
- name: Presinusoidal Portal Hypertension
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Portal pressure rises because of the periportal fibrous obstruction, producing
    splenomegaly with hypersplenic cytopenias and portosystemic collaterals —
    principally oesophageal and gastric fundal varices that bleed recurrently. The
    presinusoidal site of obstruction explains the characteristic dissociation
    between severe portal hypertension and near-normal liver biochemistry early in
    the course. Over years, repeated decompensation and progressive cholestasis
    erode hepatic reserve, converting a compensated Child-Pugh class A patient into
    a transplant candidate.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:42438734
    reference_title: "Ten-year progression of Caroli's disease with portal hypertension despite endoscopic and pharmacological therapy: Implications for liver transplantation-A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At initial presentation in 2015, she had splenomegaly, severe esophagogastric fundal varices, preserved liver biochemistry, Child-Pugh class A disease, and a low model for end-stage liver disease score."
    explanation: >-
      A worked single-patient example of the dissociation this node describes —
      severe portal hypertension (splenomegaly, fundal varices) with preserved liver
      biochemistry.
  - reference: PMID:42438734
    reference_title: "Ten-year progression of Caroli's disease with portal hypertension despite endoscopic and pharmacological therapy: Implications for liver transplantation-A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "longitudinal follow-up showed persistent portal hypertension, recurrent gastrointestinal bleeding, and progressive impairment of hepatic reserve"
    explanation: >-
      Documents the decade-long erosion of hepatic reserve described in this node.
  - reference: PMID:22197937
    reference_title: "Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nature of the portal hypertension was similar to that in other pediatric conditions (164 with varices, 74 bleeding varices, 81 underwent portosystemic shunting)."
    explanation: >-
      Quantifies the varices and variceal bleeding that constitute the clinical
      expression of portal hypertension in this disease group.
- name: Chronic Biliary Inflammation
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Decades of bile stasis and recurrent cholangitis expose the biliary epithelium
    to a sustained inflammatory and proliferative stimulus. The inflammatory state
    itself is well documented — it is the continuously destructive process that
    drives the clinical course — and it is separated here from the malignant
    transformation it is proposed to trigger, whose derivation is weaker.
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  biological_processes:
  - preferred_term: positive regulation of cholangiocyte proliferation
    term:
      id: GO:1904056
      label: positive regulation of cholangiocyte proliferation
    modifier: INCREASED
  downstream:
  - target: Cholangiocarcinoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic inflammation of the biliary epithelium with consecutive dysplasia is
      the postulated trigger for malignant transformation; the intervening steps
      are not established in Caroli tissue.
    evidence:
    - reference: PMID:32884228
      reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As one trigger for the malignant transformation, chronic inflammation of the biliary epithelium during cholangitis with consecutive dysplasia and carcinogenesis is postulated"
      explanation: >-
        States the inflammation-to-carcinoma link explicitly, but as a postulated
        trigger rather than a demonstrated one — the reason the carcinoma node is
        graded PROVISIONAL.
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to focal inflammation, likely initiated by an intrauterine malformation of the bile ductal plate, the biliary tract is continuously destroyed over decades"
    explanation: >-
      Establishes sustained inflammatory destruction of the biliary tract over
      decades as the process this node describes.
- name: Cholangiocarcinoma
  role: consequence
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Cholangiocarcinoma arises at rates far above the general population. Age at
    diagnosis is nonetheless predominantly beyond 40 years (mean 60.1 years in
    Caroli syndrome and isolated congenital hepatic fibrosis), so the excess risk
    is one of incidence rather than of markedly earlier onset.
    Reported incidence varies widely between series — from under 3% to over a third
    in small cohorts — but the two largest systematic assessments converge on
    roughly 6-7%. Tumours are frequently found incidentally in the resection
    specimen because preoperative imaging cannot reliably distinguish malignancy
    from the underlying cystic architecture, and outcomes once malignancy is present
    are poor. The node is marked PROVISIONAL because the inflammation-to-carcinoma
    link is inferred from the epidemiological association and from the general
    biliary-inflammation carcinogenesis model rather than demonstrated directly in
    Caroli tissue.
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Depending on the size of the study population the incidence of cholangiocarcinoma varied from 2.7% to 37.5% with an overall incidence of 6.6%."
    explanation: >-
      Provides the pooled cholangiocarcinoma incidence (6.6%) and the wide
      between-study range quoted in this node.
  - reference: PMID:34294522
    reference_title: "The rate of cholangiocarcinoma in Caroli Disease A German multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%)."
    explanation: >-
      An independent 198-patient multicentre series gives 7.1% overall, closely
      matching the pooled systematic-review estimate.
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumor detection was an incidental finding of the surgical specimen in most cases because it is currently often impossible to detect tumor manifestation during preoperative diagnostics."
    explanation: >-
      Supports the statement that malignancy is usually found incidentally in the
      resection specimen rather than preoperatively.
  - reference: PMID:22197937
    reference_title: "Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-one patients developed hepatobiliary cancer, with the majority having cholangiocarcinoma (n = 19)."
    explanation: >-
      Confirms cholangiocarcinoma as the dominant malignancy in this disease group.
phenotypes:
- category: Hepatobiliary
  name: Intrahepatic bile duct dilatation
  description: >-
    Segmental, non-obstructive saccular dilatation of the large intrahepatic bile
    ducts — the defining anatomical finding of Caroli disease.
  phenotype_term:
    preferred_term: Intrahepatic bile duct dilatation
    term:
      id: HP:0033149
      label: Intrahepatic bile duct dilatation
  diagnostic: true
  evidence:
  - reference: PMID:34294522
    reference_title: "The rate of cholangiocarcinoma in Caroli Disease A German multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts."
    explanation: Identifies intrahepatic bile duct dilatation as the presenting lesion.
- category: Hepatobiliary
  name: Intrahepatic bile duct cysts
  description: >-
    The dilated duct segments appear on cross-sectional imaging as intrahepatic
    cystic structures that, unlike simple hepatic cysts, communicate with the
    biliary tree.
  phenotype_term:
    preferred_term: Intrahepatic bile duct cysts
    term:
      id: HP:0005209
      label: Intrahepatic bile duct cysts
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs"
    explanation: Names biliary cysts as one of the two fundamental lesions of this disease group.
- category: Hepatobiliary
  name: Recurrent cholangitis
  description: >-
    Recurrent episodes of bacterial cholangitis arising from bile stasis within the
    dilated segments, presenting with fever, right upper quadrant pain and jaundice
    and capable of progressing to biliary sepsis.
  phenotype_term:
    preferred_term: Cholangitis
    term:
      id: HP:0030151
      label: Cholangitis
    temporality: RECURRENT
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."
    explanation: Cholangitis was the dominant clinical event across 561 pooled patients.
- category: Hepatobiliary
  name: Congenital hepatic fibrosis
  subtype: Caroli syndrome
  description: >-
    Dense periportal fibrosis accompanying ductal plate malformation of the small
    interlobular bile ducts. Its presence is what distinguishes Caroli syndrome from
    the simple form.
  phenotype_term:
    preferred_term: Congenital hepatic fibrosis
    term:
      id: HP:0002612
      label: Congenital hepatic fibrosis
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is called Caroli syndrome (CS) when it has fibrotic and cirrhotic liver morphology"
    explanation: Fibrotic liver morphology is the defining feature of the syndromic form.
- category: Hepatobiliary
  name: Portal hypertension
  description: >-
    Presinusoidal portal hypertension caused by periportal fibrous obstruction of
    portal inflow, typically with preserved hepatocellular synthetic function early
    in the course.
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42438734
    reference_title: "Ten-year progression of Caroli's disease with portal hypertension despite endoscopic and pharmacological therapy: Implications for liver transplantation-A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Caroli's disease is a rare congenital disorder of the intrahepatic bile ducts that may be complicated by congenital hepatic fibrosis, portal hypertension, and recurrent variceal bleeding."
    explanation: States portal hypertension as a recognised complication of Caroli disease.
- category: Hepatobiliary
  name: Esophageal varices with recurrent bleeding
  description: >-
    Portosystemic collaterals form as portal pressure rises; oesophageal and gastric
    fundal varices bleed recurrently and are the usual cause of acute presentation
    with haematemesis and melaena.
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:22197937
    reference_title: "Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "164 with varices, 74 bleeding varices"
    explanation: >-
      Of 1,230 pooled patients with congenital hepatic fibrosis, 164 had varices and
      74 had bleeding varices, documenting variceal haemorrhage as a core
      manifestation.
- category: Hematologic
  name: Splenomegaly
  description: >-
    Congestive splenomegaly secondary to portal hypertension, frequently accompanied
    by hypersplenic anaemia, leucopenia and thrombocytopenia — cytopenias reported
    more often in the syndromic than the simple form.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:25327281
    reference_title: "Clinical classification of Caroli's disease: an analysis of 30 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anaemia, leucopoenia and thrombocytopoenia were more frequent in patients with type II than type I CD."
    explanation: >-
      Documents the hypersplenic cytopenias and their preferential association with
      the type II (syndromic) form.
- category: Hepatobiliary
  name: Cholelithiasis and hepatolithiasis
  description: >-
    Intrahepatic pigment stones form within the stagnant dilated segments;
    gallstones are also common. Stones perpetuate obstruction and infection.
  phenotype_term:
    preferred_term: Cholelithiasis
    term:
      id: HP:0001081
      label: Cholelithiasis
  notes: >-
    The cited snippet supports the cholestatic complication set of the fibrocystic
    liver diseases rather than stone disease specifically; a hepatolithiasis-specific
    citation is a curation follow-up.
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma"
    explanation: >-
      Lists the biliary complications of the fibrocystic liver diseases including
      cholestasis, from which stone disease follows; the source does not name
      hepatolithiasis, hence PARTIAL.
- category: Hepatobiliary
  name: Abdominal pain
  description: >-
    Right upper quadrant or epigastric pain, frequently the presenting symptom and
    often recurrent over years before diagnosis.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."
    explanation: Abdominal pain is among the dominant presenting symptoms.
- category: Neoplastic
  name: Cholangiocarcinoma
  description: >-
    Intrahepatic cholangiocarcinoma complicating long-standing biliary inflammation,
    occurring at roughly 6-7% in the two largest assessments. Age at cholangiocarcinoma
    diagnosis is predominantly beyond 40 years, with a reported mean of 60.1 years in
    Caroli syndrome and isolated congenital hepatic fibrosis. The mean of 41.6 years
    reported by the surgical systematic review is the age of the whole Caroli cohort
    at the time of liver surgery, not the age at cancer diagnosis, and the two should
    not be conflated.
  phenotype_term:
    preferred_term: Cholangiocarcinoma
    term:
      id: HP:0030153
      label: Cholangiocarcinoma
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With a mean age of 41.6 years old (range 23 to 56 years old), patients were younger than other populations undergoing liver surgery."
    explanation: >-
      Documents the young age of the affected surgical population relative to other
      liver-surgery cohorts. This is age at liver surgery for the whole cohort, not
      age at cholangiocarcinoma diagnosis.
  - reference: PMID:22197937
    reference_title: "Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cholangiocarcinoma (CCA) was predominant in individuals older than 40 years with either Caroli syndrome or isolated CHF, not ARPKD (median and mean age at CCA diagnosis were 70.3 and 60.1 years, respectively; range 33-75 years)."
    explanation: >-
      Establishes the actual age at cholangiocarcinoma diagnosis in Caroli syndrome,
      correcting the conflation with the surgical cohort's mean age.
- category: Renal
  name: Polycystic kidney disease
  subtype: Caroli syndrome
  description: >-
    Autosomal recessive polycystic kidney disease frequently coexists, reflecting
    the shared PKHD1 basis; renal function impairment is central to overall disease
    progression and shapes transplant decisions.
  phenotype_term:
    preferred_term: Polycystic kidney dysplasia
    term:
      id: HP:0000113
      label: Polycystic kidney dysplasia
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, the autosomal recessive polycystic kidney disease (ARPKD) is the most frequent, and the renal function impairment is central in disease progression."
    explanation: >-
      ARPKD is the most frequent associated renal disorder and its renal impairment
      drives overall progression.
genetic:
- name: PKHD1
  notes: >-
    PKHD1 encodes fibrocystin/polyductin, a cholangiocyte and renal tubular ciliary
    protein. Biallelic variants cause autosomal recessive polycystic kidney disease
    together with the hepatic ductal plate malformation spectrum — congenital
    hepatic fibrosis, Caroli disease and Caroli syndrome. The protein's precise
    molecular function remains incompletely defined, with planar cell polarity the
    best-supported candidate role.
  gene_term:
    preferred_term: PKHD1
    term:
      id: hgnc:9016
      label: PKHD1
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (PKHD1), a gene that encodes for fibrocystin/polyductin"
    explanation: >-
      Directly attributes Caroli disease and Caroli syndrome, alongside congenital
      hepatic fibrosis and ARPKD, to PKHD1 mutations.
  - reference: PMID:14598246
    reference_title: "Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results indicate that fibrocystin is expressed in cholangiocyte cilia and that disruption of Pkhd1 by a germ line mutation in the PCK rat or by siRNA in IBDUs results in abnormalities in ciliary morphology and possibly biliary cystogenesis."
    explanation: >-
      Orthologous rat model evidence that Pkhd1 disruption causes ciliary
      abnormalities and biliary cystogenesis.
diagnosis:
- name: MR cholangiopancreatography
  description: >-
    MRCP demonstrates the saccular intrahepatic duct dilatations and their
    communication with the biliary tree, and is the mainstay of non-invasive
    diagnosis together with CT. No symptom, sign or laboratory value distinguishes
    Caroli disease from other biliary disorders.
  evidence:
  - reference: PMID:25327281
    reference_title: "Clinical classification of Caroli's disease: an analysis of 30 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No typical symptoms, signs or laboratory indicators are able to distinguish CD from other conditions. Both MRCP and CT were most valuable in diagnosis."
    explanation: >-
      Establishes cross-sectional/MRCP imaging as the diagnostic modality and the
      absence of a discriminating clinical or laboratory feature.
treatments:
- name: Antibiotic Therapy for Cholangitis
  description: >-
    Antimicrobial treatment of the recurrent bacterial cholangitis that arises from
    bile stasis, with anticipatory guidance for patients and families given how
    often infection recurs. Treatment is directed at the complication, not at the
    underlying ductal plate malformation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_mechanisms:
  - target: Recurrent Bacterial Cholangitis
    treatment_effect: INHIBITS
    description: >-
      Antimicrobials clear the bacterial infection of the stagnant biliary segments
      but do not correct the underlying stasis.
  evidence:
  - reference: PMID:22197937
    reference_title: "Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cholangitis is a major issue and necessitates anticipatory guidance and awareness."
    explanation: >-
      Establishes cholangitis as a major complication requiring active clinical
      management and anticipatory guidance.
- name: Nonselective Beta-Blocker Therapy for Portal Hypertension
  description: >-
    Propranolol or carvedilol to lower portal pressure and reduce variceal bleeding
    risk. Symptomatically effective at first, but the reported long-term course
    shows persistent portal hypertension and recurrent bleeding despite therapy,
    including after conversion from propranolol to carvedilol.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: propranolol
      term:
        id: CHEBI:8499
        label: propranolol
    - preferred_term: carvedilol
      term:
        id: CHEBI:3441
        label: carvedilol
  target_mechanisms:
  - target: Presinusoidal Portal Hypertension
    treatment_effect: INHIBITS
    description: >-
      Nonselective beta-blockade reduces portal inflow and portal pressure, the
      mechanism targeted for variceal bleeding prophylaxis.
  evidence:
  - reference: PMID:42438734
    reference_title: "Ten-year progression of Caroli's disease with portal hypertension despite endoscopic and pharmacological therapy: Implications for liver transplantation-A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms improved after nonselective beta-blocker therapy; however, longitudinal follow-up showed persistent portal hypertension, recurrent gastrointestinal bleeding, and progressive impairment of hepatic reserve."
    explanation: >-
      Single-patient evidence of initial symptomatic benefit followed by long-term
      failure to control portal hypertension — hence PARTIAL rather than SUPPORT.
- name: Endoscopic Variceal Ligation
  description: >-
    Endoscopic band ligation of bleeding oesophageal varices. Effective for acute
    haemorrhage control but, in the documented long-term course, did not prevent
    recurrent bleeding when applied sequentially over years.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Presinusoidal Portal Hypertension
    treatment_effect: INHIBITS
    description: >-
      Obliterates the variceal collaterals through which portal hypertension causes
      haemorrhage, without altering portal pressure itself.
  evidence:
  - reference: PMID:42438734
    reference_title: "Ten-year progression of Caroli's disease with portal hypertension despite endoscopic and pharmacological therapy: Implications for liver transplantation-A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she experienced recurrent hematemesis and melena despite sequential endoscopic variceal ligation and beta-blocker therapy"
    explanation: >-
      Documents recurrent bleeding despite sequential band ligation, supporting the
      described limitation of endoscopic therapy.
- name: Hepatic Resection for Localised Disease
  description: >-
    Segmental or lobar hepatectomy when the ductal dilatations are confined to a
    resectable part of the liver. Resection removes the stasis-and-infection focus,
    relieves symptoms, and eliminates the segment at risk of malignant
    transformation; occult cholangiocarcinoma is not infrequently found in the
    specimen.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Hepatectomy
    term:
      id: NCIT:C15249
      label: Hepatectomy
  target_mechanisms:
  - target: Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts
    treatment_effect: INHIBITS
    description: >-
      Removes the malformed duct segments, eliminating the anatomical substrate for
      stasis, infection and carcinogenesis in the resected territory.
  evidence:
  - reference: PMID:34294522
    reference_title: "The rate of cholangiocarcinoma in Caroli Disease A German multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised."
    explanation: >-
      Multicentre surgical series concludes that resection is strongly advised, on
      grounds of both malignancy risk and symptom relief.
- name: Liver Transplantation
  description: >-
    The definitive option for diffuse bilobar disease that cannot be resected, for
    hepatic decompensation, and for portal hypertension refractory to endoscopic and
    pharmacological therapy. Combined liver-kidney transplantation is considered
    when ARPKD has produced concurrent renal failure. Referral before advanced
    decompensation is advocated, since hepatic reserve declines progressively while
    complications recur.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: Presinusoidal Portal Hypertension
    treatment_effect: INHIBITS
    description: >-
      Replacing the fibrotic, malformed liver removes the presinusoidal obstruction
      and with it the portal hypertension.
  evidence:
  - reference: PMID:42438734
    reference_title: "Ten-year progression of Caroli's disease with portal hypertension despite endoscopic and pharmacological therapy: Implications for liver transplantation-A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case demonstrates the limitations of long-term endoscopic and pharmacological therapy in Caroli's disease complicated by portal hypertension and supports timely transplant referral before advanced hepatic decompensation occurs."
    explanation: >-
      Supports transplantation as the definitive option and argues for timely
      referral, the recommendation captured in this treatment.
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interventional radiology or surgical treatments, including liver transplantation, are used in selected cases."
    explanation: >-
      Confirms liver transplantation as an accepted treatment in selected cases of
      fibrocystic liver disease.
- name: Avoidance of Hepatotoxic and Nephrotoxic Agents
  description: >-
    Where Caroli disease occurs as the hepatobiliary presentation of ARPKD-PKHD1,
    GeneReviews advises minimising potentially hepatotoxic exposures — acetaminophen
    at doses above 30 mg/kg/day, herbal supplements and alcohol — alongside known
    nephrotoxic agents such as NSAIDs and aminoglycosides, on the rationale that
    hepatic and renal reserve are already committed by the underlying disease.
    Scope caveat: this guidance is written for ARPKD-PKHD1 and so applies to the
    PKHD1-associated Caroli syndrome form curated here; it should not be transferred
    wholesale to simple, frequently sporadic Caroli disease, whose genetic basis and
    renal involvement are not the same.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of hepatotoxic and nephrotoxic agents
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301501
    reference_title: "Autosomal Recessive Polycystic Kidney Disease - PKHD1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Minimizing use of known nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides (unless otherwise advised) and of potentially hepatotoxic agents (e.g., acetaminophen doses >30 mg/kg/day, herbal supplements, and alcohol) is advised."
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid guidance for ARPKD-PKHD1,
      recorded verbatim as the exposure-avoidance advice for the PKHD1-associated
      form of this entry.
animal_models:
- name: PCK rat (Pkhd1 splicing mutant)
  species: Rat (Rattus norvegicus)
  genotype: PCK rat, germline Pkhd1 splicing mutation (homozygous)
  category: Spontaneous orthologous mutant
  genes:
  - preferred_term: Pkhd1
    term:
      id: hgnc:9016
      label: PKHD1
  associated_phenotypes:
  - Multiple intrahepatic bile duct dilatation
  - Focal biliary budding
  - Shortened, bulbous cholangiocyte cilia
  description: >-
    The PCK rat carries a germline Pkhd1 mutation and is an orthologous model of
    ARPKD with biliary involvement. It reproduces the distorted, dilated biliary
    tree and established that fibrocystin is a cholangiocyte ciliary protein whose
    loss yields shortened, bulbous cilia — the ciliary lesion that anchors the root
    pathophysiology node of this entry.
  evidence:
  - reference: PMID:14598246
    reference_title: "Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The biliary tree in the PCK rat was distorted markedly, showing multiple bile duct dilatation and focal budding."
    explanation: >-
      The model reproduces the multiple intrahepatic bile duct dilatations that
      define the human disease.
discussions:
- discussion_id: caroli_cca_incidence_uncertainty
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the true incidence of cholangiocarcinoma in Caroli disease and Caroli
    syndrome, and can any risk factor stratify which patients will develop it?
  attaches_to:
  - pathophysiology#Cholangiocarcinoma
  rationale: >-
    Reported cholangiocarcinoma incidence ranges from 2.7% to 37.5% across studies,
    with pooled estimates of 6.6% (systematic review) and 7.1% (German multicentre
    series). All available series are retrospective and drawn from surgical cohorts,
    so they are subject to referral bias, and no predictor of malignant
    transformation has been identified. This matters clinically because malignancy
    risk is one of the arguments used to justify prophylactic resection, yet the
    tumours are almost always found incidentally in the specimen because
    preoperative imaging cannot detect them.
  proposed_experiments:
  - experiment_id: exp_caroli_prospective_cca_incidence
    name: Prospective unselected-cohort cholangiocarcinoma incidence study
    description: >-
      Registry-based prospective follow-up of an unselected (not surgically
      referred) Caroli disease and Caroli syndrome cohort with standardised imaging
      surveillance, to estimate cholangiocarcinoma incidence free of surgical
      referral bias.
    decision_criterion: >-
      An incidence estimate with confidence intervals that exclude the extremes of
      the currently reported 2.7-37.5% range would settle whether prophylactic
      resection is justified by malignancy risk alone.
  - experiment_id: exp_caroli_cca_risk_factor_case_control
    name: Nested case-control analysis of cholangiocarcinoma risk factors
    description: >-
      Within such a cohort, compare patients who did and did not develop
      cholangiocarcinoma, testing candidate risk factors (disease extent, cholangitis
      frequency, hepatolithiasis burden, age, PKHD1 genotype).
    decision_criterion: >-
      Identification of any factor that stratifies risk would convert a uniform
      resection recommendation into a targeted surveillance strategy.
  evidence:
  - reference: PMID:32884228
    reference_title: "Risk of malignancy in Caroli disease and syndrome: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The development of intrahepatic carcinoma is described in both conditions, but the reported incidence varies extensively. Potential risk factors for the malignant transformation were not described."
    explanation: >-
      States both halves of this knowledge gap explicitly — the incidence varies
      extensively and no risk factors for malignant transformation are known.
- discussion_id: caroli_no_targeted_therapy
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Can the cholangiociliopathy mechanism be targeted therapeutically, rather than
    only managing the downstream biliary and portal complications?
  attaches_to:
  - pathophysiology#Fibrocystin Loss from the Cholangiocyte Primary Cilium
  rationale: >-
    Every treatment curated in this entry acts on a consequence — infection, portal
    pressure, variceal bleeding, or the malformed anatomy itself — and none acts on
    the ciliary defect or on peribiliary fibrogenesis. A contributing obstacle is
    that fibrocystin/polyductin's molecular function is still not established, so
    there is no well-defined pathway to drug.
  proposed_experiments:
  - experiment_id: exp_caroli_fibrocystin_function_organoid
    name: Fibrocystin function in patient-derived cholangiocyte organoids
    description: >-
      Define the molecular function of fibrocystin/polyductin in cholangiocyte cilia
      (interactome and ciliary signalling readouts) in human cholangiocyte organoids
      derived from PKHD1-mutant patients versus isogenic controls.
    decision_criterion: >-
      Identification of a defined signalling axis downstream of ciliary fibrocystin
      would provide the first druggable target in this disease.
  - experiment_id: exp_caroli_antifibrotic_pck_rat
    name: Antifibrotic intervention trial in the PCK rat
    description: >-
      Test antifibrotic candidates against peribiliary fibrogenesis in the PCK rat,
      using portal pressure and periportal collagen deposition as endpoints.
    decision_criterion: >-
      A reduction in portal pressure and periportal collagen relative to untreated
      PCK controls would justify translation toward a portal-hypertension-modifying
      therapy.
  evidence:
  - reference: PMID:33824930
    reference_title: "Fibrocystic liver disease: novel concepts and translational perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted medical therapy is not available yet and thus the current treatment aims at controlling the complications."
    explanation: >-
      States directly that no targeted medical therapy exists and that management is
      complication-directed.
references:
- reference: PMID:20301501
  title: "Autosomal Recessive Polycystic Kidney Disease - PKHD1."
  tags:
  - GeneReviews
  findings:
  - statement: >-
      Clinical characteristics. The childhood-to-young-adult presentation of
      ARPKD-PKHD1 is the hepatobiliary one, and GeneReviews names that
      presentation Caroli disease and attributes it to defective biliary ductal
      plate remodeling — the same developmental mechanism this entry models.
    supporting_text: "The less common initial presentation in childhood (after age one year) to young adulthood can be associated with predominant hepatobiliary manifestations characterized by the clinical consequences of developmental anomalies of biliary ductal plate remodeling (also known as Caroli disease)."
  - statement: >-
      Diagnosis/testing. Molecular confirmation rests on biallelic PKHD1
      pathogenic variants in a proband with suggestive findings, consistent with
      the autosomal recessive PKHD1 genetics curated in the genetic block.
    supporting_text: "The molecular diagnosis of ARPKD-PKHD1 is established in a proband with suggestive findings and biallelic pathogenic variants in PKHD1 identified by molecular genetic testing."
  - statement: >-
      Management. The hepatobiliary complications requiring specialist management
      are ascending cholangitis, cholestasis, and portal hypertension — the three
      clinical endpoints of the bile-stasis and portal-hypertension arms of this
      entry's pathograph — with liver or combined liver-kidney transplantation as
      the definitive option.
    supporting_text: "hepatobiliary disease specialists to assure timely management of complications (that can include ascending cholangitis, cholestasis, and portal hypertension) and LTx/CLKTx"
  - statement: >-
      Genetic counseling. Autosomal recessive inheritance with a 25% recurrence
      risk per conception for sibs of an affected individual, supporting the
      inheritance block.
    supporting_text: "If both parents are known to be heterozygous for a PKHD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier."
tracked_issues:
- url: https://github.com/monarch-initiative/dismech/issues/6526
  title: "[lit-scan:new] Caroli disease: congenital hepatic fibrosis, portal hypertension, and progressive cholestasis"
  tracked_issue_role: curation_followup
  tracked_issue_status: OPEN
  notes: >-
    Issue that requested this entry. Remaining follow-ups noted there: structured
    Orphanet provenance (ORPHA:53035 / ORPHA:480520 are not yet in
    references_cache), a snippet-backed prevalence record, a
    hepatolithiasis-specific citation, and histopathology/imaging_findings blocks.
notes: >-
  Scope and naming. MONDO carries two live sibling terms — MONDO:0010913 (Caroli
  disease) and MONDO:0018808 (Caroli syndrome) — plus an obsolete MONDO:0000506.
  They are modelled here as one entry with two subtypes rather than two entries,
  because they share a single ductal plate malformation mechanism and differ only
  in which level of the biliary tree is malformed; the literature routinely reports
  them together as CD/CS. The older clinical literature labels the two forms type I
  and type II; both labelings are captured on the subtypes. Curators extending this
  entry should keep the distinction sharp, since a source about Caroli syndrome is
  not automatically a source about simple Caroli disease.

  Not yet curated. No prevalence record is included: no source in the current
  evidence set states a population rate with a quotable figure, and the commonly
  repeated 1-in-1,000,000 estimate is not traceable to a citable abstract here.
  Structured Orphanet records (ORPHA:53035, ORPHA:480520) would supply both the
  prevalence class and an HPO frequency table, but neither is present in
  references_cache and building them requires an Orphadata refresh. Phenotype
  frequency bands are omitted for the same reason — per the frequency-evidence
  guidelines, no band is asserted without its own quantitative support.
  Histopathology, imaging_findings and biochemical blocks are likewise left for a
  second pass.
📚

References & Deep Research

References

1
PMID:20301501
Autosomal Recessive Polycystic Kidney Disease - PKHD1.
4 findings
Clinical characteristics. The childhood-to-young-adult presentation of ARPKD-PKHD1 is the hepatobiliary one, and GeneReviews names that presentation Caroli disease and attributes it to defective biliary ductal plate remodeling — the same developmental mechanism this entry models.
"The less common initial presentation in childhood (after age one year) to young adulthood can be associated with predominant hepatobiliary manifestations characterized by the clinical consequences of developmental anomalies of biliary ductal plate remodeling (also known as Caroli disease)."
Diagnosis/testing. Molecular confirmation rests on biallelic PKHD1 pathogenic variants in a proband with suggestive findings, consistent with the autosomal recessive PKHD1 genetics curated in the genetic block.
"The molecular diagnosis of ARPKD-PKHD1 is established in a proband with suggestive findings and biallelic pathogenic variants in PKHD1 identified by molecular genetic testing."
Management. The hepatobiliary complications requiring specialist management are ascending cholangitis, cholestasis, and portal hypertension — the three clinical endpoints of the bile-stasis and portal-hypertension arms of this entry's pathograph — with liver or combined liver-kidney transplantation as the definitive option.
"hepatobiliary disease specialists to assure timely management of complications (that can include ascending cholangitis, cholestasis, and portal hypertension) and LTx/CLKTx"
Genetic counseling. Autosomal recessive inheritance with a 25% recurrence risk per conception for sibs of an affected individual, supporting the inheritance block.
"If both parents are known to be heterozygous for a PKHD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier."

Deep Research

1
Falcon ▸
Caroli Disease: Comprehensive Disease-Characteristics Report
Edison Scientific Literature 16 citations 2026-08-20T02:57:18.185581

Caroli Disease: Comprehensive Disease-Characteristics Report

Target: Caroli disease (CD)
Category: rare Mendelian cholangiopathy / developmental ciliopathy
Core distinction: CD denotes non-obstructive segmental or diffuse ectasia of the large intrahepatic bile ducts without congenital hepatic fibrosis. Caroli syndrome (CS) denotes the same duct abnormality plus congenital hepatic fibrosis (CHF), often with portal hypertension and renal manifestations of the autosomal-recessive polycystic kidney disease spectrum. The distinction is clinically important and is sometimes blurred in publications and databases. (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)

The following table summarizes the principal structured findings; the narrative thereafter addresses all 15 requested domains.

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 (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)
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 (tidwell2024heritablechroniccholestatic pages 5-6, OpenTargets Search: Caroli disease-PKHD1)
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 (tidwell2024heritablechroniccholestatic pages 5-6)
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 (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)
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 (mariotti2018animalmodelsof pages 13-17, tidwell2024heritablechroniccholestatic pages 1-2, mahboobipour2024clinicalmanifestationepidemiology pages 5-7, tidwell2024heritablechroniccholestatic pages 5-6)
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 (tidwell2024heritablechroniccholestatic pages 6-7, NCT04007575 chunk 1)
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. — (tidwell2024heritablechroniccholestatic pages 6-7, NCT04007575 chunk 1)
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 (tidwell2024heritablechroniccholestatic pages 6-7)
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 (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)
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 (tidwell2024heritablechroniccholestatic pages 5-6, tidwell2024heritablechroniccholestatic pages 6-7)
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 (mariotti2018animalmodelsof pages 13-17)

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.

Evidence scope and limitations

The strongest recent sources retrieved were two peer-reviewed 2024 reviews: Tidwell and Wu, published June 2024 (DOI 10.14218/JCTH.2024.00119), and Mahboobipour et al., published April 2024 (DOI 10.1186/s13023-024-03187-w). Mechanistic model evidence was supplemented by Mariotti et al. (DOI 10.1016/j.bbadis.2017.06.027, published April 2018). Most quantitative clinical estimates come from small retrospective cohorts or systematic reviews assembled from case series; they should not be interpreted as population-level precision estimates. No individual-patient EHR data were used.

1. Disease information

Definition and nomenclature

Caroli disease is a congenital malformation of the large intrahepatic bile ducts characterized by non-obstructive, communicating, saccular or fusiform duct dilatation. It predisposes to bile stasis, hepatolithiasis, recurrent bacterial cholangitis, hepatic abscess, sepsis, and cholangiocarcinoma. Pure CD lacks the portal fibrosis and portal hypertension that define CS. (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)

Common names: Caroli disease; Caroli’s disease; communicating cavernous ectasia of the intrahepatic ducts; simple-type Caroli disease. “Caroli syndrome” is related but not synonymous.

Identifiers:

  • MONDO: MONDO:0010913, as supplied and corroborated by the retrieved Open Targets disease record.
  • Orphanet: commonly indexed within the Caroli disease/Caroli syndrome spectrum; an exact ORPHA number was not independently verified in the retrieved full text.
  • OMIM: the molecularly overlapping PKHD1/ARPKD–CHF spectrum is generally represented through PKHD1-associated polycystic kidney disease; an isolated-CD OMIM number was not verified here.
  • MeSH: Caroli Disease.
  • ICD: no uniquely validated ICD-10-CM code was established from retrieved evidence; implementations often place it under congenital malformations of bile ducts. ICD coding should therefore be validated against the target jurisdiction and release rather than inferred.

The knowledge represented here is aggregated disease-level evidence from reviews, cohorts, genetic databases, and model studies—not observations extracted from a particular patient record.

2. Etiology, risk, and protective factors

Causal factors

The established causal framework is developmental and genetic. Pathogenic dysfunction in PKHD1, encoding fibrocystin/polyductin, disrupts cholangiocyte primary-cilium and epithelial-tubule biology. The resulting ductal-plate/tubular-architecture abnormality produces large-duct ectasia. Open Targets gives PKHD1–CD an association score of 0.514, supported by genetic literature, clinical variation resources, and animal models; weaker database associations with CYS1 and DZIP1L should not be treated as equivalent, clinically established causes of isolated human CD. (OpenTargets Search: Caroli disease-PKHD1)

A whole-exome study in a Chinese twin family identified recessive compound-heterozygous PKHD1 variants (PMID 24710345). The same report emphasized that PKHD1 variant detection has historically been lower in patients labeled specifically as CD than in severe ARPKD/CHF, consistent with genetic heterogeneity, incomplete testing, or phenotype-classification problems. (OpenTargets Search: Caroli disease-PKHD1)

Risk factors

  • Genetic: biallelic pathogenic PKHD1 variants, an affected sibling, parental carrier status, and consanguinity increase risk under an autosomal-recessive model.
  • Clinical modifiers: duct distribution and bile stasis determine vulnerability to stones and infection. Chronic inflammation is a downstream risk factor for cholangiocarcinoma rather than a primary cause.
  • Environmental/lifestyle: no reproducible toxin, dietary, occupational, smoking, alcohol, sex, or pollution exposure has been shown to cause the congenital malformation. Infection is a complication facilitated by stasis, not the initiating etiology.

Protective factors and gene–environment interaction

No validated protective allele, diet, lifestyle exposure, or pharmacologic primary-prevention factor was identified. A practical gene–environment interaction is that genetically abnormal duct anatomy creates bile stasis, after which bacterial exposure and obstruction precipitate cholangitis and inflammatory injury. This is mechanistically plausible and clinically observed, but formal G×E effect estimates are unavailable.

3. Phenotypes

The course is highly variable and may remain clinically silent for years. In one 14-patient series summarized in the 2024 review, acute cholangitis occurred in 64%, intrahepatic stones/choledocholithiasis in 33%, right-upper-quadrant pain in 50%, jaundice in 35.7%, fever in 28.6%, and asymptomatic disease in 14.3%. Reported laboratory abnormalities included elevated GGT in 64.3%, alkaline phosphatase in 35.7%, and bilirubin in 28.6%. These percentages are series-specific, not universal frequencies. (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)

Phenotype Type and characteristics Suggested HPO annotation
Intrahepatic bile-duct ectasia Congenital structural sign; localized or diffuse; lifelong Abnormality/dilatation of intrahepatic bile duct
Recurrent cholangitis Episodic, potentially severe; often adult-recognized Cholangitis; recurrent fever
Hepatolithiasis Structural/clinical complication from bile stasis; recurrent Intrahepatic cholelithiasis
RUQ abdominal pain Episodic symptom, often accompanying infection/obstruction Abdominal pain
Fever Episodic symptom during cholangitis Fever
Jaundice/cholestasis Fluctuating symptom/laboratory phenotype Jaundice; hyperbilirubinemia; cholestasis
Elevated GGT/ALP Laboratory abnormality, especially during cholestasis Elevated gamma-glutamyltransferase; elevated alkaline phosphatase
Hepatomegaly Physical sign, variable Hepatomegaly
Hepatic abscess/sepsis Severe infectious complications Hepatic abscess; sepsis
Portal hypertension, splenomegaly, ascites, varices Primarily CS/CHF rather than pure CD Portal hypertension; splenomegaly; ascites; esophageal varices
Renal cystic disease Primarily PKHD1-associated CS/ARPKD spectrum Renal cyst; polycystic kidney dysplasia
Cholangiocarcinoma Late malignant complication Cholangiocarcinoma

In a 16-patient CS cohort, abdominal pain occurred in eight, fever in six, variceal bleeding in one, and fatigue in one; ten had thrombocytopenia and five prolonged prothrombin time. These findings should not be transferred uncritically to simple CD. (tidwell2024heritablechroniccholestatic pages 6-7)

Quality of life: no validated CD-specific EQ-5D, SF-36, or PROMIS dataset was retrieved. Nevertheless, recurrent painful cholangitis, hospitalization, antibiotic exposure, procedures, and fear of sepsis or cancer impose substantial burden; the 2024 review explicitly associates recurrent cholangitis with early quality-of-life loss. (tidwell2024heritablechroniccholestatic pages 6-7)

4. Genetic and molecular information

Causal gene and protein

  • PKHD1: human gene ENSG00000170927; encodes fibrocystin/polyductin, a large ciliary/plasma-membrane protein involved in epithelial tubulogenesis and duct-lumen architecture.
  • Origin: disease-causing variants are constitutional/germline, generally biallelic under an autosomal-recessive model—not somatic drivers.
  • Functional direction: loss or severe reduction of fibrocystin function.
  • Protein interaction: fibrocystin’s C-terminal region interacts with the N-terminal region of polycystin-2 (PC2); fibrocystin loss reduces PC2 expression and perturbs calcium signaling. (mariotti2018animalmodelsof pages 13-17, mahboobipour2024clinicalmanifestationepidemiology pages 5-7)

Variant classes and interpretation

PKHD1 disease alleles across the ARPKD/CHF/CD spectrum include missense, nonsense, frameshift, and splice-altering variants. However, no comprehensive CD-specific ClinVar extraction, ACMG classification table, HGVS list, or gnomAD frequency analysis was available in the retrieved evidence. Knowledge-base curation should therefore import variant-level assertions directly from current ClinVar records and retain submitter/date/review-status fields. Pathogenic recessive alleles are expected to be individually rare; a VUS should not be considered diagnostic without segregation, phenotype, population, and functional evidence.

No established recurrent chromosomal abnormality, repeat expansion, mitochondrial variant, somatic mutation mechanism, genetic anticipation, or germline mosaicism pattern was identified. No validated modifier gene or protective allele is known. DZIP1L is biologically relevant to ciliary transition-zone trafficking of PC1/PC2, but its weaker disease association should be labeled emerging/indirect rather than a routine isolated-CD gene. (OpenTargets Search: Caroli disease-PKHD1, mahboobipour2024clinicalmanifestationepidemiology pages 5-7)

Epigenetics

No disease-specific, replicated DNA-methylation, histone-mark, or chromatin-remodeling signature suitable for clinical annotation was retrieved. Epigenomic testing is not standard diagnosis.

5. Environmental information

There is no evidence that toxins, radiation, pollution, occupational exposure, smoking, alcohol, diet, or inactivity cause CD. Ascending bacteria are clinically important in cholangitis, but no single pathogen defines the disease. Common biliary organisms may act opportunistically after stasis or instrumentation. Environmental and lifestyle information should therefore be annotated as not established, rather than “absent by proof.”

6. Mechanism and pathophysiology

Causal chain

  1. Upstream germline defect: biallelic PKHD1 dysfunction reduces or alters fibrocystin.
  2. Ciliary/tubular defect: abnormal fibrocystin at the cholangiocyte primary cilium/plasma membrane disrupts PC2-associated calcium sensing, planar-cell-polarity/tubulogenesis, and maintenance of duct-lumen architecture.
  3. Developmental lesion: malformed large intrahepatic ducts become segmentally or diffusely ectatic and remain connected to the biliary tree.
  4. Biophysical consequence: ectatic ducts cause sluggish flow and bile stasis, promoting pigment stones, sludge, obstruction, and bacterial colonization.
  5. Clinical consequence: recurrent cholangitis produces pain, fever, jaundice, abscess, and sepsis.
  6. Inflammatory/fibrotic amplification: cAMP/β-catenin and NF-κB signaling increases IL-1β, CXCL1, CXCL10, and CXCL12; JAK/STAT and NLRP3/caspase-1 signaling amplify inflammation. Recruited macrophages provide TNF-α and TGF-β; cholangiocyte αvβ6 integrin activates latent TGF-β1, recruiting portal myofibroblasts and extracellular-matrix deposition. This axis is especially important in CS/CHF. (mariotti2018animalmodelsof pages 13-17, tidwell2024heritablechroniccholestatic pages 1-2)
  7. Long-term malignant risk: prolonged stasis, epithelial turnover, and inflammation create a field favoring cholangiocarcinoma. (tidwell2024heritablechroniccholestatic pages 6-7)

Human biliary epithelium in CD has shown strong NOTCH1–4 expression relative to weak/negative expression in CHF, but whether this is initiating, compensatory, or downstream remains unresolved. (tidwell2024heritablechroniccholestatic pages 5-6)

Cells, processes, and ontology suggestions

  • Primary cell: cholangiocyte / biliary epithelial cell — CL:0000068 may be used after ontology-version validation.
  • Secondary cells: macrophages, portal fibroblasts/myofibroblasts, hepatic stellate cells, and vascular cells within portal tracts.
  • GO biological processes: cilium organization; epithelial tube morphogenesis; calcium-ion transmembrane transport/signaling; canonical Wnt/β-catenin signaling; NF-κB signaling; chemokine production; macrophage chemotaxis; TGF-β receptor signaling; extracellular-matrix organization; inflammatory response.
  • GO cellular components: primary cilium, ciliary membrane, plasma membrane, basal-body/centrosomal region.

Molecular profiling and advanced technologies

No validated CD-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic clinical signature was retrieved. Contemporary ciliopathy organoids can model patient-specific genotype–phenotype relationships and permit drug screening, but this remains a research application rather than a validated CD diagnostic or therapy.

7. Anatomical structures affected

  • Primary organ/system: liver and biliary system; large intrahepatic bile ducts.
  • Distribution: diffuse in 50%, right-lobe localized in 28.6%, and left-lobe localized in 21.4% in one small cohort. CD is not intrinsically lateralized; it can be segmental, lobar, or bilobar. (tidwell2024heritablechroniccholestatic pages 5-6)
  • Tissue: biliary epithelium and peribiliary/portal connective tissue.
  • Cell: cholangiocyte; macrophages and portal myofibroblasts become involved downstream.
  • Subcellular: primary cilium/ciliary membrane and plasma-membrane fibrocystin–PC2 complex.
  • Secondary structures: portal venous system and spleen in CS; kidneys and occasionally pancreatic cysts in the broader PKHD1 spectrum. (tidwell2024heritablechroniccholestatic pages 6-7)

Suggested anatomical annotations are UBERON liver, intrahepatic bile duct, biliary tree, portal tract, kidney collecting duct, and spleen; exact numeric UBERON identifiers should be ontology-release validated before ingestion.

8. Temporal development

The anatomical defect is congenital, but recognition is often delayed. Most patients reportedly remain asymptomatic until approximately age 20, while more than 80% become symptomatic before age 30. A small adult CD series had a mean diagnostic age of 42 years (range 15–68), illustrating ascertainment variability. (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)

The course is lifelong and commonly episodic: asymptomatic structural disease may progress to recurrent cholangitis and stones, followed by abscess/sepsis, repeated interventions, or malignancy. Pure CD need not progress to cirrhosis; portal-hypertension progression suggests CS/CHF or secondary advanced injury. Spontaneous anatomical remission is not expected. A critical intervention window occurs when disease remains localized enough for curative-intent resection, before diffuse infection or malignant transformation.

9. Inheritance and population

  • Incidence/prevalence: approximately 1 per 1,000,000 is frequently cited, but the retrieved review labels this as incidence and does not establish a rigorous population denominator or annual incidence. Robust registry-based prevalence is lacking. (tidwell2024heritablechroniccholestatic pages 6-7)
  • Inheritance: autosomal recessive in the PKHD1-associated spectrum. (tidwell2024heritablechroniccholestatic pages 5-6)
  • Penetrance/expressivity: exact penetrance is unknown; expressivity is clearly variable, spanning isolated duct ectasia, CS/CHF, and renal-predominant ARPKD.
  • Sex: no sex predominance in the cited 14-patient series. (tidwell2024heritablechroniccholestatic pages 5-6)
  • Ethnicity/geography: worldwide case reports exist, but no validated high-risk ancestry or geographic endemicity was identified.
  • Founder effects/carrier frequency: no CD-specific founder allele or carrier-frequency estimate was retrieved.
  • Anticipation: not expected for a recessive loss-of-function ciliopathy and not reported.
  • Consanguinity: increases the probability of biallelic recessive disease, but a CD-specific attributable fraction is unknown.

For confirmed biallelic disease, recurrence risk is conventionally 25% for each pregnancy when both parents are heterozygous carriers, subject to confirmation of phase and parentage.

10. Diagnostics

Imaging and clinical evaluation

MRCP is the preferred non-invasive diagnostic modality. It maps the morphology and communication of intrahepatic duct ectasia while avoiding diagnostic ERCP risks. Contrast CT or MRI may reveal the central dot sign: a portal-vein branch or hepatic-artery branch surrounded by an ectatic duct. Ultrasound can identify duct dilatation and stones; hepatobiliary scintigraphy may show beading. The central dot sign is highly characteristic but its absence does not exclude disease. (tidwell2024heritablechroniccholestatic pages 6-7)

NCT04007575 (IMACA), completed in 2020, retrospectively studied 61 patients to develop MRCP criteria based on duct shape and distribution, the dot sign, calculi, liver abnormalities, and portal-hypertension signs, with the aim of distinguishing CD from benign or malignant obstructive dilatation. This was an observational diagnostic study, not a therapeutic trial. ClinicalTrials.gov: NCT04007575. (NCT04007575 chunk 1)

Laboratory and pathology

During cholangitis, expected findings include neutrophilic leukocytosis, direct hyperbilirubinemia, and elevated alkaline phosphatase/GGT; blood cultures should be obtained before antibiotics when feasible. Renal function, blood counts, coagulation, and portal-hypertension indices help distinguish broader CS/ARPKD involvement. Histology can show dilated non-obstructed ducts with intraluminal wall protrusions and patent portal vascular channels. CK7, MUC1, and β-catenin expression supports fetal/congenital duct phenotype, although biopsy is not routinely necessary when imaging is diagnostic. (tidwell2024heritablechroniccholestatic pages 6-7)

Genetic testing

A practical algorithm is:

  1. Confirm compatible communicating intrahepatic duct ectasia by MRCP.
  2. Assess kidneys, portal hypertension, fibrosis, and family history.
  3. Use a cystic-kidney/cholangiopathy multigene panel including PKHD1 when phenotype is atypical or syndromic.
  4. If suspicion remains high, perform deletion/duplication analysis and WES/WGS with phenotype-driven reanalysis.
  5. Confirm candidate recessive variants by segregation and ACMG/AMP classification.

PKHD1 next-generation sequencing is available. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless an independent indication exists. (tidwell2024heritablechroniccholestatic pages 6-7)

Differential diagnosis

Principal alternatives include primary sclerosing cholangitis, recurrent pyogenic cholangitis, obstructive stones or strictures, cholangiocarcinoma, choledochal cyst/type V duct disease terminology, polycystic liver disease, primary biliary disorders, and secondary sclerosing cholangitis. PSC tends to show multifocal stricturing and beading rather than congenital saccular ectasia with central vascular dots; recurrent pyogenic cholangitis is usually accompanied by obstructing pigment stones and acquired strictures. (tidwell2024heritablechroniccholestatic pages 6-7, NCT04007575 chunk 1)

There is no population or newborn screening program. Cascade testing is appropriate after a molecular diagnosis.

11. Outcome and prognosis

Major morbidity arises from recurrent cholangitis, hepatolithiasis, abscesses, sepsis, hospitalization, and repeated biliary procedures. In CS, portal hypertension, variceal bleeding, hypersplenism, and kidney failure add substantial morbidity. Sepsis and hepatic abscess are reported major causes of death. (tidwell2024heritablechroniccholestatic pages 6-7)

Cancer risk

A multicenter dataset found cholangiocarcinoma in 6.3% of CD and 7.6% of CS patients. A systematic review of 561 CD patients reported a 6.6% incidence; among affected cancer cases, one-year survival was 36% and recurrence 75%. Heterogeneous referral and surgical ascertainment likely inflate or destabilize these estimates, but the direction of risk is clear. (tidwell2024heritablechroniccholestatic pages 6-7)

Treatment-associated prognosis

After transplantation, reported patient survival was 99%, 96.2%, and 94.6% at one, three, and five years; corresponding graft survival was 94.9%, 91.1%, and 89.6%. These excellent selected-cohort outcomes should not be interpreted as untreated natural-history survival. (tidwell2024heritablechroniccholestatic pages 5-6)

No validated CD-specific prognostic biomarker or risk calculator exists. Clinically adverse indicators include diffuse/bilobar disease, recurrent uncontrolled infection, abscess, portal hypertension, renal failure, and suspected malignancy.

12. Treatment and current implementation

No approved drug corrects the congenital duct lesion or PKHD1 defect. Management is anatomy- and complication-directed.

Medical and interventional care

  • Acute cholangitis: prompt broad-spectrum antibiotics, cultures, supportive care, and biliary decompression when obstruction or failure of medical therapy is present. Suggested NCIt concept: antibiotic therapy.
  • Hepatolithiasis: ursodeoxycholic acid may be used for intrahepatic stones, although robust CD-specific response trials are lacking. Suggested chemical annotation: ursodeoxycholic acid; NCIt intervention: pharmacologic treatment.
  • Bridging: chronic suppressive antibiotics may be used in selected patients with recurrent infection awaiting transplantation. (tidwell2024heritablechroniccholestatic pages 6-7, tidwell2024heritablechroniccholestatic pages 5-6)
  • Endoscopic/percutaneous drainage: useful for accessible stones, strictures, abscesses, or acute decompression; repeated instrumentation can itself introduce infection.

Surgery

  • Localized unilobar/segmental CD: anatomical hepatectomy can remove the diseased reservoir and may be definitive.
  • Diffuse/bilobar disease, recurrent life-threatening cholangitis, portal-hypertensive CS, or unresectable disease: liver transplantation.
  • Clinically important renal failure/ARPKD: simultaneous liver–kidney transplantation may be appropriate. (tidwell2024heritablechroniccholestatic pages 5-6)

Reported surgical complications include bile leak 26%, revision 16%, pleural effusion 5.5%, and urinary infection 5.5%. A reviewed surgical cohort of 21 patients had no deaths over five years, but the sample was small and selected. (tidwell2024heritablechroniccholestatic pages 6-7)

Suggested NCIt intervention concepts: hepatectomy, partial hepatectomy, liver transplantation, combined liver–kidney transplantation, endoscopic biliary drainage, percutaneous drainage, antibiotic therapy, and ursodeoxycholic acid treatment.

Advanced and experimental treatment

No established gene therapy, CRISPR therapy, ASO/siRNA therapy, cell therapy, or targeted anti-ciliary drug is approved for CD. cAMP, β-catenin, inflammatory, and TGF-β pathways are preclinical targets, but systemic inhibition may be toxic and evidence has not reached disease-specific clinical efficacy. The trial search identified observational natural-history/imaging studies rather than active interventional CD drug trials. NCT01401998 is an observational ARPKD database study, relevant to the broader PKHD1 spectrum but not a CD treatment trial.

No CD-specific pharmacogenomic guideline from CPIC/PharmGKB was identified.

13. Prevention

Primary prevention: the congenital genetic lesion cannot currently be prevented by lifestyle modification or vaccination. Genetic counseling, carrier testing after familial variants are known, prenatal diagnosis, and preimplantation genetic testing are reproductive-risk options—not treatments of an affected person.

Secondary prevention: no population screening is recommended. Family cascade testing and imaging/genetic evaluation of at-risk siblings can enable earlier detection. Periodic clinical, biochemical, and imaging review is reasonable, although an evidence-based surveillance interval was not established.

Tertiary prevention: rapid treatment of cholangitis, removal or drainage of obstructing stones, avoidance of unnecessary biliary instrumentation, management of portal hypertension and renal disease, and timely referral for resection/transplantation can reduce complications. Given the increased cholangiocarcinoma risk, expert hepatobiliary follow-up is appropriate, but no screening method or interval has proven mortality benefit. Vaccination according to chronic-liver-disease/transplant schedules may reduce unrelated infectious morbidity; it does not prevent CD.

14. Other species and natural disease

No well-established, common naturally occurring veterinary counterpart with validated breed-specific inheritance was retrieved. Caroli-like hepatobiliary lesions can occur in animal disease descriptions, but the principal comparative evidence comes from engineered or spontaneous laboratory models rather than a recognized zoonosis.

There is no zoonotic potential and no cross-species transmission: CD is an inherited developmental disorder. PKHD1/fibrocystin function is evolutionarily conserved across vertebrates, enabling rodent modeling.

15. Model organisms

PCK rat

The PCK rat carries an orthologous Pkhd1 splicing defect and develops progressive intrahepatic bile-duct dilatation and hepatic cystic lesions, together with renal outer-medullary collecting-duct cysts. With age, some cystic structures disconnect from the biliary system. The model develops mild portal fibrosis but generally lacks the full fibrous septa and portal hypertension of severe human CS. It is useful for studying cholangiocyte cilia, cyst growth, bile-duct remodeling, and candidate antifibrotic/cyst-directed treatments. (mariotti2018animalmodelsof pages 13-17)

Pkhd1del4/del4 mouse

This mouse develops intrahepatic duct dysgenesis followed by cyst-like configuration and peribiliary fibrosis after approximately three months; more than 50% show splenomegaly by six months, consistent with clinically relevant portal hypertension. It is especially useful for dissecting macrophage–cholangiocyte–myofibroblast signaling. (mariotti2018animalmodelsof pages 13-17)

Mechanistic findings and limitations

Fibrocystin-deficient cholangiocytes produce CXCL1, CXCL10, and CXCL12 through overactive β-catenin signaling. Macrophage-derived TNF-α/TGF-β promotes αvβ6-integrin-mediated local activation of TGF-β1 and portal fibrosis; macrophage depletion with clodronate reduces fibrosis in model systems. Pkhd1 knockout also increases cholangiocyte CTGF production. (mariotti2018animalmodelsof pages 13-17, mahboobipour2024clinicalmanifestationepidemiology pages 5-7)

These models recapitulate major features of the ARPKD–CHF–CS spectrum better than they reproduce isolated adult simple CD. Species differences, variable renal involvement, and incomplete human phenotypic heterogeneity limit direct translation. Liver/cholangiocyte organoids and patient-derived iPSC systems offer a complementary human platform, but no validated organoid-guided treatment is currently implemented clinically.

Overall assessment

Caroli disease is best understood as a rare developmental cholangiociliopathy centered on abnormal large intrahepatic ducts. PKHD1/fibrocystin dysfunction is the strongest established genetic mechanism, but variant detection and genotype–phenotype mapping are less complete for isolated CD than for classic ARPKD/CHF. The major real-world priorities are accurate MRCP-based diagnosis, strict separation of CD from CS, rapid management of cholangitis and stones, anatomical resection for localized disease, transplantation for diffuse or life-threatening disease, and long-term expert monitoring for infection and cholangiocarcinoma. Recent 2024 literature primarily refines genetic-cholestasis classification and ciliary mechanisms; it has not yet delivered a disease-modifying molecular therapy. (tidwell2024heritablechroniccholestatic pages 6-7, OpenTargets Search: Caroli disease-PKHD1, tidwell2024heritablechroniccholestatic pages 1-2, tidwell2024heritablechroniccholestatic pages 5-6)

References

  1. (tidwell2024heritablechroniccholestatic pages 6-7): Jasmine Tidwell and George Y. Wu. Heritable chronic cholestatic liver diseases: a review. Journal of Clinical and Translational Hepatology, 12:726-738, Jun 2024. URL: https://doi.org/10.14218/jcth.2024.00119, doi:10.14218/jcth.2024.00119. This article has 14 citations.

  2. (tidwell2024heritablechroniccholestatic pages 5-6): Jasmine Tidwell and George Y. Wu. Heritable chronic cholestatic liver diseases: a review. Journal of Clinical and Translational Hepatology, 12:726-738, Jun 2024. URL: https://doi.org/10.14218/jcth.2024.00119, doi:10.14218/jcth.2024.00119. This article has 14 citations.

  3. (OpenTargets Search: Caroli disease-PKHD1): Open Targets Query (Caroli disease-PKHD1, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  4. (mariotti2018animalmodelsof pages 13-17): Valeria Mariotti, Mario Strazzabosco, Luca Fabris, and Diego F. Calvisi. Animal models of biliary injury and altered bile acid metabolism. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1864:1254-1261, Apr 2018. URL: https://doi.org/10.1016/j.bbadis.2017.06.027, doi:10.1016/j.bbadis.2017.06.027. This article has 237 citations and is from a peer-reviewed journal.

  5. (tidwell2024heritablechroniccholestatic pages 1-2): Jasmine Tidwell and George Y. Wu. Heritable chronic cholestatic liver diseases: a review. Journal of Clinical and Translational Hepatology, 12:726-738, Jun 2024. URL: https://doi.org/10.14218/jcth.2024.00119, doi:10.14218/jcth.2024.00119. This article has 14 citations.

  6. (mahboobipour2024clinicalmanifestationepidemiology pages 5-7): Amir Ali Mahboobipour, Moein Ala, Javad Safdari Lord, and Arash Yaghoobi. Clinical manifestation, epidemiology, genetic basis, potential molecular targets, and current treatment of polycystic liver disease. Orphanet Journal of Rare Diseases, Apr 2024. URL: https://doi.org/10.1186/s13023-024-03187-w, doi:10.1186/s13023-024-03187-w. This article has 23 citations and is from a peer-reviewed journal.

  7. (NCT04007575 chunk 1): Study of New Imaging Criteria for the Diagnosis of Caroli's Disease. Assistance Publique - Hôpitaux de Paris. 2020. ClinicalTrials.gov Identifier: NCT04007575

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