Caroli disease

Mendelian MONDO:0010913 Pathograph 59 Show in embeddings browser non-neoplastic bile duct disorder liver disorder

Caroli disease is a congenital malformation with segmental non-obstructive dilatation of large intrahepatic bile ducts that communicate with the biliary tree. Simple Caroli disease lacks congenital hepatic fibrosis; Caroli syndrome combines duct ectasia with CHF and often PKHD1-associated renal disease. Bile stasis predisposes to stones, cholangitis, abscesses and sepsis. In Caroli syndrome, progressive peribiliary fibrosis causes portal hypertension, hypersplenism and variceal bleeding, often despite relatively preserved hepatic function. Cholangiocarcinoma is a recognized complication, but its population incidence remains uncertain. Care is complication-directed, with resection for selected localized disease and transplant assessment for unresectable recurrent cholangitis or severe portal complications.

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Mappings

MONDO

MONDO:0010913 Caroli disease

MONDO:0010913 anchors Caroli disease; MONDO:0018808 anchors the Caroli syndrome subtype with additional congenital hepatic fibrosis. This entry models the related large-duct disorders together while retaining subtype-specific renal, genetic and fibrotic findings.

MONDO:0018808 Caroli syndrome Not Yet Curated

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.

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Inheritance

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 Expressivity: VARIABLE

Show evidence (2 references)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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

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 REVIEW SYNTHESIS 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

Caroli disease with congenital hepatic fibrosis involving smaller ducts. Often associated with ARPKD, with portal hypertension, hypersplenism and variceal bleeding. Distribution, renal function and severity of complications determine treatment; transplantation is not inevitable in every patient.

Show evidence (2 references)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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 PRIMARY RESULT 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.

Discussions and Knowledge Gaps

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#Biliary Malignant Transformation

Cancer was reported in 6.6% of pooled surgical cases and 7.1% of a German surgical cohort. Selection bias, uncertain cohort independence and limited preoperative detection prevent interpretation as population incidence. Prospective disease-specific surveillance performance is also unknown.

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

Estimate cancer incidence with person-time and uncertainty, and assess screening yield. Treatment recommendations additionally require evidence about benefits and harms.

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

Validate candidate predictors prospectively before using them to personalize surveillance or surgery.

Show evidence (1 reference)

PMID:32884228 SUPPORT REVIEW SYNTHESIS 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 Dysfunction in PKHD1-associated Disease

Beta-catenin/STAT3, epithelial chemokine secretion, macrophage recruitment and integrin/TGF-beta signaling are experimentally tractable pathways. Translation to patient benefit remains unproven, particularly outside PKHD1-associated CHF.

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

Demonstrate reproducible functional rescue in human disease-derived cells and establish applicability across genotypes.

Antifibrotic intervention in complementary PKHD1 models

exp_caroli_antifibrotic_pck_rat

Use the Pkhd1del4/del4 mouse for progressive portal fibrosis and the PCK rat for cystic/renal phenotypes, with human cell validation.

Decision criterion

Replicated effects on fibrosis and clinically relevant physiology, with toxicity assessment, would support translational development.

Show evidence (2 references)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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.

PMID:26645994 SUPPORT PRIMARY RESULT Model Organism

"Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts."

Preclinical pathway manipulation is available even though patient therapy is not established.

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Pathophysiology

Fibrocystin Dysfunction in PKHD1-associated Disease

Mechanism confidence: Established

Biallelic pathogenic PKHD1 variants impair fibrocystin/polyductin in the PKHD1-associated fibrocystic spectrum, particularly Caroli syndrome with ARPKD. This membrane and ciliary protein has incompletely resolved molecular functions. The PCK rat demonstrates loss of ciliary fibrocystin, but neither complete protein absence nor a single ciliary structural defect is established for every human variant or every sporadic simple Caroli case.

intrahepatic cholangiocyte CL:0002538

PKHD1 hgnc:9016

intrahepatic bile duct UBERON:0003704

Downstream

Ductal Plate Malformation of the Intrahepatic Biliary Tree PKHD1 dysfunction is linked to ductal dysgenesis; the complete developmental sequence is unresolved.

Abnormal Cholangiocyte Ciliary Morphology The PCK model links Pkhd1 disruption to abnormal ciliary morphology.

Increased Beta-catenin Signaling Fibrocystin-defective cholangiocytes exhibit altered beta-catenin signaling in the model.

Inflammasome-mediated Interleukin-1beta Maturation Fibrocystin deficiency is associated with increased inflammasome-dependent IL-1beta secretion; the upstream activation sequence is unresolved.

Polycystic kidney disease In the PKHD1-associated Caroli syndrome subset, the same genetic defect also affects renal tubular development.

Show evidence (2 references)

PMID:24710345 SUPPORT PRIMARY RESULT Human Clinical

"This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes."

A small human pedigree supports PKHD1-associated Caroli disease; it does not establish the cause of all isolated cases.

PMID:14598246 SUPPORT PRIMARY RESULT 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.

Abnormal Cholangiocyte Ciliary Morphology

Mechanism confidence: Provisional

In PCK rat cholangiocytes, cilia are shortened and have bulbous extensions. This experimental structural phenotype supports ciliary dysfunction in PKHD1-associated disease; it is not an obligatory ultrastructural finding in all patients.

intrahepatic cholangiocyte CL:0002538

Animal models

PCK rat (Pkhd1 splicing mutant) Rat (Rattus norvegicus) recapitulates Shortened, bulbous cholangiocyte cilia.

Show evidence (1 reference)

PMID:14598246 SUPPORT PRIMARY RESULT Model Organism

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.

Increased Beta-catenin Signaling

Mechanism confidence: Provisional

Fibrocystin-defective mouse cholangiocytes exhibit increased PKA-dependent beta-catenin activity. This experimental pathway promotes chemokine production and nuclear accumulation of phosphorylated STAT3; its importance across human simple Caroli disease remains unproven.

intrahepatic cholangiocyte CL:0002538

liver UBERON:0002107

Experimental models

Primary Pkhd1del4/del4 cholangiocytes and RAW264.7 migration system CO CULTURE Beta-catenin inhibitor and silencing experiments.

Downstream

Increased Nuclear Phosphorylated STAT3 Beta-catenin promotes nuclear localization of phosphorylated STAT3.

Increased Pro-interleukin-1beta Transcription Beta-catenin and STAT3 regulate NF-kB activity in cultured mutant cholangiocytes.

Show evidence (2 references)

PMID:29140564 SUPPORT BACKGROUND Model Organism

"Using the Pkhd1del4/del4 mouse, an orthologous model of CHF/CD (8, 9), we previously demonstrated that increased PKA-dependent phosphorylation of β-Catenin at Ser675 promoted the nuclear translocation of transcriptionally active pSer-675-β-Catenin (10)."

The paper describes the prior experimental basis for beta-catenin activation in this model.

PMID:29140564 SUPPORT PRIMARY RESULT In Vitro

"Moreover, increasing cAMP levels induced CXCL10 gene expression and protein secretion was abolished upon PKA inhibition."

In cultured FPC-defective cholangiocytes, cAMP/PKA-dependent signaling contributes to chemokine production.

Increased Pro-interleukin-1beta Transcription

Mechanism confidence: Provisional

In cultured fibrocystin-defective mouse cholangiocytes, elevated NF-kB transcriptional activity increases pro-IL-1beta production. This is the transcriptional component of the experimental autoinflammatory loop.

intrahepatic cholangiocyte CL:0002538

liver UBERON:0002107

Downstream

Inflammasome-mediated Interleukin-1beta Maturation Pro-IL-1beta supplies the precursor for cleavage and secretion; transcription and maturation are distinct regulated steps.

Show evidence (1 reference)

PMID:29140564 SUPPORT PRIMARY RESULT In Vitro

"NF-kB inhibition resulted in 60% reduction of IL-1β gene expression in FPC-defective cholangiocytes (Supplementary Figure 6C) and in 50% reduction in the IL-1β secretion (Supplementary Figure 6D)."

NF-kB perturbation supports its role in pro-IL-1beta expression in cultured mutant cholangiocytes.

Inflammasome-mediated Interleukin-1beta Maturation

Mechanism confidence: Provisional

In fibrocystin-defective mouse cholangiocytes, increased NLRP3 and cleaved caspase-1 accompany increased secretion of active IL-1beta. NLRP3 inhibition reduces secretion, providing evidence for an epithelial autoinflammatory mechanism distinct from bacterial cholangitis.

intrahepatic cholangiocyte CL:0002538

liver UBERON:0002107

Downstream

Increased Nuclear Phosphorylated STAT3 Secreted active IL-1beta promotes STAT3 phosphorylation.

Show evidence (1 reference)

PMID:29140564 SUPPORT PRIMARY RESULT In Vitro

"In addition, MCC950 10 μM, an inhibitor of the NLRP3 inflammasome caused a significant reduction (40%) in IL-1β secretion in FPC-defective but not in WT cholangiocytes (Figure 8D)."

In vitro inhibitor results support NLRP3-dependent maturation/secretion of bioactive IL-1beta.

Increased Nuclear Phosphorylated STAT3

Mechanism confidence: Provisional

In isolated fibrocystin-defective mouse cholangiocytes, IL-1beta promotes JAK/STAT3 phosphorylation and beta-catenin facilitates nuclear translocation of phosphorylated STAT3. Both inputs contribute to CXCL10 transcription.

intrahepatic cholangiocyte CL:0002538

liver UBERON:0002107

Downstream

Increased Cholangiocyte Chemokine Secretion JAK/STAT3 activity supports increased CXCL10 production.

Show evidence (1 reference)

PMID:29140564 SUPPORT PRIMARY RESULT In Vitro

"Specifically, IL-1β promotes signal transducer and activator of transcription 3 phosphorylation, whereas β-catenin promotes its nuclear translocation."

Isolated mutant mouse cholangiocytes distinguish IL-1beta-driven phosphorylation from beta-catenin-dependent nuclear localization.

Increased Cholangiocyte Chemokine Secretion

Mechanism confidence: Provisional

Fibrocystin-defective mouse cholangiocytes increase secretion of CXCL1, CXCL10 and CXCL12. CXCL10 regulation depends on beta-catenin and IL-1beta/JAK/STAT3, and the chemokines provide a paracrine recruitment signal for macrophages.

intrahepatic cholangiocyte CL:0002538

chemokine production GO:0032602 ↑ INCREASED

liver UBERON:0002107

Experimental models

Primary Pkhd1del4/del4 cholangiocytes and RAW264.7 migration system CO CULTURE Polarized cholangiocyte secretion into conditioned medium.

Downstream

Peribiliary Macrophage Recruitment Cholangiocyte-derived chemokines recruit macrophages around ducts.

Show evidence (1 reference)

PMID:26645994 SUPPORT PRIMARY RESULT In Vitro

"Using a fibrocystin-defective (Pkhd1(del4/del4)) mouse, which is orthologous of CHF, we show that Pkhd1(del4/del4) cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including chemokine (C-X-C motif) ligands 1, 10, and 12, which stimulate bone..."

Experiments with mutant mouse cholangiocytes demonstrate chemokine secretion and macrophage recruitment; this is experimental cellular evidence, not human clinical evidence.

Peribiliary Macrophage Recruitment

Mechanism confidence: Provisional

Chemokines from the dysgenetic epithelium recruit predominantly bone marrow-derived macrophages around malformed ducts in the Pkhd1del4/del4 model. Recruitment and progressive fibrosis occur in sterile livers, demonstrating that this Caroli-syndrome-associated fibrosis pathway does not require bacterial cholangitis.

macrophage CL:0000235

macrophage chemotaxis GO:0048246 ↑ INCREASED

liver UBERON:0002107

Experimental models

Primary Pkhd1del4/del4 cholangiocytes and RAW264.7 migration system CO CULTURE Conditioned-medium-induced macrophage migration.

Animal models

Pkhd1del4/del4 mouse Mouse (Mus musculus) recapitulates Peribiliary macrophage infiltration.

Downstream

Cholangiocyte Integrin alphavbeta6 Upregulation Recruited macrophage cytokines induce epithelial integrin expression.

Show evidence (2 references)

PMID:26645994 SUPPORT PRIMARY RESULT In Vitro

Experiments with mutant mouse cholangiocytes demonstrate chemokine secretion and macrophage recruitment; this is experimental cellular evidence, not human clinical evidence.

PMID:26645994 SUPPORT PRIMARY RESULT Model Organism

"Microbiological analysis showed that Pkhd1del4/del4 livers from all ages were sterile (not shown); in addition, gut decontamination with polymyxin B and neomycin had no effect on the progressive accumulation of CD45+ cells in the portal space (not shown)."

The model provides evidence for sterile inflammation, separate from ascending biliary infection.

Cholangiocyte Integrin alphavbeta6 Upregulation

Mechanism confidence: Provisional

Macrophage-derived TNF-alpha and TGF-beta1 upregulate epithelial alphavbeta6 integrin in fibrocystin-defective mouse cholangiocytes. The integrin provides a local route for latent TGF-beta1 activation.

intrahepatic cholangiocyte CL:0002538

liver UBERON:0002107

Downstream

Local Latent TGF-beta1 Activation Integrin alphavbeta6 activates local latent TGF-beta1.

Show evidence (1 reference)

PMID:26645994 SUPPORT PRIMARY RESULT In Vitro

"We also show that Pkhd1(del4/del4) cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local transforming growth factor-β1."

Mutant mouse cholangiocytes respond to macrophage cytokines with integrin upregulation.

Local Latent TGF-beta1 Activation

Mechanism confidence: Provisional

Upregulated cholangiocyte alphavbeta6 activates latent TGF-beta1 near dysgenetic ducts. Nuclear phospho-SMAD3 and Snail1 in integrin-positive cystic epithelia were observed in the mouse model and archival human CHF specimens, supporting translational relevance without establishing every causal step in patients.

intrahepatic cholangiocyte CL:0002538

liver UBERON:0002107

Downstream

Portal Myofibroblast Accumulation The profibrogenic cytokine environment favors accumulation of collagen-producing cells.

Show evidence (2 references)

PMID:26645994 SUPPORT PRIMARY RESULT In Vitro

Mutant mouse cholangiocytes respond to macrophage cytokines with integrin upregulation.

PMID:26645994 SUPPORT PRIMARY RESULT Other

"Immunohistochemical analysis of serial liver sections from Pkhd1del4/del4 mice and from archival specimens of CHF patients showed nuclear expression of Snail1 and pSmad3 (transcription factors activated by TGFβ1 signaling) in cystic cells expressing αvβ6 (Supplemental Fig.5)."

This sentence reports parallel human CHF and mouse tissue staining; it provides correlative tissue evidence for local signaling. Functional perturbation evidence is from experimental cells.

Portal Myofibroblast Accumulation

Mechanism confidence: Provisional

Portal myofibroblasts accumulate as experimental CHF progresses. Together with increasing TGF-beta signaling and a changing macrophage infiltrate, these collagen-producing cells accelerate peribiliary fibrosis.

myofibroblast cell CL:0000186

liver UBERON:0002107

Downstream

Progressive Peribiliary Fibrosis Accumulation of matrix-producing cells accelerates peribiliary fibrosis.

Show evidence (1 reference)

PMID:26645994 SUPPORT PRIMARY RESULT Model Organism

"While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts."

The time-course in mutant mice associates myofibroblast accumulation with progressive fibrogenesis.

Ductal Plate Malformation of the Intrahepatic Biliary Tree

Mechanism confidence: Established

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

intrahepatic bile duct development GO:0035622 ⚠ ABNORMAL

intrahepatic bile duct UBERON:0003704

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 In Caroli syndrome, small-duct dysgenesis accompanies progressive congenital hepatic fibrosis; the developmental and inflammatory pathways are incompletely resolved in humans.

Show evidence (1 reference)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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

Mechanism confidence: Established

Segmental or multifocal non-obstructive saccular/fusiform dilatation of large intrahepatic ducts defines Caroli disease. The dilated spaces communicate with the biliary tree. Monolobar versus bilobar distribution, fibrosis and portal hypertension together determine whether resection is feasible.

intrahepatic bile duct UBERON:0003704

Animal models

PCK rat (Pkhd1 splicing mutant) Rat (Rattus norvegicus) recapitulates Distorted dilated biliary tree.

Downstream

Bile Stasis in the Dilated Segments Bile pools within the saccular outpouchings, where it drains poorly from the dilated segments.

Intrahepatic bile duct dilatation Clinical manifestation of segmental saccular dilatation of the large intrahepatic bile ducts.

Intrahepatic bile duct cysts Clinical manifestation of segmental saccular dilatation of the large intrahepatic bile ducts.

Show evidence (2 references)

PMID:34294522 SUPPORT BACKGROUND 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 PRIMARY RESULT 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

Mechanism confidence: Established

Poor drainage from ectatic communicating bile ducts causes bile stasis and cholestasis, predisposing to intrahepatic stone formation and ascending bacterial cholangitis.

intrahepatic bile duct UBERON:0003704

Downstream

Formation of Intrahepatic Bile Duct Stones Bile stasis increases the risk of intrahepatic stones.

Recurrent Bacterial Cholangitis Bile stasis increases the risk of ascending biliary infection.

Cholestasis Clinical manifestation of bile stasis in the dilated segments.

Jaundice Cholestasis from poorly drained ducts can manifest as jaundice.

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"The disruption of the tubular architecture of the larger intrahepatic bile ducts results in ductal ectasia, predisposing individuals to stagnant bile with an increased risk of stone formation and cholangitis (Fig. 1)."

Review directly connects ectasia, bile stagnation, stones and cholangitis.

Formation of Intrahepatic Bile Duct Stones

Mechanism confidence: Established

Stones develop within dilated intrahepatic ducts and may obstruct drainage further, contributing to cholangitis and hepatic abscess formation.

intrahepatic bile duct UBERON:0003704

Downstream

Recurrent Bacterial Cholangitis Stone-related biliary obstruction predisposes to infection.

Hepatolithiasis Clinical manifestation of hepatolithiasis.

Show evidence (1 reference)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation."

Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.

Recurrent Bacterial Cholangitis

Mechanism confidence: Established

Repeated ascending infection of poorly drained bile ducts produces cholangitis, with fever, abdominal pain and sometimes jaundice. Infection can progress to hepatic abscess or sepsis. This complication is distinct from the sterile fibrogenic pathway demonstrated in PKHD1-defective models.

intrahepatic bile duct UBERON:0003704

Downstream

Chronic Biliary Inflammation Repeated episodes of cholangitis maintain a chronic inflammatory microenvironment in the biliary epithelium.

Recurrent cholangitis Clinical manifestation of recurrent bacterial cholangitis.

Fever Clinical manifestation of recurrent bacterial cholangitis.

Abdominal pain Clinical manifestation of recurrent bacterial cholangitis.

Hepatic abscess Clinical manifestation of recurrent bacterial cholangitis.

Biliary sepsis Clinical manifestation of recurrent bacterial cholangitis.

Show evidence (2 references)

PMID:32884228 SUPPORT PRIMARY RESULT 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 REVIEW SYNTHESIS 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

Mechanism confidence: Established

In Caroli syndrome, malformed small intrahepatic ducts coexist with progressive portal/peribiliary fibrosis. The congenital ductal abnormality does not imply that all collagen deposition is complete at birth: PKHD1-defective models demonstrate progressive sterile inflammatory fibrogenesis. Portal and bridging fibrosis can cause severe portal hypertension while lobular architecture and hepatic synthetic function remain relatively preserved.

extracellular matrix organization GO:0030198 ↑ INCREASED

liver UBERON:0002107

Animal models

PCK rat (Pkhd1 splicing mutant) Rat (Rattus norvegicus) partially recapitulates Fibrosis is milder than human CHF.

Pkhd1del4/del4 mouse Mouse (Mus musculus) recapitulates Progressive pericystic and portal collagen deposition.

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.

Congenital hepatic fibrosis Clinical manifestation of progressive peribiliary fibrosis.

Show evidence (2 references)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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.

PMID:26645994 SUPPORT PRIMARY RESULT Model Organism

"In contrast with other experimental models of liver fibrosis, collagen deposition in Pkhd1del4/del4 mice initiates with little contribution from myofibroblasts, but then accelerates as the proportion of M2 polarized macrophages, TGFβ1 production and portal myofibroblasts increase."

Experimental time-course distinguishes early epithelial inflammation from later myofibroblast-rich fibrosis.

Presinusoidal Portal Hypertension

Mechanism confidence: Established

Portal/periportal fibrosis in Caroli syndrome increases presinusoidal resistance and can cause splenomegaly, hypersplenism and bleeding gastroesophageal varices. Liver biochemical and synthetic function may remain relatively preserved despite severe portal hypertension. Hepatic reserve may deteriorate in some patients, but a single reported decade-long progression is not a universal natural history.

liver UBERON:0002107

Animal models

Pkhd1del4/del4 mouse Mouse (Mus musculus) recapitulates Spleen enlargement serves as a portal-hypertension readout.

Downstream

Portal hypertension Clinical manifestation of presinusoidal portal hypertension.

Splenomegaly Clinical manifestation of presinusoidal portal hypertension.

Esophageal varices with recurrent bleeding Clinical manifestation of presinusoidal portal hypertension.

Gastrointestinal bleeding Clinical manifestation of presinusoidal portal hypertension.

Anemia Clinical manifestation of presinusoidal portal hypertension.

Leukopenia Clinical manifestation of presinusoidal portal hypertension.

Thrombocytopenia Clinical manifestation of presinusoidal portal hypertension.

Ascites Portal hypertension can contribute to ascites in Caroli syndrome; ascites is uncommon and may have additional causes.

Show evidence (3 references)

PMID:42438734 SUPPORT PRIMARY RESULT 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 PRIMARY RESULT 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 PRIMARY RESULT 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

Mechanism confidence: Established

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

intrahepatic bile duct UBERON:0003704

Downstream

Biliary Malignant Transformation Chronic biliary inflammation is a proposed route to epithelial dysplasia and carcinoma; this causal route remains provisional.

Show evidence (1 reference)

PMID:32884228 SUPPORT REVIEW SYNTHESIS 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.

Biliary Malignant Transformation

Mechanism confidence: Established

Cholangiocarcinoma is a documented complication of Caroli disease and syndrome. A systematic review of 561 surgically treated patients reported 37 cancers (6.6%); a German surgical cohort found 14 among 198 (7.1%). These selected retrospective proportions are not population incidence, and the datasets need not be independent. Preoperative recognition is difficult and malignancy is often found incidentally in surgical specimens. The specific causal route from chronic inflammation remains provisional.

intrahepatic bile duct UBERON:0003704

Downstream

Cholangiocarcinoma Clinical manifestation of cholangiocarcinoma.

Show evidence (4 references)

PMID:32884228 SUPPORT PRIMARY RESULT 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%."

The 6.6% proportion comes from selected retrospective surgical series, not an unselected population or person-time incidence study.

PMID:34294522 SUPPORT PRIMARY RESULT Human Clinical

"In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%)."

The German surgical cohort reports 14 cancers among 198 patients. Independence from cohorts in other reviews is not assumed.

PMID:32884228 SUPPORT PRIMARY RESULT 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

Aberrant Notch-Hes1 Signaling

Mechanism confidence: Provisional

Human Caroli liver specimens show increased nuclear Notch1 and biliary Hes1 with increased proliferative activity. This is an observational tissue association supporting a possible cyst-growth pathway, not proof that Notch activation initiates the congenital ductal defect.

intrahepatic cholangiocyte CL:0002538

Notch signaling pathway GO:0007219 ↑ INCREASED

Downstream

Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts Aberrant Notch-Hes1 activation is proposed to contribute to progression of biliary cystogenesis.

Show evidence (2 references)

PMID:34166554 SUPPORT PRIMARY RESULT Human Clinical

"The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC."

Primary human tissue study demonstrates nuclear Notch1, not universal Notch1–4 activation in Caroli tissue.

PMID:34166554 SUPPORT PRIMARY RESULT Human Clinical

"Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD."

Human tissue data associate pathway readout and proliferation.

✶

Histopathology

Non-obstructive duct ectasia with intraluminal vascular channels

Dilated communicating bile ducts show intraluminal wall protrusions and patent portal venous and hepatic arterial channels. This architecture underlies the central dot sign on imaging.

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"Characteristic findings of CD on histology include localized, non-obstructive dilated bile ducts, intraluminal protrusions of the ductal wall, and patent hepatic arterial and portal venous channels that terminate within the duct lumen."

Review describes Caroli-specific duct morphology.

Ductal plate malformation with portal-portal fibrous bands

The congenital hepatic fibrosis component includes irregular embryonic-type bile ducts embedded in portal-portal fibrous bands. Hepatic lobular architecture may remain preserved despite marked portal disease.

Show evidence (2 references)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"The fibrosis is characterized by portal-portal bands with embedded elongated, tortuous, or branched bile duct structures."

The CHF section describes the small-duct and fibrotic component of Caroli syndrome.

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"The hepatic lobules typically have normal hepatocyte morphology unless there is progression to cirrhosis."

This distinguishes typical CHF architecture from established cirrhosis.

Nuclear Notch1 and biliary Hes1 expression

A human tissue study found increased nuclear Notch1 and Hes1 expression in Caroli disease, with higher biliary proliferative activity. These research observations do not establish a clinical diagnostic test or activation of all Notch receptors in Caroli disease.

Show evidence (1 reference)

PMID:34166554 SUPPORT PRIMARY RESULT Human Clinical

"The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC."

Primary human tissue study demonstrates nuclear Notch1, not universal Notch1–4 activation in Caroli tissue.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 4

Anemia HP:0001903

Show evidence (1 reference)

PMID:25327281 SUPPORT PRIMARY RESULT Human Clinical

"Anaemia, leucopoenia and thrombocytopoenia were more frequent in patients with type II than type I CD."

The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.

Leukopenia Decreased total leukocyte count HP:0001882

Show evidence (1 reference)

PMID:25327281 SUPPORT PRIMARY RESULT Human Clinical

"Anaemia, leucopoenia and thrombocytopoenia were more frequent in patients with type II than type I CD."

The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.

Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:25327281 SUPPORT PRIMARY RESULT Human Clinical

"Anaemia, leucopoenia and thrombocytopoenia were more frequent in patients with type II than type I CD."

The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.

Gastrointestinal bleeding Gastrointestinal hemorrhage HP:0002239

Show evidence (1 reference)

PMID:42438734 SUPPORT PRIMARY RESULT Human Clinical

"she experienced recurrent hematemesis and melena despite sequential endoscopic variceal ligation and beta-blocker therapy"

This longitudinal case documents recurrent variceal bleeding.

Cardiovascular 2

Portal hypertension HP:0001409

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:42438734 SUPPORT BACKGROUND 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

Show evidence (1 reference)

PMID:42438734 SUPPORT PRIMARY RESULT Human Clinical

A worked single-patient example of the dissociation this node describes — severe portal hypertension (splenomegaly, fundal varices) with preserved liver biochemistry.

Digestive 12

Intrahepatic bile duct dilatation HP:0033149

Show evidence (1 reference)

PMID:34294522 SUPPORT PRIMARY RESULT 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

Show evidence (1 reference)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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

Temporal: RECURRENT

Show evidence (1 reference)

PMID:32884228 SUPPORT PRIMARY RESULT 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

Show evidence (1 reference)

PMID:32884228 SUPPORT REVIEW SYNTHESIS 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.

Esophageal varices with recurrent bleeding Esophageal varix HP:0002040

Show evidence (1 reference)

PMID:22197937 SUPPORT PRIMARY RESULT Human Clinical

"164 with varices, 74 bleeding varices"

Varices and hemorrhage were reported in a mixed CHF/ARPKD/Caroli literature cohort. The totals are not Caroli-specific frequencies.

Hepatolithiasis HP:6000063

Show evidence (1 reference)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation."

Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.

Cholangiocarcinoma HP:0030153

Show evidence (3 references)

PMID:32884228 SUPPORT PRIMARY RESULT 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%."

The 6.6% proportion comes from selected retrospective surgical series, not an unselected population or person-time incidence study.

PMID:34294522 SUPPORT PRIMARY RESULT Human Clinical

"In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%)."

The German surgical cohort reports 14 cancers among 198 patients. Independence from cohorts in other reviews is not assumed.

PMID:32884228 SUPPORT PRIMARY RESULT 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.

Jaundice FREQUENT HP:0000952

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"In a study of 14 CD patients, 50% reported right upper quadrant pain, 35.7% had jaundice, 28.6% experienced fever, and 14.3% were asymptomatic."

The reported 35.7% falls in the FREQUENT band, scoped to this small cohort.

Cholestasis HP:0001396

Show evidence (1 reference)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation."

Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.

Hepatic abscess Liver abscess HP:0100523

Show evidence (1 reference)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation."

Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"Physical examination findings may include hepatomegaly, splenomegaly, ascites, peripheral edema, and jaundice."

The Caroli syndrome section describes the examination findings.

Ascites HP:0001541

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"Physical examination findings may include hepatomegaly, splenomegaly, ascites, peripheral edema, and jaundice."

The Caroli syndrome section describes the examination findings.

Genitourinary 1

Polycystic kidney disease Polycystic kidney dysplasia HP:0000113

Show evidence (1 reference)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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.

Immune 1

Biliary sepsis HP:0100806

Show evidence (1 reference)

PMID:32884228 SUPPORT PRIMARY RESULT Human Clinical

"Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."

Clinical presentations in the selected Caroli surgical series include fever, sepsis and abdominal pain.

Metabolism 1

Fever OCCASIONAL HP:0001945

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"In a study of 14 CD patients, 50% reported right upper quadrant pain, 35.7% had jaundice, 28.6% experienced fever, and 14.3% were asymptomatic."

The reported 28.6% falls in the OCCASIONAL band, scoped to this small cohort.

Constitutional 1

Abdominal pain FREQUENT HP:0002027

Show evidence (2 references)

PMID:32884228 SUPPORT PRIMARY RESULT Human Clinical

"Most patients had episodes of cholangitis, sepsis, fever or abdominal pain."

Abdominal pain is among the dominant presenting symptoms.

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"In a study of 14 CD patients, 50% reported right upper quadrant pain, 35.7% had jaundice, 28.6% experienced fever, and 14.3% were asymptomatic."

The reported 50% falls in the FREQUENT band, scoped to this small cohort.

🧬

Genetic Associations

PKHD1

Gene: PKHD1 hgnc:9016 gene page relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:33824930 SUPPORT REVIEW SYNTHESIS 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 PRIMARY RESULT 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.

PMID:24710345 SUPPORT PRIMARY RESULT Human Clinical

"The father harbors the p.Val836Ala mutant, while the mother carries the p.Arg781* variant."

The reported compound heterozygous genotype was inherited in trans. The pedigree provides segregation evidence, not a current expert-panel classification.

+ 1 more reference

🔬

Variants

Reported PKHD1 p.Arg781* / p.Val836Ala compound heterozygous genotype

Gene: PKHD1 hgnc:9016

A 2014 report described c.2341C>T (p.Arg781*) and c.2507T>C (p.Val836Ala), on NM_138694.3, inherited from different parents in dizygotic twins. One twin had a severe syndromic phenotype and the other had isolated duct dilatation. These are historical pedigree observations; the missense allele was not functionally proven, and no current clinical-significance classification is asserted here.

Show evidence (3 references)

PMID:24710345 SUPPORT PRIMARY RESULT Human Clinical

"RESULTS: A combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala), and the nonsense mutation..."

The primary report describes the genotype, segregation and control comparison.

PMID:24710345 SUPPORT PRIMARY RESULT Human Clinical

"The first twin (Patient B) had no obvious clinical symptoms except for intrahepatic bile duct dilatation."

The twins illustrate phenotypic variability despite sharing the reported genotype.

PMID:24710345 SUPPORT PRIMARY RESULT Human Clinical

"The p.Val836Ala mutation results in an amino acid change from valine to alanine, but as both amino acids are neutral the potential impairment on protein function is unclear; however, the amino acid at position 836 is highly conserved between species."

The authors explicitly leave the missense allele’s functional effect unresolved.

💊

Medical Actions

Antibiotic Therapy for Cholangitis

Action: Antibiotic Therapy NCIT:C15620

Platform: Small molecule

Treat bacterial cholangitis promptly, with biliary drainage when obstruction requires it. In ARPKD-associated disease, chronic antibiotic prophylaxis is individualized: GeneReviews considers its routine use controversial and gives no general recommendation.

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 (2 references)

PMID:32884228 SUPPORT REVIEW SYNTHESIS Human Clinical

"The initial treatment of CS and CD is often nonsurgical and supportive therapy using analgesia, antibiotics in case of biliary infections and ursodeoxycholic acid[31,32]."

The review explicitly documents antibiotic treatment of biliary infection.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial."

Routine prophylaxis in all children with ARPKD is not established.

Nonselective Beta-Blocker Therapy for Portal Hypertension

Action: Pharmacotherapy NCIT:C15986

Agent: propranolol CHEBI:8499 carvedilol CHEBI:3441

Platform: Small molecule

Nonselective beta-blockers such as propranolol or carvedilol are used for portal-hypertension/variceal prophylaxis. One Caroli case showed initial symptomatic improvement but recurrent bleeding over time; this does not establish durable Caroli-specific efficacy.

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 PRIMARY RESULT 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 observation supports reported use and its limitations, not a population treatment-effect estimate.

Endoscopic Variceal Ligation

Action: Endoscopic variceal band ligation Ontology label: Ligation NCIT:C15270

Platform: Device

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 Gastrointestinal bleeding — Band ligation treats variceal hemorrhage by obliterating the collateral vessel; it does not directly lower portal pressure.

Show evidence (2 references)

PMID:42438734 SUPPORT PRIMARY RESULT 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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Esophageal varices should be treated with endoscopic banding or sclerotherapy according to local standard procedures as for children with other causes of portal hypertension [Guay-Woodford et al 2014, Jeanniard-Malet et al 2017]."

GeneReviews supports endoscopic treatment in ARPKD-associated portal hypertension.

Hepatic Resection for Localised Disease

Action: Hepatectomy NCIT:C15249

Platform: Surgery

Resection can relieve symptoms when disease is confined to a resectable segment or lobe, particularly without substantial fibrosis or portal hypertension. It removes the diseased territory but does not prove elimination of all future cancer risk in residual liver.

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 (2 references)

PMID:34294522 SUPPORT PRIMARY RESULT 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.

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"This may be feasible in symptomatic cases with monolobar involvement without liver ﬁbrosis or portal hyper- tension."

EASL qualifies resection by distribution and absence of major fibrosis/portal hypertension.

Liver Transplantation

Action: Liver Transplantation NCIT:C15271

Platform: Surgery

Consider transplant referral for recurrent cholangitis with bilobar disease, or monolobar disease with fibrosis/portal hypertension when resection is excluded. Referral before acute infection or physical deterioration is advised. Combined liver-kidney transplantation requires individualized weighing of hepatic complications, CKD and operative risk.

Mechanism Target:

INHIBITS Presinusoidal Portal Hypertension — Replacing the fibrotic, malformed liver removes the presinusoidal obstruction and with it the portal hypertension.

Show evidence (4 references)

PMID:42438734 SUPPORT PRIMARY RESULT 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 REVIEW SYNTHESIS 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.

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Referral for liver transplantation should be considered in patients with Caroli disease or syndrome with recurrent cholangitis and i) bilobar involvement, or ii) monolobar involvement in combination with liver ﬁbrosis or portal hypertension, when the possibility of liver resection has been..."

Guideline gives the extent and complication criteria for transplant referral.

+ 1 more reference

Avoidance of Hepatotoxic and Nephrotoxic Agents

Action: avoidance of hepatotoxic and nephrotoxic agents Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

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 REVIEW SYNTHESIS 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.

Ursodeoxycholic Acid for Cholestasis and Stones

Action: Pharmacotherapy NCIT:C15986

Agent: ursodeoxycholic acid CHEBI:9907

Platform: Small molecule

EASL describes UDCA for cholestasis and stone formation in Caroli disease/syndrome, including narrative advice for asymptomatic patients. Evidence is limited. GeneReviews for ARPKD-PKHD1 states that routine UDCA as a choleretic generally cannot be recommended, so this is not an unqualified recommendation for every syndromic child.

Mechanism Target:

INHIBITS Bile Stasis in the Dilated Segments — UDCA is used to improve cholestasis and limit stone formation in the EASL Caroli guidance; evidence and recommendations differ for ARPKD-PKHD1.

Show evidence (2 references)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Cholestasis and gallstone formation can be treated with ursodeoxycholic acid and abscesses should be drained"

EASL lists UDCA for cholestasis and gallstones.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [Guay-Woodford et al 2014]."

GeneReviews provides a different recommendation for the ARPKD population.

Percutaneous Transhepatic Biliary Drainage

Action: Percutaneous Transhepatic Biliary Drainage NCIT:C93008

Platform: Surgery

Percutaneous drainage is one route for relieving biliary obstruction and improving drainage. Endoscopic treatment with ERCP is an alternative when appropriate; neither is a routine cancer-screening test.

Mechanism Target:

INHIBITS Bile Stasis in the Dilated Segments — A percutaneous transhepatic catheter decompresses obstructed ducts and improves bile drainage from affected segments.

Show evidence (1 reference)

PMID:32884228 SUPPORT REVIEW SYNTHESIS Human Clinical

"Surgical or interventional drainage procedures may be performed to remove biliary tract obstructions and improve biliary passage to decrease the risk and burden of cholangitis[33,34]."

Review states the purpose of drainage for obstruction and cholangitis.

Drainage of Hepatic Abscess

Action: Drainage NCIT:C50434

Hepatic abscesses require drainage by an appropriate image-guided, endoscopic or surgical route alongside infection treatment.

Mechanism Target:

INHIBITS Hepatic abscess — Drainage removes infected fluid from the abscess cavity as part of source control.

Show evidence (1 reference)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"abscesses should be drained (which can be achieved radiologically/ultrasound guided, endoscopically or surgically)."

Guideline specifies drainage options.

Portosystemic Shunting for Refractory Portal Complications

Action: Transjugular Intrahepatic Portosystemic Shunt NCIT:C126288

Platform: Surgery

TIPS or surgical shunting may be considered for refractory portal-hypertension complications in Caroli syndrome. Preserved renal function favors feasibility; encephalopathy and kidney disease require careful selection.

Mechanism Target:

INHIBITS Presinusoidal Portal Hypertension — A portosystemic shunt diverts blood past intrahepatic resistance to decompress the portal circulation; kidney function and encephalopathy risk constrain selection.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Interventional or surgical portosystemic shunting may be necessary to treat progressive portal hypertension"

GeneReviews supports shunting in selected ARPKD-associated portal complications.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"and may be an option especially in individuals with good residual kidney function."

Renal function informs selection for shunting.

Genetic Counseling and Family Evaluation

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

For confirmed PKHD1-associated disease, provide recurrence-risk counseling, parental/relative testing and discussion of reproductive options. When both parents are carriers, each conception has a 25% affected-child risk; prenatal/preimplantation testing requires identification of familial variants.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Once the PKHD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and molecular genetic prenatal testing and preimplantation genetic testing are possible."

Familial-variant identification permits reproductive testing.

Experimental Macrophage Depletion with Liposomal Clodronate

Action: Pharmacotherapy NCIT:C15986

Agent: clodronic acid CHEBI:110423

Platform: Small molecule Delivery: Liposome

In Pkhd1del4/del4 mice, liposomal clodronate reduced macrophage infiltration, fibrosis and spleen enlargement. This is a preclinical CHF/Caroli-syndrome model intervention, not established patient therapy.

Mechanism Target:

INHIBITS Peribiliary Macrophage Recruitment — Liposomal clodronate depletes macrophages and reduces the peribiliary macrophage infiltrate in Pkhd1del4/del4 mice.

Show evidence (2 references)

PMID:26645994 SUPPORT PRIMARY RESULT Model Organism

"Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts."

Macrophage depletion was tested in mice; no human therapeutic efficacy is implied.

PMID:26645994 SUPPORT Model Organism

"To induce a selective macrophage depletion, Pkhd1del4/del4 mice of 3 months of age were treated for 3 months with clodronate liposomes (100mg/kg every three days, I.P., n=4) or with vehicle (sterile phosphate-buffered saline (PBS) + liposomes every three days by I.P., n=3)12."

The methods specify liposomal delivery in a small mouse experiment.

Experimental CXCR3 Inhibition with AMG-487

Action: Pharmacotherapy NCIT:C15986

Agent: AMG-487

Platform: Small molecule

AMG-487 reduced inflammatory infiltration, fibrosis, cyst growth and spleen size in Pkhd1del4/del4 mice. These results support the experimental CXCL10/CXCR3 mechanism; clinical benefit in Caroli disease has not been established.

Mechanism Target:

INHIBITS Peribiliary Macrophage Recruitment — AMG-487 inhibits CXCR3, the receptor for CXCL10, reducing chemokine-mediated macrophage recruitment in Pkhd1del4/del4 mice.

Show evidence (1 reference)

PMID:29140564 SUPPORT PRIMARY RESULT Model Organism

"We demonstrate that treatment of Pkhd1del4/del4 mice for 3 months with AMG-487, an inhibitor of CXC chemokine receptor family 3, the cognate receptor of CXCL10, reduces the peribiliary recruitment of alternative activated macrophages (cluster of differentiation 45+ F4/80+ cells), spleen size,..."

Three-month mouse intervention supports the pathway, not human efficacy.

Endoscopic Sclerotherapy for Varices

Action: Sclerotherapy NCIT:C62732

Endoscopic sclerotherapy is an alternative local treatment for varices in ARPKD-associated Caroli syndrome. Selection follows specialist practice and does not correct the congenital duct abnormality.

Mechanism Target:

INHIBITS Gastrointestinal bleeding

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT Human Clinical

"Esophageal varices should be treated with endoscopic banding or sclerotherapy according to local standard procedures as for children with other causes of portal hypertension"

GeneReviews recommends local endoscopic treatment for varices.

🔬

Biochemical Markers

Gamma-glutamyltransferase (INCREASED)

Context: Cholestatic enzyme elevation; 64.3% in a reported 14-patient cohort.

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"In a study of 14 CD patients, 64.3% exhibited elevated GGT, 35.7% had elevated alkaline phosphatase, and 28.6% had elevated bilirubin."

Small selected Caroli cohort summarized in the review; these measurements are not diagnostic thresholds.

Alkaline phosphatase (INCREASED)

Context: Cholestatic enzyme elevation; 35.7% in a reported 14-patient cohort.

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"In a study of 14 CD patients, 64.3% exhibited elevated GGT, 35.7% had elevated alkaline phosphatase, and 28.6% had elevated bilirubin."

Small selected Caroli cohort summarized in the review; these measurements are not diagnostic thresholds.

Bilirubin (INCREASED)

Context: Hyperbilirubinemia; 28.6% in a reported 14-patient cohort.

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"In a study of 14 CD patients, 64.3% exhibited elevated GGT, 35.7% had elevated alkaline phosphatase, and 28.6% had elevated bilirubin."

Small selected Caroli cohort summarized in the review; these measurements are not diagnostic thresholds.

🔬

Diagnosis

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.

Magnetic Resonance Cholangiopancreatography NCIT:C113775

Show evidence (2 references)

PMID:25327281 SUPPORT PRIMARY RESULT 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.

clinicaltrials:NCT04007575 SUPPORT PRIMARY RESULT Human Clinical

"The Caroli disease is a very rare pathology that can be revealed early in childhood or in adulthood, whose diagnosis is based on Magnetic Resonance CholangioPancreatography, which shows the communication of these malformations with the rest of the biliary tree and allows to eliminate biliary stenosis."

The diagnostic study protocol states the MRCP features used to establish Caroli disease.

Assessment for congenital hepatic fibrosis and renal involvement

Ductal ectasia should prompt assessment for CHF to distinguish Caroli syndrome, including liver stiffness, portal-hypertension findings and renal imaging. Renal and hepatic severity need not correlate. Histology can resolve uncertain fibrosis morphology when clinically indicated.

Show evidence (2 references)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The ﬁnding of multiple segmental cystic or saccular di- latations of bile ducts should initiate a search for congenital hepatic ﬁbrosis in order to differentiate Caroli disease from Caroli syndrome (LoE 4, strong recommendation, 100% consensus)."

EASL recommends actively distinguishing simple from syndromic disease.

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"While the majority of patients with Caroli syndrome possess renal cystic lesions and renal impairment may ensue, there is no correlation between the severity of renal and hepatic manifestations."

Renal lesions are common in Caroli syndrome but severity does not track hepatic severity.

Molecular diagnosis of PKHD1-associated disease

In a compatible hepatorenal phenotype, biallelic pathogenic or likely pathogenic PKHD1 variants establish ARPKD-PKHD1. A phenotype-focused multigene panel or exome/genome testing may be appropriate. A VUS or a negative PKHD1 result does not by itself establish or exclude imaging-defined simple Caroli disease.

Show evidence (2 references)

PMID:20301501 SUPPORT REVIEW SYNTHESIS Human Clinical

"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."

GeneReviews molecular criteria apply to the PKHD1-associated hepatorenal subset.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Identification of biallelic PKHD1 variants of uncertain significance (or of one known PKHD1 pathogenic variant and one PKHD1 variant of uncertain significance) does not establish or rule out the diagnosis."

GeneReviews distinguishes uncertain from diagnostic variants.

Cholangiocarcinoma surveillance

The 2022 EASL guideline permits MRCP every 12 months after Caroli diagnosis, as a weak recommendation based on low-level evidence. The guideline acknowledges a lack of disease-specific screening accuracy data. ERCP is not recommended for cancer screening because of infection risk, and CA19-9 has poor diagnostic performance in this setting.

Magnetic Resonance Cholangiopancreatography NCIT:C113775

Show evidence (2 references)

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Patients with Caroli disease and syndrome may receive surveillance for cholangiocarcinoma with magnetic reso- nance cholangiopancreaticography every 12 months after diagnosis (LoE 4, weak recommendation, 90% consensus)."

Annual MRCP is a weak, low-evidence recommendation, not proven outcome-improving screening.

url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"We do not recommend endoscopic retrograde chol- angiopancreaticography for cholangiocarcinoma screening because this procedure is associated with increased risk of biliary infection."

Guideline discourages ERCP as a screening procedure.

Hepatoportal and renal surveillance in ARPKD-associated Caroli syndrome

Monitor blood pressure, kidney function, blood counts, synthetic liver function and nutritional/fat-soluble vitamin status. Ultrasound/Doppler, elastography and MRCP are selected according to complications and prior imaging; renal dysfunction affects contrast and transplant decisions.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hepatoportal involvement. Perform physical examination; obtain complete blood counts, prothrombin time, and serum concentrations of albumin, 25-hydroxyvitamin D, and other fat-soluble vitamins."

GeneReviews specifies laboratory and examination surveillance for ARPKD-associated hepatobiliary disease.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Kidney function. Close monitoring for the complications of CKD should be undertaken by the treating pediatric nephrologist according to standard practices."

Associated CKD requires nephrology surveillance.

🩻

Imaging Findings

Communicating saccular intrahepatic duct dilatation on MRCP

MRCP demonstrates saccular or fusiform intrahepatic duct dilatation communicating with the biliary tree and helps exclude a primary obstructing stenosis.

Mri Diagnostic

intrahepatic bile duct UBERON:0003704 Intrahepatic bile duct dilatation HP:0033149

Show evidence (1 reference)

clinicaltrials:NCT04007575 SUPPORT PRIMARY RESULT Human Clinical

The diagnostic study protocol states the MRCP features used to establish Caroli disease.

Central dot sign

On contrast-enhanced MRI or CT, a portal venous radicle and hepatic arterial branch within a dilated duct create an enhancing central dot. This supports Caroli disease in the appropriate ductal morphology.

Mri

intrahepatic bile duct UBERON:0003704

Show evidence (1 reference)

PMID:39130622 SUPPORT REVIEW SYNTHESIS Human Clinical

"Contrast-enhanced CT or MRI of the abdomen may reveal a pathognomonic finding, the central dot sign. Histologically, this relates to a branch of the hepatic artery and a portal vein radical bridging a saccule resembling a central dot."

Review connects the cross-sectional imaging finding with its vascular substrate.

🔬

Clinical Trials

NCT04007575 NOT_APPLICABLE COMPLETED

IMACA is a completed retrospective observational MRCP diagnostic study with 61 actual participants, comparing imaging features with pathology. It is not a drug trial; no registry results are posted.

Show evidence (1 reference)

clinicaltrials:NCT04007575 SUPPORT Human Clinical

"The benefit of this research is to reduce diagnostic errors by highlighting imaging criteria specific to the Caroli disease"

Registry summary states the observational study purpose.

NCT01401998 NOT_APPLICABLE RECRUITING

Hepatorenal fibrocystic disease observational registry including Caroli syndrome; builds clinical/genetic databases and biospecimen resources. It is not a therapeutic trial.

Show evidence (1 reference)

clinicaltrials:NCT01401998 SUPPORT Human Clinical

"This study aims to build a registry of a clinical database (medical health information), a mutational database (genetic information) and an educational resource about HRFD to eventually provide information about these diseases to families, physicians and genetic counselors via our existing..."

Registry summary states the observational study purpose.

🧫

Experimental Models

Primary Pkhd1del4/del4 cholangiocytes and RAW264.7 migration system CO_CULTURE

Primary mutant and wild-type mouse cholangiocytes supply apical or basolateral conditioned medium to RAW264.7 macrophages. Chemokine secretion, macrophage migration and pathway inhibition resolve epithelial signaling separately from whole-animal fibrosis.

Cell source

Primary mouse cholangiocytes and a mouse macrophage cell line

Pathograph links

Increased Cholangiocyte Chemokine Secretion recapitulates Polarized cholangiocyte secretion into conditioned medium.

Peribiliary Macrophage Recruitment recapitulates Conditioned-medium-induced macrophage migration.

Increased Beta-catenin Signaling perturbs Beta-catenin inhibitor and silencing experiments.

Show evidence (1 reference)

PMID:26645994 SUPPORT PRIMARY RESULT In Vitro

"To test the polarity-dependent ability of Pkhd1del4/del4 cholangiocytes to recruit macrophages, we studied the effect of conditioned medium differentially harvested from basolateral and apical sides, on a mouse macrophage cell line (RAW264.7)."

The primary paper specifies the non-animal experimental system.

🐁

Animal Models

PCK rat (Pkhd1 splicing mutant) Spontaneous orthologous mutant

The PCK rat reproduces intrahepatic duct dilatation and abnormal ciliary morphology. Compared with the Pkhd1del4/del4 mouse, it has more prominent cystic disease and renal involvement but milder portal fibrosis; it is a limited model of human CHF-related portal hypertension.

Species

Rat (Rattus norvegicus)

Genotype

PCK rat, germline Pkhd1 splicing mutation (homozygous)

Genes

Pkhd1 hgnc:9016

Pathograph links

Abnormal Cholangiocyte Ciliary Morphology recapitulates Shortened, bulbous cholangiocyte cilia.

Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts recapitulates Distorted dilated biliary tree.

Progressive Peribiliary Fibrosis partially recapitulates Fibrosis is milder than human CHF.

The genotype and gene symbol refer to rat Pkhd1. The HGNC binding identifies the human PKHD1 ortholog for cross-model comparison, following the schema’s HGNC gene vocabulary; it is not a rat gene identifier.

Show evidence (2 references)

PMID:14598246 SUPPORT PRIMARY RESULT 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.

PMID:28709963 SUPPORT REVIEW SYNTHESIS Model Organism

"However, in contrast with the Pkhd1del4/del4 mouse, the PCK rat shows some critical differences, including a more pronounced development of the hepatic cysts, the renal involvement with cyst lesions affecting the outer medullary-collecting ducts, and the mild degree of portal fibrosis, without..."

Comparative review describes the model’s limits.

Pkhd1del4/del4 mouse Genetic model

Orthologous CHF model with progressive peribiliary fibrosis, duct dysgenesis, macrophage recruitment and spleen enlargement. It models the fibrotic component of Caroli syndrome and lacks the renal phenotype of many human PKHD1 cases.

Species

Mouse (Mus musculus)

Genotype

Homozygous Pkhd1 exon 4 deletion

Pathograph links

Progressive Peribiliary Fibrosis recapitulates Progressive pericystic and portal collagen deposition.

Peribiliary Macrophage Recruitment recapitulates Peribiliary macrophage infiltration.

Presinusoidal Portal Hypertension recapitulates Spleen enlargement serves as a portal-hypertension readout.

Show evidence (1 reference)

PMID:26645994 SUPPORT PRIMARY RESULT Model Organism

"Serial analysis of Pkhd1del4/del4 mouse liver and spleen demonstrate an age-dependent increase in the biliary cystic malformations (Supplemental Fig.1A–B), peribiliary fibrosis (Fig.1A), increased collagen-I deposition, as shown by the progressive increase in Sirius Red staining (Fig.1B) and in..."

Time-course demonstrates progressive fibrosis in the mouse model.

{ }

Source YAML

click to show

name: Caroli disease
creation_date: "2026-08-07T00:00:00Z"
category: Mendelian
description: >-
  Caroli disease is a congenital malformation with segmental non-obstructive dilatation of large intrahepatic
  bile ducts that communicate with the biliary tree. Simple Caroli disease lacks congenital hepatic fibrosis;
  Caroli syndrome combines duct ectasia with CHF and often PKHD1-associated renal disease. Bile stasis predisposes
  to stones, cholangitis, abscesses and sepsis. In Caroli syndrome, progressive peribiliary fibrosis causes
  portal hypertension, hypersplenism and variceal bleeding, often despite relatively preserved hepatic function.
  Cholangiocarcinoma is a recognized complication, but its population incidence remains uncertain. Care is
  complication-directed, with resection for selected localized disease and transplant assessment for unresectable
  recurrent cholangitis or severe portal complications.
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 anchors Caroli disease; MONDO:0018808 anchors the Caroli syndrome subtype with additional
      congenital hepatic fibrosis. This entry models the related large-duct disorders together while retaining
      subtype-specific renal, genetic and fibrotic findings.
  - 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: >-
    The simple form uses the entry-level Caroli disease concept; Caroli syndrome has its own subtype term.
    Clinical findings and mechanisms sourced only from CHF/ARPKD are scoped to the syndromic component.
  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.
    quote_role: REVIEW_SYNTHESIS
- 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 with congenital hepatic fibrosis involving smaller ducts. Often associated with ARPKD, with
    portal hypertension, hypersplenism and variceal bleeding. Distribution, renal function and severity of
    complications determine treatment; transplantation is not inevitable in every patient.
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
  expressivity: VARIABLE
pathophysiology:
- name: Fibrocystin Dysfunction in PKHD1-associated Disease
  role: root
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic pathogenic PKHD1 variants impair fibrocystin/polyductin in the PKHD1-associated fibrocystic spectrum,
    particularly Caroli syndrome with ARPKD. This membrane and ciliary protein has incompletely resolved molecular
    functions. The PCK rat demonstrates loss of ciliary fibrocystin, but neither complete protein absence nor
    a single ciliary structural defect is established for every human variant or every sporadic simple Caroli
    case.
  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
  downstream:
  - target: Ductal Plate Malformation of the Intrahepatic Biliary Tree
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      PKHD1 dysfunction is linked to ductal dysgenesis; the complete developmental sequence is unresolved.
    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: >-
        Review-level support for the ciliary dysfunction to ductal-malformation relationship.
      quote_role: REVIEW_SYNTHESIS
  - target: Abnormal Cholangiocyte Ciliary Morphology
    causal_link_type: DIRECT
    description: >-
      The PCK model links Pkhd1 disruption to abnormal ciliary morphology.
    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: "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.
      quote_role: PRIMARY_RESULT
  - target: Increased Beta-catenin Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Fibrocystin-defective cholangiocytes exhibit altered beta-catenin signaling in the model.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Using the Pkhd1del4/del4 mouse, an orthologous model of CHF/CD (8, 9), we previously demonstrated that increased PKA-dependent phosphorylation of β-Catenin at Ser675 promoted the nuclear translocation of transcriptionally active pSer-675-β-Catenin (10).
      explanation: >-
        The paper describes the prior experimental basis for beta-catenin activation in this model.
      quote_role: BACKGROUND
  - target: Inflammasome-mediated Interleukin-1beta Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Fibrocystin deficiency is associated with increased inflammasome-dependent IL-1beta secretion; the upstream
      activation sequence is unresolved.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In addition, MCC950 10 μM, an inhibitor of the NLRP3 inflammasome caused a significant reduction (40%) in IL-1β secretion in FPC-defective but not in WT cholangiocytes (Figure 8D).
      explanation: >-
        In vitro inhibitor results support NLRP3-dependent maturation/secretion of bioactive IL-1beta.
      quote_role: PRIMARY_RESULT
  - target: Polycystic kidney disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      In the PKHD1-associated Caroli syndrome subset, the same genetic defect also affects renal tubular development.
    evidence:
    - reference: PMID:20301501
      reference_title: Autosomal Recessive Polycystic Kidney Disease – PKHD1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 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.
      explanation: >-
        The causal PKHD1-associated hepatorenal disorder provides the genetic link to the renal phenotype,
        which is scoped to Caroli syndrome.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - reference: PMID:24710345
    reference_title: Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes.
    explanation: >-
      A small human pedigree supports PKHD1-associated Caroli disease; it does not establish the cause of all
      isolated cases.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
- name: Abnormal Cholangiocyte Ciliary Morphology
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In PCK rat cholangiocytes, cilia are shortened and have bulbous extensions. This experimental structural
    phenotype supports ciliary dysfunction in PKHD1-associated disease; it is not an obligatory ultrastructural
    finding in all patients.
  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: "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.
    quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
- name: Increased Beta-catenin Signaling
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Fibrocystin-defective mouse cholangiocytes exhibit increased PKA-dependent beta-catenin activity. This
    experimental pathway promotes chemokine production and nuclear accumulation of phosphorylated STAT3; its
    importance across human simple Caroli disease remains unproven.
  evidence:
  - reference: PMID:29140564
    reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Using the Pkhd1del4/del4 mouse, an orthologous model of CHF/CD (8, 9), we previously demonstrated that increased PKA-dependent phosphorylation of β-Catenin at Ser675 promoted the nuclear translocation of transcriptionally active pSer-675-β-Catenin (10).
    explanation: >-
      The paper describes the prior experimental basis for beta-catenin activation in this model.
    quote_role: BACKGROUND
  - reference: PMID:29140564
    reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Moreover, increasing cAMP levels induced CXCL10 gene expression and protein secretion was abolished upon PKA inhibition.
    explanation: >-
      In cultured FPC-defective cholangiocytes, cAMP/PKA-dependent signaling contributes to chemokine production.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Increased Nuclear Phosphorylated STAT3
    causal_link_type: DIRECT
    description: >-
      Beta-catenin promotes nuclear localization of phosphorylated STAT3.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Specifically, IL-1β promotes signal transducer and activator of transcription 3 phosphorylation, whereas β-catenin promotes its nuclear translocation.
      explanation: >-
        Isolated mutant mouse cholangiocytes distinguish IL-1beta-driven phosphorylation from beta-catenin-dependent
        nuclear localization.
      quote_role: PRIMARY_RESULT
  - target: Increased Pro-interleukin-1beta Transcription
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Beta-catenin and STAT3 regulate NF-kB activity in cultured mutant cholangiocytes.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The decrease of NF-kB transcriptional activity upon β-catenin silencing was shown also for IL-1β because under these conditions, a 40% reduction in IL-1β gene expression and secretion was observed (Supplementary Figure 6G, H).
      explanation: >-
        Experimental silencing links beta-catenin activity to the IL-1beta transcriptional arm.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- name: Increased Pro-interleukin-1beta Transcription
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In cultured fibrocystin-defective mouse cholangiocytes, elevated NF-kB transcriptional activity increases
    pro-IL-1beta production. This is the transcriptional component of the experimental autoinflammatory loop.
  evidence:
  - reference: PMID:29140564
    reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: NF-kB inhibition resulted in 60% reduction of IL-1β gene expression in FPC-defective cholangiocytes (Supplementary Figure 6C) and in 50% reduction in the IL-1β secretion (Supplementary Figure 6D).
    explanation: >-
      NF-kB perturbation supports its role in pro-IL-1beta expression in cultured mutant cholangiocytes.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Inflammasome-mediated Interleukin-1beta Maturation
    causal_link_type: DIRECT
    description: >-
      Pro-IL-1beta supplies the precursor for cleavage and secretion; transcription and maturation are distinct
      regulated steps.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: IL-1β is produced as pro-IL1β, and needs specific enzymatic cleavage to become active (26).
      explanation: >-
        The precursor-product relation defines the two-step maturation pathway.
      quote_role: BACKGROUND
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- name: Inflammasome-mediated Interleukin-1beta Maturation
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In fibrocystin-defective mouse cholangiocytes, increased NLRP3 and cleaved caspase-1 accompany increased
    secretion of active IL-1beta. NLRP3 inhibition reduces secretion, providing evidence for an epithelial
    autoinflammatory mechanism distinct from bacterial cholangitis.
  evidence:
  - reference: PMID:29140564
    reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In addition, MCC950 10 μM, an inhibitor of the NLRP3 inflammasome caused a significant reduction (40%) in IL-1β secretion in FPC-defective but not in WT cholangiocytes (Figure 8D).
    explanation: >-
      In vitro inhibitor results support NLRP3-dependent maturation/secretion of bioactive IL-1beta.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Increased Nuclear Phosphorylated STAT3
    causal_link_type: DIRECT
    description: >-
      Secreted active IL-1beta promotes STAT3 phosphorylation.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Specifically, IL-1β promotes signal transducer and activator of transcription 3 phosphorylation, whereas β-catenin promotes its nuclear translocation.
      explanation: >-
        Isolated mutant mouse cholangiocytes distinguish IL-1beta-driven phosphorylation from beta-catenin-dependent
        nuclear localization.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- name: Increased Nuclear Phosphorylated STAT3
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In isolated fibrocystin-defective mouse cholangiocytes, IL-1beta promotes JAK/STAT3 phosphorylation and
    beta-catenin facilitates nuclear translocation of phosphorylated STAT3. Both inputs contribute to CXCL10
    transcription.
  evidence:
  - reference: PMID:29140564
    reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Specifically, IL-1β promotes signal transducer and activator of transcription 3 phosphorylation, whereas β-catenin promotes its nuclear translocation.
    explanation: >-
      Isolated mutant mouse cholangiocytes distinguish IL-1beta-driven phosphorylation from beta-catenin-dependent
      nuclear localization.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Increased Cholangiocyte Chemokine Secretion
    causal_link_type: DIRECT
    description: >-
      JAK/STAT3 activity supports increased CXCL10 production.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In addition, treatment for 24 hours using a JAK inhibitor (pan-JAK inhibitor, 10 μM), or a STAT3 inhibitor (Static V, 10 μM) significantly reduced CXCL10 gene expression and secretion (Figure 3E, F).
      explanation: >-
        Perturbation in cultured mutant cholangiocytes supports this regulatory link.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- name: Increased Cholangiocyte Chemokine Secretion
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Fibrocystin-defective mouse cholangiocytes increase secretion of CXCL1, CXCL10 and CXCL12. CXCL10 regulation
    depends on beta-catenin and IL-1beta/JAK/STAT3, and the chemokines provide a paracrine recruitment signal
    for macrophages.
  evidence:
  - &id001
    reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Using a fibrocystin-defective (Pkhd1(del4/del4)) mouse, which is orthologous of CHF, we show that Pkhd1(del4/del4) cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including chemokine (C-X-C motif) ligands 1, 10, and 12, which stimulate bone marrow-derived macrophage recruitment.
    explanation: >-
      Experiments with mutant mouse cholangiocytes demonstrate chemokine secretion and macrophage recruitment;
      this is experimental cellular evidence, not human clinical evidence.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Peribiliary Macrophage Recruitment
    causal_link_type: DIRECT
    description: >-
      Cholangiocyte-derived chemokines recruit macrophages around ducts.
    evidence:
    - reference: PMID:26645994
      reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Using a fibrocystin-defective (Pkhd1(del4/del4)) mouse, which is orthologous of CHF, we show that Pkhd1(del4/del4) cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including chemokine (C-X-C motif) ligands 1, 10, and 12, which stimulate bone marrow-derived macrophage recruitment.
      explanation: >-
        Experiments with mutant mouse cholangiocytes demonstrate chemokine secretion and macrophage recruitment;
        this is experimental cellular evidence, not human clinical evidence.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: chemokine production
    term:
      id: GO:0032602
      label: chemokine production
    modifier: INCREASED
- name: Peribiliary Macrophage Recruitment
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Chemokines from the dysgenetic epithelium recruit predominantly bone marrow-derived macrophages around
    malformed ducts in the Pkhd1del4/del4 model. Recruitment and progressive fibrosis occur in sterile livers,
    demonstrating that this Caroli-syndrome-associated fibrosis pathway does not require bacterial cholangitis.
  evidence:
  - *id001
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Microbiological analysis showed that Pkhd1del4/del4 livers from all ages were sterile (not shown); in addition, gut decontamination with polymyxin B and neomycin had no effect on the progressive accumulation of CD45+ cells in the portal space (not shown).
    explanation: >-
      The model provides evidence for sterile inflammation, separate from ascending biliary infection.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  biological_processes:
  - preferred_term: macrophage chemotaxis
    term:
      id: GO:0048246
      label: macrophage chemotaxis
    modifier: INCREASED
  downstream:
  - target: Cholangiocyte Integrin alphavbeta6 Upregulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Recruited macrophage cytokines induce epithelial integrin expression.
    evidence:
    - reference: PMID:26645994
      reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We also show that Pkhd1(del4/del4) cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local transforming growth factor-β1.
      explanation: >-
        Mutant mouse cholangiocytes respond to macrophage cytokines with integrin upregulation.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- name: Cholangiocyte Integrin alphavbeta6 Upregulation
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Macrophage-derived TNF-alpha and TGF-beta1 upregulate epithelial alphavbeta6 integrin in fibrocystin-defective
    mouse cholangiocytes. The integrin provides a local route for latent TGF-beta1 activation.
  evidence:
  - &id002
    reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We also show that Pkhd1(del4/del4) cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local transforming growth factor-β1.
    explanation: >-
      Mutant mouse cholangiocytes respond to macrophage cytokines with integrin upregulation.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Local Latent TGF-beta1 Activation
    causal_link_type: DIRECT
    description: >-
      Integrin alphavbeta6 activates local latent TGF-beta1.
    evidence:
    - reference: PMID:26645994
      reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We also show that Pkhd1(del4/del4) cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local transforming growth factor-β1.
      explanation: >-
        Mutant mouse cholangiocytes respond to macrophage cytokines with integrin upregulation.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- name: Local Latent TGF-beta1 Activation
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Upregulated cholangiocyte alphavbeta6 activates latent TGF-beta1 near dysgenetic ducts. Nuclear phospho-SMAD3
    and Snail1 in integrin-positive cystic epithelia were observed in the mouse model and archival human CHF
    specimens, supporting translational relevance without establishing every causal step in patients.
  evidence:
  - *id002
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Immunohistochemical analysis of serial liver sections from Pkhd1del4/del4 mice and from archival specimens of CHF patients showed nuclear expression of Snail1 and pSmad3 (transcription factors activated by TGFβ1 signaling) in cystic cells expressing αvβ6 (Supplemental Fig.5).
    explanation: >-
      This sentence reports parallel human CHF and mouse tissue staining; it provides correlative tissue evidence
      for local signaling. Functional perturbation evidence is from experimental cells.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Portal Myofibroblast Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The profibrogenic cytokine environment favors accumulation of collagen-producing cells.
    evidence:
    - reference: PMID:29140564
      reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In the Pkhd1del4/del4 mouse (8) the phenotype of infiltrating macrophages progressively change due to an increase in M2 macrophages; this is associated with increased production of TGF-β, and other growth factors that promote proliferation of collagen producing cells, and extracellular matrix deposition (28).
      explanation: >-
        Review of the mouse experiments supports a growth-factor-mediated fibrogenic response.
      quote_role: BACKGROUND
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- name: Portal Myofibroblast Accumulation
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Portal myofibroblasts accumulate as experimental CHF progresses. Together with increasing TGF-beta signaling
    and a changing macrophage infiltrate, these collagen-producing cells accelerate peribiliary fibrosis.
  evidence:
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts.
    explanation: >-
      The time-course in mutant mice associates myofibroblast accumulation with progressive fibrogenesis.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Progressive Peribiliary Fibrosis
    causal_link_type: DIRECT
    description: >-
      Accumulation of matrix-producing cells accelerates peribiliary fibrosis.
    evidence:
    - &id005
      reference: PMID:26645994
      reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In contrast with other experimental models of liver fibrosis, collagen deposition in Pkhd1del4/del4 mice initiates with little contribution from myofibroblasts, but then accelerates as the proportion of M2 polarized macrophages, TGFβ1 production and portal myofibroblasts increase.
      explanation: >-
        Experimental time-course distinguishes early epithelial inflammation from later myofibroblast-rich
        fibrosis.
      quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: myofibroblast cell
    term:
      id: CL:0000186
      label: myofibroblast cell
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
- 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.
    evidence:
    - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The cystic dilatation results from ductal plate malformation of the large intrahepatic bile ducts.
      explanation: >-
        Guideline directly relates ductal malformation to cystic large-duct dilatation.
      quote_role: REVIEW_SYNTHESIS
  - target: Progressive Peribiliary Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In Caroli syndrome, small-duct dysgenesis accompanies progressive congenital hepatic fibrosis; the developmental
      and inflammatory pathways are incompletely resolved in humans.
    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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Segmental or multifocal non-obstructive saccular/fusiform dilatation of large intrahepatic ducts defines
    Caroli disease. The dilated spaces communicate with the biliary tree. Monolobar versus bilobar distribution,
    fibrosis and portal hypertension together determine whether resection is feasible.
  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:
    - &id003
      reference: PMID:39130622
      reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The disruption of the tubular architecture of the larger intrahepatic bile ducts results in ductal ectasia, predisposing individuals to stagnant bile with an increased risk of stone formation and cholangitis (Fig. 1).
      explanation: >-
        Review directly connects ectasia, bile stagnation, stones and cholangitis.
      quote_role: REVIEW_SYNTHESIS
  - target: Intrahepatic bile duct dilatation
    causal_link_type: DIRECT
    description: >-
      Clinical manifestation of segmental saccular dilatation of the large intrahepatic bile ducts.
    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.
      quote_role: PRIMARY_RESULT
  - target: Intrahepatic bile duct cysts
    causal_link_type: DIRECT
    description: >-
      Clinical manifestation of segmental saccular dilatation of the large intrahepatic bile ducts.
    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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: BACKGROUND
  - 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.
    quote_role: PRIMARY_RESULT
- name: Bile Stasis in the Dilated Segments
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Poor drainage from ectatic communicating bile ducts causes bile stasis and cholestasis, predisposing to
    intrahepatic stone formation and ascending bacterial cholangitis.
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  downstream:
  - target: Formation of Intrahepatic Bile Duct Stones
    causal_link_type: DIRECT
    description: >-
      Bile stasis increases the risk of intrahepatic stones.
    evidence:
    - reference: PMID:39130622
      reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The disruption of the tubular architecture of the larger intrahepatic bile ducts results in ductal ectasia, predisposing individuals to stagnant bile with an increased risk of stone formation and cholangitis (Fig. 1).
      explanation: >-
        Review directly connects ectasia, bile stagnation, stones and cholangitis.
      quote_role: REVIEW_SYNTHESIS
  - target: Recurrent Bacterial Cholangitis
    causal_link_type: DIRECT
    description: >-
      Bile stasis increases the risk of ascending biliary infection.
    evidence:
    - reference: PMID:39130622
      reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The disruption of the tubular architecture of the larger intrahepatic bile ducts results in ductal ectasia, predisposing individuals to stagnant bile with an increased risk of stone formation and cholangitis (Fig. 1).
      explanation: >-
        Review directly connects ectasia, bile stagnation, stones and cholangitis.
      quote_role: REVIEW_SYNTHESIS
  - target: Cholestasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of bile stasis in the dilated segments.
    evidence:
    - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation.
      explanation: >-
        Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.
      quote_role: REVIEW_SYNTHESIS
  - target: Jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Cholestasis from poorly drained ducts can manifest as jaundice.
    evidence:
    - reference: PMID:39130622
      reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients may be asymptomatic; however, when present, the typical symptoms are pruritus, jaundice, fatigue, and alcoholic stools.
      explanation: >-
        The review describes jaundice as a clinical manifestation of chronic cholestasis; this supports the
        downstream manifestation, not a Caroli-specific frequency.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - *id003
- name: Formation of Intrahepatic Bile Duct Stones
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Stones develop within dilated intrahepatic ducts and may obstruct drainage further, contributing to cholangitis
    and hepatic abscess formation.
  locations:
  - preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  downstream:
  - target: Recurrent Bacterial Cholangitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Stone-related biliary obstruction predisposes to infection.
    evidence:
    - &id004
      reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation.
      explanation: >-
        Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.
      quote_role: REVIEW_SYNTHESIS
  - target: Hepatolithiasis
    causal_link_type: DIRECT
    description: >-
      Clinical manifestation of hepatolithiasis.
    evidence:
    - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation.
      explanation: >-
        Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.
      quote_role: REVIEW_SYNTHESIS
  evidence:
  - *id004
- name: Recurrent Bacterial Cholangitis
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Repeated ascending infection of poorly drained bile ducts produces cholangitis, with fever, abdominal pain
    and sometimes jaundice. Infection can progress to hepatic abscess or sepsis. This complication is distinct
    from the sterile fibrogenic pathway demonstrated in PKHD1-defective models.
  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.
    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.
      quote_role: REVIEW_SYNTHESIS
  - target: Recurrent cholangitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of recurrent bacterial cholangitis.
    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.
      quote_role: PRIMARY_RESULT
  - target: Fever
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of recurrent bacterial cholangitis.
    evidence:
    - reference: PMID:39130622
      reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In a study of 14 CD patients, 50% reported right upper quadrant pain, 35.7% had jaundice, 28.6% experienced fever, and 14.3% were asymptomatic.
      explanation: >-
        Small retrospective cohort data summarized in the review; not an unselected population frequency estimate.
      quote_role: REVIEW_SYNTHESIS
  - target: Abdominal pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of recurrent bacterial cholangitis.
    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.
      quote_role: PRIMARY_RESULT
  - target: Hepatic abscess
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of recurrent bacterial cholangitis.
    evidence:
    - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation.
      explanation: >-
        Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.
      quote_role: REVIEW_SYNTHESIS
  - target: Biliary sepsis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of recurrent bacterial cholangitis.
    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: >-
        Clinical presentations in the selected Caroli surgical series include fever, sepsis and abdominal pain.
      quote_role: PRIMARY_RESULT
  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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: Progressive Peribiliary Fibrosis
  role: intermediate
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    In Caroli syndrome, malformed small intrahepatic ducts coexist with progressive portal/peribiliary fibrosis.
    The congenital ductal abnormality does not imply that all collagen deposition is complete at birth: PKHD1-defective
    models demonstrate progressive sterile inflammatory fibrogenesis. Portal and bridging fibrosis can cause
    severe portal hypertension while lobular architecture and hepatic synthetic function remain relatively
    preserved.
  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.
      quote_role: REVIEW_SYNTHESIS
  - target: Congenital hepatic fibrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of progressive peribiliary 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.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
  - *id005
  subtypes:
  - Caroli syndrome
- name: Presinusoidal Portal Hypertension
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Portal/periportal fibrosis in Caroli syndrome increases presinusoidal resistance and can cause splenomegaly,
    hypersplenism and bleeding gastroesophageal varices. Liver biochemical and synthetic function may remain
    relatively preserved despite severe portal hypertension. Hepatic reserve may deteriorate in some patients,
    but a single reported decade-long progression is not a universal natural history.
  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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
  subtypes:
  - Caroli syndrome
  downstream:
  - target: Portal hypertension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of presinusoidal 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: "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.
      quote_role: BACKGROUND
  - target: Splenomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of presinusoidal 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: "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.
      quote_role: PRIMARY_RESULT
  - target: Esophageal varices with recurrent bleeding
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of presinusoidal portal hypertension.
    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: >-
        Varices and hemorrhage were reported in a mixed CHF/ARPKD/Caroli literature cohort. The totals are
        not Caroli-specific frequencies.
      quote_role: PRIMARY_RESULT
  - target: Gastrointestinal bleeding
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of presinusoidal 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: she experienced recurrent hematemesis and melena despite sequential endoscopic variceal ligation and beta-blocker therapy
      explanation: >-
        This longitudinal case documents recurrent variceal bleeding.
      quote_role: PRIMARY_RESULT
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of presinusoidal portal hypertension.
    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: >-
        The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.
      quote_role: PRIMARY_RESULT
  - target: Leukopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of presinusoidal portal hypertension.
    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: >-
        The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.
      quote_role: PRIMARY_RESULT
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clinical manifestation of presinusoidal portal hypertension.
    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: >-
        The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.
      quote_role: PRIMARY_RESULT
  - target: Ascites
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Portal hypertension can contribute to ascites in Caroli syndrome; ascites is uncommon and may have additional
      causes.
    evidence:
    - reference: PMID:22197937
      reference_title: Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Portal hypertension in CHF is associated with well-known potential clinical complications, namely, clinically relevant splenomegaly, hypersplenism, variceal hemorrhage, ascites, spontaneous bacterial peritonitis, hepatopulmonary syndrome, portopulmonary hypertension, and hepatic encephalopathy.
      explanation: >-
        Ascites is a recognized portal complication in the CHF component; other contributing causes should
        still be assessed.
      quote_role: REVIEW_SYNTHESIS
- 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
  downstream:
  - target: Biliary Malignant Transformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic biliary inflammation is a proposed route to epithelial dysplasia and carcinoma; this causal route
      remains 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: "As one trigger for the malignant transformation, chronic inflammation of the biliary epithelium during cholangitis with consecutive dysplasia and carcinogenesis is postulated"
      explanation: >-
        The source presents inflammation-driven carcinogenesis as a hypothesis. The cancer occurrence itself
        is clinically established.
      quote_role: REVIEW_SYNTHESIS
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Biliary Malignant Transformation
  role: consequence
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Cholangiocarcinoma is a documented complication of Caroli disease and syndrome. A systematic review of
    561 surgically treated patients reported 37 cancers (6.6%); a German surgical cohort found 14 among 198
    (7.1%). These selected retrospective proportions are not population incidence, and the datasets need not
    be independent. Preoperative recognition is difficult and malignancy is often found incidentally in surgical
    specimens. The specific causal route from chronic inflammation remains provisional.
  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: >-
      The 6.6% proportion comes from selected retrospective surgical series, not an unselected population or
      person-time incidence study.
    quote_role: PRIMARY_RESULT
  - 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: >-
      The German surgical cohort reports 14 cancers among 198 patients. Independence from cohorts in other
      reviews is not assumed.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Cholangiocarcinoma
    causal_link_type: DIRECT
    description: >-
      Clinical manifestation of 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: "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: >-
        The 6.6% proportion comes from selected retrospective surgical series, not an unselected population
        or person-time incidence study.
      quote_role: PRIMARY_RESULT
- name: Aberrant Notch-Hes1 Signaling
  role: intermediate
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Human Caroli liver specimens show increased nuclear Notch1 and biliary Hes1 with increased proliferative
    activity. This is an observational tissue association supporting a possible cyst-growth pathway, not proof
    that Notch activation initiates the congenital ductal defect.
  evidence:
  - reference: PMID:34166554
    reference_title: Notch-Hes1 signaling activation in Caroli disease and polycystic liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC.
    explanation: >-
      Primary human tissue study demonstrates nuclear Notch1, not universal Notch1–4 activation in Caroli tissue.
    quote_role: PRIMARY_RESULT
  - reference: PMID:34166554
    reference_title: Notch-Hes1 signaling activation in Caroli disease and polycystic liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD.
    explanation: >-
      Human tissue data associate pathway readout and proliferation.
    quote_role: PRIMARY_RESULT
  cell_types:
  - preferred_term: intrahepatic cholangiocyte
    term:
      id: CL:0002538
      label: intrahepatic cholangiocyte
  downstream:
  - target: Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Aberrant Notch-Hes1 activation is proposed to contribute to progression of biliary cystogenesis.
    evidence:
    - reference: PMID:34166554
      reference_title: Notch-Hes1 signaling activation in Caroli disease and polycystic liver disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These results indicate that aberrant activation of the Notch-Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD.
      explanation: >-
        The primary authors explicitly frame cystogenesis as a possible consequence.
      quote_role: PRIMARY_RESULT
  biological_processes:
  - preferred_term: Notch signaling pathway
    term:
      id: GO:0007219
      label: Notch signaling pathway
    modifier: INCREASED
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.
    quote_role: PRIMARY_RESULT
- 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.
    quote_role: REVIEW_SYNTHESIS
- 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.
    quote_role: PRIMARY_RESULT
- 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.
    quote_role: REVIEW_SYNTHESIS
- 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.
    quote_role: BACKGROUND
  subtype: Caroli syndrome
- category: Hepatobiliary
  name: Esophageal varices with recurrent bleeding
  description: >-
    Esophageal varices develop with portal hypertension in Caroli syndrome and may bleed; recurrent hemorrhage
    is a clinically important complication.
  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: >-
      Varices and hemorrhage were reported in a mixed CHF/ARPKD/Caroli literature cohort. The totals are not
      Caroli-specific frequencies.
    quote_role: PRIMARY_RESULT
  subtype: Caroli syndrome
- 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: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.
    quote_role: PRIMARY_RESULT
  subtype: Caroli syndrome
- category: Hepatobiliary
  name: Hepatolithiasis
  description: >-
    Intrahepatic bile duct stones form in stagnant dilated ducts and can worsen biliary obstruction.
  phenotype_term:
    preferred_term: Hepatolithiasis
    term:
      id: HP:6000063
      label: Hepatolithiasis
  evidence:
  - *id004
- 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.
    quote_role: PRIMARY_RESULT
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a study of 14 CD patients, 50% reported right upper quadrant pain, 35.7% had jaundice, 28.6% experienced fever, and 14.3% were asymptomatic.
    explanation: >-
      The reported 50% falls in the FREQUENT band, scoped to this small cohort.
    quote_role: REVIEW_SYNTHESIS
  frequency: FREQUENT
  context: Reported 14-patient Caroli cohort summarized by Tidwell and Wu; referral and sample-size limitations preclude a population estimate.
- category: Neoplastic
  name: Cholangiocarcinoma
  description: >-
    Cholangiocarcinoma occurs in both simple and syndromic forms. Cancer proportions of approximately 6–7%
    have been reported in selected surgical cohorts, with substantial referral bias; these are not population
    risks.
  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: "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: >-
      The 6.6% proportion comes from selected retrospective surgical series, not an unselected population or
      person-time incidence study.
    quote_role: PRIMARY_RESULT
  - 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: >-
      The German surgical cohort reports 14 cancers among 198 patients. Independence from cohorts in other
      reviews is not assumed.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
- 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.
    quote_role: REVIEW_SYNTHESIS
- name: Fever
  category: Constitutional
  description: >-
    Fever commonly accompanies episodes of cholangitis.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a study of 14 CD patients, 50% reported right upper quadrant pain, 35.7% had jaundice, 28.6% experienced fever, and 14.3% were asymptomatic.
    explanation: >-
      The reported 28.6% falls in the OCCASIONAL band, scoped to this small cohort.
    quote_role: REVIEW_SYNTHESIS
  frequency: OCCASIONAL
  context: Reported 14-patient Caroli cohort summarized by Tidwell and Wu; referral and sample-size limitations preclude a population estimate.
- name: Jaundice
  category: Hepatobiliary
  description: >-
    Jaundice can accompany cholestasis and cholangitis; it is not required for diagnosis.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a study of 14 CD patients, 50% reported right upper quadrant pain, 35.7% had jaundice, 28.6% experienced fever, and 14.3% were asymptomatic.
    explanation: >-
      The reported 35.7% falls in the FREQUENT band, scoped to this small cohort.
    quote_role: REVIEW_SYNTHESIS
  frequency: FREQUENT
  context: Reported 14-patient Caroli cohort summarized by Tidwell and Wu; referral and sample-size limitations preclude a population estimate.
- name: Cholestasis
  category: Hepatobiliary
  description: >-
    Impaired bile drainage from malformed ducts causes cholestasis.
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation.
    explanation: >-
      Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatic abscess
  category: Hepatobiliary
  description: >-
    Biliary infection can lead to hepatic abscess formation.
  phenotype_term:
    preferred_term: Liver abscess
    term:
      id: HP:0100523
      label: Liver abscess
  evidence:
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The main presentation of Caroli disease is cholestasis, which can give rise to stone formation and subsequent biliary obstruction. This results in cholangitis and abscess formation.
    explanation: >-
      Guideline explicitly describes cholestasis, stone-related obstruction, cholangitis and abscess formation.
    quote_role: REVIEW_SYNTHESIS
- name: Biliary sepsis
  category: Infectious
  description: >-
    Ascending biliary infection may progress to sepsis.
  phenotype_term:
    preferred_term: Sepsis
    term:
      id: HP:0100806
      label: Sepsis
  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: >-
      Clinical presentations in the selected Caroli surgical series include fever, sepsis and abdominal pain.
    quote_role: PRIMARY_RESULT
- name: Anemia
  category: Hematologic
  description: >-
    Reported especially in Caroli syndrome, where portal hypertension and hypersplenism contribute to cytopenias.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  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: >-
      The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.
    quote_role: PRIMARY_RESULT
  subtype: Caroli syndrome
- name: Leukopenia
  category: Hematologic
  description: >-
    Reported especially in Caroli syndrome, where portal hypertension and hypersplenism contribute to cytopenias.
  phenotype_term:
    preferred_term: Decreased total leukocyte count
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  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: >-
      The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.
    quote_role: PRIMARY_RESULT
  subtype: Caroli syndrome
- name: Thrombocytopenia
  category: Hematologic
  description: >-
    Reported especially in Caroli syndrome, where portal hypertension and hypersplenism contribute to cytopenias.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  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: >-
      The 30-patient Caroli cohort reports these cytopenias, particularly in the syndromic form.
    quote_role: PRIMARY_RESULT
  subtype: Caroli syndrome
- name: Hepatomegaly
  category: Hepatobiliary
  description: >-
    Hepatomegaly can occur in Caroli syndrome.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Physical examination findings may include hepatomegaly, splenomegaly, ascites, peripheral edema, and jaundice.
    explanation: >-
      The Caroli syndrome section describes the examination findings.
    quote_role: REVIEW_SYNTHESIS
  subtype: Caroli syndrome
- name: Ascites
  category: Hepatobiliary
  description: >-
    Ascites can occur with advanced portal complications; it is less characteristic than varices or splenomegaly
    and warrants evaluation for additional causes.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Physical examination findings may include hepatomegaly, splenomegaly, ascites, peripheral edema, and jaundice.
    explanation: >-
      The Caroli syndrome section describes the examination findings.
    quote_role: REVIEW_SYNTHESIS
  subtype: Caroli syndrome
- name: Gastrointestinal bleeding
  category: Hepatobiliary
  description: >-
    Bleeding gastroesophageal varices can cause hematemesis or melena in Caroli syndrome.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  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: >-
      This longitudinal case documents recurrent variceal bleeding.
    quote_role: PRIMARY_RESULT
  subtype: Caroli syndrome
genetic:
- name: PKHD1
  notes: >-
    Biallelic pathogenic PKHD1 variants cause the ARPKD/CHF spectrum, including Caroli syndrome. Reported variants
    include truncating, missense and splice variants, with occasional deep intronic variants and exon deletions.
    Biallelic truncating variants are associated with severe ARPKD overall, but exceptions and intrafamilial
    variability preclude predicting an individual Caroli phenotype from variant class alone. Sporadic isolated
    large-duct disease need not have an established PKHD1 cause.
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24710345
    reference_title: Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The father harbors the p.Val836Ala mutant, while the mother carries the p.Arg781* variant.
    explanation: >-
      The reported compound heterozygous genotype was inherited in trans. The pedigree provides segregation
      evidence, not a current expert-panel classification.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While the majority of PKHD1 pathogenic variants reported to date are within the coding or canonical splice site region, several pathogenic variants have been identified that are deep within intronic regions and are therefore likely to be identified by genome sequencing [Michel-Calemard et al 2009, Chen et al 2019, Doreille et al 2022, Liu et al 2022].
    explanation: >-
      GeneReviews describes coding, splice-site and deep intronic pathogenic variants in ARPKD-PKHD1.
    quote_role: REVIEW_SYNTHESIS
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.
    quote_role: PRIMARY_RESULT
  - reference: clinicaltrials:NCT04007575
    reference_title: Magnetic Resonance CholangioPancreatography Signs for the Diagnosis of Caroli Disease
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The Caroli disease is a very rare pathology that can be revealed early in childhood or in adulthood, whose diagnosis is based on Magnetic Resonance CholangioPancreatography, which shows the communication of these malformations with the rest of the biliary tree and allows to eliminate biliary stenosis.
    explanation: >-
      The diagnostic study protocol states the MRCP features used to establish Caroli disease.
    quote_role: PRIMARY_RESULT
  diagnosis_term:
    preferred_term: Magnetic Resonance Cholangiopancreatography
    term:
      id: NCIT:C113775
      label: Magnetic Resonance Cholangiopancreatography
- name: Assessment for congenital hepatic fibrosis and renal involvement
  description: >-
    Ductal ectasia should prompt assessment for CHF to distinguish Caroli syndrome, including liver stiffness,
    portal-hypertension findings and renal imaging. Renal and hepatic severity need not correlate. Histology
    can resolve uncertain fibrosis morphology when clinically indicated.
  evidence:
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ﬁnding of multiple segmental cystic or saccular di- latations of bile ducts should initiate a search for congenital hepatic ﬁbrosis in order to differentiate Caroli disease from Caroli syndrome (LoE 4, strong recommendation, 100% consensus).
    explanation: >-
      EASL recommends actively distinguishing simple from syndromic disease.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While the majority of patients with Caroli syndrome possess renal cystic lesions and renal impairment may ensue, there is no correlation between the severity of renal and hepatic manifestations.
    explanation: >-
      Renal lesions are common in Caroli syndrome but severity does not track hepatic severity.
    quote_role: REVIEW_SYNTHESIS
- name: Molecular diagnosis of PKHD1-associated disease
  description: >-
    In a compatible hepatorenal phenotype, biallelic pathogenic or likely pathogenic PKHD1 variants establish
    ARPKD-PKHD1. A phenotype-focused multigene panel or exome/genome testing may be appropriate. A VUS or a
    negative PKHD1 result does not by itself establish or exclude imaging-defined simple Caroli disease.
  evidence:
  - reference: PMID:20301501
    reference_title: Autosomal Recessive Polycystic Kidney Disease – PKHD1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: >-
      GeneReviews molecular criteria apply to the PKHD1-associated hepatorenal subset.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Identification of biallelic PKHD1 variants of uncertain significance (or of one known PKHD1 pathogenic variant and one PKHD1 variant of uncertain significance) does not establish or rule out the diagnosis.
    explanation: >-
      GeneReviews distinguishes uncertain from diagnostic variants.
    quote_role: REVIEW_SYNTHESIS
- name: Cholangiocarcinoma surveillance
  description: >-
    The 2022 EASL guideline permits MRCP every 12 months after Caroli diagnosis, as a weak recommendation based
    on low-level evidence. The guideline acknowledges a lack of disease-specific screening accuracy data. ERCP
    is not recommended for cancer screening because of infection risk, and CA19-9 has poor diagnostic performance
    in this setting.
  diagnosis_term:
    preferred_term: Magnetic Resonance Cholangiopancreatography
    term:
      id: NCIT:C113775
      label: Magnetic Resonance Cholangiopancreatography
  evidence:
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with Caroli disease and syndrome may receive surveillance for cholangiocarcinoma with magnetic reso- nance cholangiopancreaticography every 12 months after diagnosis (LoE 4, weak recommendation, 90% consensus).
    explanation: >-
      Annual MRCP is a weak, low-evidence recommendation, not proven outcome-improving screening.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We do not recommend endoscopic retrograde chol- angiopancreaticography for cholangiocarcinoma screening because this procedure is associated with increased risk of biliary infection.
    explanation: >-
      Guideline discourages ERCP as a screening procedure.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatoportal and renal surveillance in ARPKD-associated Caroli syndrome
  description: >-
    Monitor blood pressure, kidney function, blood counts, synthetic liver function and nutritional/fat-soluble
    vitamin status. Ultrasound/Doppler, elastography and MRCP are selected according to complications and prior
    imaging; renal dysfunction affects contrast and transplant decisions.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hepatoportal involvement. Perform physical examination; obtain complete blood counts, prothrombin time, and serum concentrations of albumin, 25-hydroxyvitamin D, and other fat-soluble vitamins.
    explanation: >-
      GeneReviews specifies laboratory and examination surveillance for ARPKD-associated hepatobiliary disease.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Kidney function. Close monitoring for the complications of CKD should be undertaken by the treating pediatric nephrologist according to standard practices.
    explanation: >-
      Associated CKD requires nephrology surveillance.
    quote_role: REVIEW_SYNTHESIS
treatments:
- name: Antibiotic Therapy for Cholangitis
  description: >-
    Treat bacterial cholangitis promptly, with biliary drainage when obstruction requires it. In ARPKD-associated
    disease, chronic antibiotic prophylaxis is individualized: GeneReviews considers its routine use controversial
    and gives no general recommendation.
  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:32884228
    reference_title: 'Risk of malignancy in Caroli disease and syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The initial treatment of CS and CD is often nonsurgical and supportive therapy using analgesia, antibiotics in case of biliary infections and ursodeoxycholic acid[31,32].
    explanation: >-
      The review explicitly documents antibiotic treatment of biliary infection.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial.
    explanation: >-
      Routine prophylaxis in all children with ARPKD is not established.
    quote_role: REVIEW_SYNTHESIS
- name: Nonselective Beta-Blocker Therapy for Portal Hypertension
  description: >-
    Nonselective beta-blockers such as propranolol or carvedilol are used for portal-hypertension/variceal
    prophylaxis. One Caroli case showed initial symptomatic improvement but recurrent bleeding over time; this
    does not establish durable Caroli-specific efficacy.
  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 observation supports reported use and its limitations, not a population treatment-effect
      estimate.
    quote_role: PRIMARY_RESULT
- 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: Endoscopic variceal band ligation
    term:
      id: NCIT:C15270
      label: Ligation
  target_mechanisms:
  - target: Gastrointestinal bleeding
    treatment_effect: INHIBITS
    description: >-
      Band ligation treats variceal hemorrhage by obliterating the collateral vessel; it does not directly
      lower portal pressure.
  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.
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Esophageal varices should be treated with endoscopic banding or sclerotherapy according to local standard procedures as for children with other causes of portal hypertension [Guay-Woodford et al 2014, Jeanniard-Malet et al 2017].
    explanation: >-
      GeneReviews supports endoscopic treatment in ARPKD-associated portal hypertension.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatic Resection for Localised Disease
  description: >-
    Resection can relieve symptoms when disease is confined to a resectable segment or lobe, particularly without
    substantial fibrosis or portal hypertension. It removes the diseased territory but does not prove elimination
    of all future cancer risk in residual liver.
  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.
    quote_role: PRIMARY_RESULT
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This may be feasible in symptomatic cases with monolobar involvement without liver ﬁbrosis or portal hyper- tension.
    explanation: >-
      EASL qualifies resection by distribution and absence of major fibrosis/portal hypertension.
    quote_role: REVIEW_SYNTHESIS
- name: Liver Transplantation
  description: >-
    Consider transplant referral for recurrent cholangitis with bilobar disease, or monolobar disease with
    fibrosis/portal hypertension when resection is excluded. Referral before acute infection or physical deterioration
    is advised. Combined liver-kidney transplantation requires individualized weighing of hepatic complications,
    CKD and operative risk.
  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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Referral for liver transplantation should be considered in patients with Caroli disease or syndrome with recurrent cholangitis and i) bilobar involvement, or ii) monolobar involvement in combination with liver ﬁbrosis or portal hypertension, when the possibility of liver resection has been excluded (LoE 3, strong recommendation, 96% consensus).
    explanation: >-
      Guideline gives the extent and complication criteria for transplant referral.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In summary, individual decision making regarding single or combined transplantation is indispensable because clear-cut criteria evaluating risks and benefits for decision making in individuals with ARPKD remain to be defined.
    explanation: >-
      GeneReviews emphasizes individualized risk-benefit assessment.
    quote_role: REVIEW_SYNTHESIS
- 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.
    quote_role: REVIEW_SYNTHESIS
- name: Ursodeoxycholic Acid for Cholestasis and Stones
  description: >-
    EASL describes UDCA for cholestasis and stone formation in Caroli disease/syndrome, including narrative
    advice for asymptomatic patients. Evidence is limited. GeneReviews for ARPKD-PKHD1 states that routine
    UDCA as a choleretic generally cannot be recommended, so this is not an unqualified recommendation for
    every syndromic child.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ursodeoxycholic acid
      term:
        id: CHEBI:9907
        label: ursodeoxycholic acid
  evidence:
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cholestasis and gallstone formation can be treated with ursodeoxycholic acid and abscesses should be drained
    explanation: >-
      EASL lists UDCA for cholestasis and gallstones.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The use of ursodeoxycholic acid (UDCA) as choleretic agent generally cannot be recommended [Guay-Woodford et al 2014].
    explanation: >-
      GeneReviews provides a different recommendation for the ARPKD population.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Bile Stasis in the Dilated Segments
    treatment_effect: INHIBITS
    description: >-
      UDCA is used to improve cholestasis and limit stone formation in the EASL Caroli guidance; evidence and
      recommendations differ for ARPKD-PKHD1.
- name: Percutaneous Transhepatic Biliary Drainage
  description: >-
    Percutaneous drainage is one route for relieving biliary obstruction and improving drainage. Endoscopic
    treatment with ERCP is an alternative when appropriate; neither is a routine cancer-screening test.
  treatment_term:
    preferred_term: Percutaneous Transhepatic Biliary Drainage
    term:
      id: NCIT:C93008
      label: Percutaneous Transhepatic Biliary Drainage
  evidence:
  - reference: PMID:32884228
    reference_title: 'Risk of malignancy in Caroli disease and syndrome: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Surgical or interventional drainage procedures may be performed to remove biliary tract obstructions and improve biliary passage to decrease the risk and burden of cholangitis[33,34].
    explanation: >-
      Review states the purpose of drainage for obstruction and cholangitis.
    quote_role: REVIEW_SYNTHESIS
  target_mechanisms:
  - target: Bile Stasis in the Dilated Segments
    treatment_effect: INHIBITS
    description: >-
      A percutaneous transhepatic catheter decompresses obstructed ducts and improves bile drainage from affected
      segments.
  therapeutic_modality: SURGERY
- name: Drainage of Hepatic Abscess
  description: >-
    Hepatic abscesses require drainage by an appropriate image-guided, endoscopic or surgical route alongside
    infection treatment.
  treatment_term:
    preferred_term: Drainage
    term:
      id: NCIT:C50434
      label: Drainage
  evidence:
  - reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    reference_title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: abscesses should be drained (which can be achieved radiologically/ultrasound guided, endoscopically or surgically).
    explanation: >-
      Guideline specifies drainage options.
    quote_role: REVIEW_SYNTHESIS
  target_mechanisms:
  - target: Hepatic abscess
    treatment_effect: INHIBITS
    description: >-
      Drainage removes infected fluid from the abscess cavity as part of source control.
- name: Portosystemic Shunting for Refractory Portal Complications
  description: >-
    TIPS or surgical shunting may be considered for refractory portal-hypertension complications in Caroli
    syndrome. Preserved renal function favors feasibility; encephalopathy and kidney disease require careful
    selection.
  treatment_term:
    preferred_term: Transjugular Intrahepatic Portosystemic Shunt
    term:
      id: NCIT:C126288
      label: Transjugular Intrahepatic Portosystemic Shunt
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Interventional or surgical portosystemic shunting may be necessary to treat progressive portal hypertension
    explanation: >-
      GeneReviews supports shunting in selected ARPKD-associated portal complications.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: and may be an option especially in individuals with good residual kidney function.
    explanation: >-
      Renal function informs selection for shunting.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Presinusoidal Portal Hypertension
    treatment_effect: INHIBITS
    description: >-
      A portosystemic shunt diverts blood past intrahepatic resistance to decompress the portal circulation;
      kidney function and encephalopathy risk constrain selection.
- name: Genetic Counseling and Family Evaluation
  description: >-
    For confirmed PKHD1-associated disease, provide recurrence-risk counseling, parental/relative testing and
    discussion of reproductive options. When both parents are carriers, each conception has a 25% affected-child
    risk; prenatal/preimplantation testing requires identification of familial variants.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Once the PKHD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and molecular genetic prenatal testing and preimplantation genetic testing are possible.
    explanation: >-
      Familial-variant identification permits reproductive testing.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: BEHAVIORAL
- name: Experimental Macrophage Depletion with Liposomal Clodronate
  description: >-
    In Pkhd1del4/del4 mice, liposomal clodronate reduced macrophage infiltration, fibrosis and spleen enlargement.
    This is a preclinical CHF/Caroli-syndrome model intervention, not established patient therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clodronic acid
      term:
        id: CHEBI:110423
        label: clodronic acid
  evidence:
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts.
    explanation: >-
      Macrophage depletion was tested in mice; no human therapeutic efficacy is implied.
    quote_role: PRIMARY_RESULT
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: To induce a selective macrophage depletion, Pkhd1del4/del4 mice of 3 months of age were treated for 3 months with clodronate liposomes (100mg/kg every three days, I.P., n=4) or with vehicle (sterile phosphate-buffered saline (PBS) + liposomes every three days by I.P., n=3)12.
    explanation: >-
      The methods specify liposomal delivery in a small mouse experiment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Peribiliary Macrophage Recruitment
    treatment_effect: INHIBITS
    description: >-
      Liposomal clodronate depletes macrophages and reduces the peribiliary macrophage infiltrate in Pkhd1del4/del4
      mice.
  delivery_system:
    delivery_platform: LIPOSOME
- name: Experimental CXCR3 Inhibition with AMG-487
  description: >-
    AMG-487 reduced inflammatory infiltration, fibrosis, cyst growth and spleen size in Pkhd1del4/del4 mice.
    These results support the experimental CXCL10/CXCR3 mechanism; clinical benefit in Caroli disease has not
    been established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: AMG-487
  evidence:
  - reference: PMID:29140564
    reference_title: β-Catenin and interleukin-1β-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We demonstrate that treatment of Pkhd1del4/del4 mice for 3 months with AMG-487, an inhibitor of CXC chemokine receptor family 3, the cognate receptor of CXCL10, reduces the peribiliary recruitment of alternative activated macrophages (cluster of differentiation 45+ F4/80+ cells), spleen size, liver fibrosis (sirius red), and cyst growth (cytokeratin 19-positive area), consistent with a pathogenetic role of CXCL10.
    explanation: >-
      Three-month mouse intervention supports the pathway, not human efficacy.
    quote_role: PRIMARY_RESULT
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Peribiliary Macrophage Recruitment
    treatment_effect: INHIBITS
    description: >-
      AMG-487 inhibits CXCR3, the receptor for CXCL10, reducing chemokine-mediated macrophage recruitment in
      Pkhd1del4/del4 mice.
- name: Endoscopic Sclerotherapy for Varices
  description: >-
    Endoscopic sclerotherapy is an alternative local treatment for varices in ARPKD-associated Caroli syndrome.
    Selection follows specialist practice and does not correct the congenital duct abnormality.
  treatment_term:
    preferred_term: Sclerotherapy
    term:
      id: NCIT:C62732
      label: Sclerotherapy
  target_mechanisms:
  - target: Gastrointestinal bleeding
    treatment_effect: INHIBITS
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1326/pdf/Bookshelf_NBK1326.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Esophageal varices should be treated with endoscopic banding or sclerotherapy according to local standard procedures as for children with other causes of portal hypertension
    explanation: >-
      GeneReviews recommends local endoscopic treatment for varices.
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 reproduces intrahepatic duct dilatation and abnormal ciliary morphology. Compared with the
    Pkhd1del4/del4 mouse, it has more prominent cystic disease and renal involvement but milder portal fibrosis;
    it is a limited model of human CHF-related portal hypertension.
  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.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28709963
    reference_title: Animal models of biliary injury and altered bile acid metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: However, in contrast with the Pkhd1del4/del4 mouse, the PCK rat shows some critical differences, including a more pronounced development of the hepatic cysts, the renal involvement with cyst lesions affecting the outer medullary-collecting ducts, and the mild degree of portal fibrosis, without formation of fibrous septa or development of portal hypertension [108,109].
    explanation: >-
      Comparative review describes the model’s limits.
    quote_role: REVIEW_SYNTHESIS
  modeled_mechanisms:
  - target: Abnormal Cholangiocyte Ciliary Morphology
    relationship: RECAPITULATES
    description: >-
      Shortened, bulbous cholangiocyte cilia.
  - target: Segmental Saccular Dilatation of the Large Intrahepatic Bile Ducts
    relationship: RECAPITULATES
    description: >-
      Distorted dilated biliary tree.
  - target: Progressive Peribiliary Fibrosis
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      Fibrosis is milder than human CHF.
  notes: >-
    The genotype and gene symbol refer to rat Pkhd1. The HGNC binding identifies the human PKHD1 ortholog for
    cross-model comparison, following the schema’s HGNC gene vocabulary; it is not a rat gene identifier.
- name: Pkhd1del4/del4 mouse
  species: Mouse (Mus musculus)
  genotype: Homozygous Pkhd1 exon 4 deletion
  category: Genetic model
  description: >-
    Orthologous CHF model with progressive peribiliary fibrosis, duct dysgenesis, macrophage recruitment and
    spleen enlargement. It models the fibrotic component of Caroli syndrome and lacks the renal phenotype of
    many human PKHD1 cases.
  modeled_mechanisms:
  - target: Progressive Peribiliary Fibrosis
    relationship: RECAPITULATES
    description: >-
      Progressive pericystic and portal collagen deposition.
  - target: Peribiliary Macrophage Recruitment
    relationship: RECAPITULATES
    description: >-
      Peribiliary macrophage infiltration.
  - target: Presinusoidal Portal Hypertension
    relationship: RECAPITULATES
    description: >-
      Spleen enlargement serves as a portal-hypertension readout.
  evidence:
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Serial analysis of Pkhd1del4/del4 mouse liver and spleen demonstrate an age-dependent increase in the biliary cystic malformations (Supplemental Fig.1A–B), peribiliary fibrosis (Fig.1A), increased collagen-I deposition, as shown by the progressive increase in Sirius Red staining (Fig.1B) and in COL1(A1) (procollagen α1(I)) gene expression, as compared to wild type (WT) littermates (Fig.1C).
    explanation: >-
      Time-course demonstrates progressive fibrosis in the mouse model.
    quote_role: PRIMARY_RESULT
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#Biliary Malignant Transformation
  rationale: >-
    Cancer was reported in 6.6% of pooled surgical cases and 7.1% of a German surgical cohort. Selection bias,
    uncertain cohort independence and limited preoperative detection prevent interpretation as population incidence.
    Prospective disease-specific surveillance performance is also unknown.
  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: >-
      Estimate cancer incidence with person-time and uncertainty, and assess screening yield. Treatment recommendations
      additionally require evidence about benefits and harms.
  - 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: >-
      Validate candidate predictors prospectively before using them to personalize surveillance or surgery.
  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.
    quote_role: REVIEW_SYNTHESIS
- 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 Dysfunction in PKHD1-associated Disease
  rationale: >-
    Beta-catenin/STAT3, epithelial chemokine secretion, macrophage recruitment and integrin/TGF-beta signaling
    are experimentally tractable pathways. Translation to patient benefit remains unproven, particularly outside
    PKHD1-associated CHF.
  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: >-
      Demonstrate reproducible functional rescue in human disease-derived cells and establish applicability
      across genotypes.
  - experiment_id: exp_caroli_antifibrotic_pck_rat
    name: Antifibrotic intervention in complementary PKHD1 models
    description: >-
      Use the Pkhd1del4/del4 mouse for progressive portal fibrosis and the PCK rat for cystic/renal phenotypes,
      with human cell validation.
    decision_criterion: >-
      Replicated effects on fibrosis and clinically relevant physiology, with toxicity assessment, would support
      translational development.
  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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts.
    explanation: >-
      Preclinical pathway manipulation is available even though patient therapy is not established.
    quote_role: PRIMARY_RESULT
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."
- reference: PMID:35728731
  title: EASL Clinical Practice Guidelines on the management of cystic liver diseases.
  findings:
  - statement: >-
      The 2022 EASL guideline covers diagnosis and management of Caroli disease and syndrome within the cystic
      liver disease spectrum.
    supporting_text: These Clinical Practice Guidelines cover the diagnosis and management of hepatic cysts, mucinous cystic neoplasms of the liver, biliary hamartomas, polycystic liver disease, Caroli disease, Caroli syndrome, biliary hamartomas and peribiliary cysts.
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: CLOSED
  notes: >-
    Original curation request for the entry, including the longitudinal portal-hypertension case report.
notes: >-
  This entry covers simple Caroli disease and Caroli syndrome together as large-duct malformation with or without
  the additional CHF component. Human isolated duct ectasia, human PKHD1-associated hepatorenal disease and
  experimental CHF models are distinguished throughout. Published one-in-a-million estimates are variably called
  incidence and lack a clear population denominator in the cited reviews; no population prevalence or lifetime
  cancer risk is inferred from them.
variants:
- name: Reported PKHD1 p.Arg781* / p.Val836Ala compound heterozygous genotype
  gene:
    preferred_term: PKHD1
    term:
      id: hgnc:9016
      label: PKHD1
  description: >-
    A 2014 report described c.2341C>T (p.Arg781*) and c.2507T>C (p.Val836Ala), on NM_138694.3, inherited from
    different parents in dizygotic twins. One twin had a severe syndromic phenotype and the other had isolated
    duct dilatation. These are historical pedigree observations; the missense allele was not functionally proven,
    and no current clinical-significance classification is asserted here.
  evidence:
  - reference: PMID:24710345
    reference_title: Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'RESULTS: A combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala), and the nonsense mutation c.2341C>T, which is predicted to result in an arginine to stop codon at codon 781 (c.2341C>T, p.Arg781*). This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes.'
    explanation: >-
      The primary report describes the genotype, segregation and control comparison.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24710345
    reference_title: Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first twin (Patient B) had no obvious clinical symptoms except for intrahepatic bile duct dilatation.
    explanation: >-
      The twins illustrate phenotypic variability despite sharing the reported genotype.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24710345
    reference_title: Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The p.Val836Ala mutation results in an amino acid change from valine to alanine, but as both amino acids are neutral the potential impairment on protein function is unclear; however, the amino acid at position 836 is highly conserved between species.
    explanation: >-
      The authors explicitly leave the missense allele’s functional effect unresolved.
    quote_role: PRIMARY_RESULT
histopathology:
- name: Non-obstructive duct ectasia with intraluminal vascular channels
  description: >-
    Dilated communicating bile ducts show intraluminal wall protrusions and patent portal venous and hepatic
    arterial channels. This architecture underlies the central dot sign on imaging.
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Characteristic findings of CD on histology include localized, non-obstructive dilated bile ducts, intraluminal protrusions of the ductal wall, and patent hepatic arterial and portal venous channels that terminate within the duct lumen.
    explanation: >-
      Review describes Caroli-specific duct morphology.
    quote_role: REVIEW_SYNTHESIS
- name: Ductal plate malformation with portal-portal fibrous bands
  subtype: Caroli syndrome
  description: >-
    The congenital hepatic fibrosis component includes irregular embryonic-type bile ducts embedded in portal-portal
    fibrous bands. Hepatic lobular architecture may remain preserved despite marked portal disease.
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The fibrosis is characterized by portal-portal bands with embedded elongated, tortuous, or branched bile duct structures.
    explanation: >-
      The CHF section describes the small-duct and fibrotic component of Caroli syndrome.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hepatic lobules typically have normal hepatocyte morphology unless there is progression to cirrhosis.
    explanation: >-
      This distinguishes typical CHF architecture from established cirrhosis.
    quote_role: REVIEW_SYNTHESIS
- name: Nuclear Notch1 and biliary Hes1 expression
  description: >-
    A human tissue study found increased nuclear Notch1 and Hes1 expression in Caroli disease, with higher
    biliary proliferative activity. These research observations do not establish a clinical diagnostic test
    or activation of all Notch receptors in Caroli disease.
  evidence:
  - reference: PMID:34166554
    reference_title: Notch-Hes1 signaling activation in Caroli disease and polycystic liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC.
    explanation: >-
      Primary human tissue study demonstrates nuclear Notch1, not universal Notch1–4 activation in Caroli tissue.
    quote_role: PRIMARY_RESULT
imaging_findings:
- name: Communicating saccular intrahepatic duct dilatation on MRCP
  modality: MRI
  description: >-
    MRCP demonstrates saccular or fusiform intrahepatic duct dilatation communicating with the biliary tree
    and helps exclude a primary obstructing stenosis.
  located_in:
    preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  phenotype_term:
    preferred_term: Intrahepatic bile duct dilatation
    term:
      id: HP:0033149
      label: Intrahepatic bile duct dilatation
  diagnostic: true
  evidence:
  - reference: clinicaltrials:NCT04007575
    reference_title: Magnetic Resonance CholangioPancreatography Signs for the Diagnosis of Caroli Disease
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The Caroli disease is a very rare pathology that can be revealed early in childhood or in adulthood, whose diagnosis is based on Magnetic Resonance CholangioPancreatography, which shows the communication of these malformations with the rest of the biliary tree and allows to eliminate biliary stenosis.
    explanation: >-
      The diagnostic study protocol states the MRCP features used to establish Caroli disease.
    quote_role: PRIMARY_RESULT
- name: Central dot sign
  modality: MRI
  description: >-
    On contrast-enhanced MRI or CT, a portal venous radicle and hepatic arterial branch within a dilated duct
    create an enhancing central dot. This supports Caroli disease in the appropriate ductal morphology.
  located_in:
    preferred_term: intrahepatic bile duct
    term:
      id: UBERON:0003704
      label: intrahepatic bile duct
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Contrast-enhanced CT or MRI of the abdomen may reveal a pathognomonic finding, the central dot sign. Histologically, this relates to a branch of the hepatic artery and a portal vein radical bridging a saccule resembling a central dot.
    explanation: >-
      Review connects the cross-sectional imaging finding with its vascular substrate.
    quote_role: REVIEW_SYNTHESIS
biochemical:
- name: Gamma-glutamyltransferase
  presence: INCREASED
  context: Cholestatic enzyme elevation; 64.3% in a reported 14-patient cohort.
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a study of 14 CD patients, 64.3% exhibited elevated GGT, 35.7% had elevated alkaline phosphatase, and 28.6% had elevated bilirubin.
    explanation: >-
      Small selected Caroli cohort summarized in the review; these measurements are not diagnostic thresholds.
    quote_role: REVIEW_SYNTHESIS
- name: Alkaline phosphatase
  presence: INCREASED
  context: Cholestatic enzyme elevation; 35.7% in a reported 14-patient cohort.
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a study of 14 CD patients, 64.3% exhibited elevated GGT, 35.7% had elevated alkaline phosphatase, and 28.6% had elevated bilirubin.
    explanation: >-
      Small selected Caroli cohort summarized in the review; these measurements are not diagnostic thresholds.
    quote_role: REVIEW_SYNTHESIS
- name: Bilirubin
  presence: INCREASED
  context: Hyperbilirubinemia; 28.6% in a reported 14-patient cohort.
  evidence:
  - reference: PMID:39130622
    reference_title: 'Heritable Chronic Cholestatic Liver Diseases: A Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In a study of 14 CD patients, 64.3% exhibited elevated GGT, 35.7% had elevated alkaline phosphatase, and 28.6% had elevated bilirubin.
    explanation: >-
      Small selected Caroli cohort summarized in the review; these measurements are not diagnostic thresholds.
    quote_role: REVIEW_SYNTHESIS
experimental_models:
- name: Primary Pkhd1del4/del4 cholangiocytes and RAW264.7 migration system
  experimental_model_type: CO_CULTURE
  description: >-
    Primary mutant and wild-type mouse cholangiocytes supply apical or basolateral conditioned medium to RAW264.7
    macrophages. Chemokine secretion, macrophage migration and pathway inhibition resolve epithelial signaling
    separately from whole-animal fibrosis.
  cell_source: Primary mouse cholangiocytes and a mouse macrophage cell line
  modeled_mechanisms:
  - target: Increased Cholangiocyte Chemokine Secretion
    relationship: RECAPITULATES
    description: >-
      Polarized cholangiocyte secretion into conditioned medium.
  - target: Peribiliary Macrophage Recruitment
    relationship: RECAPITULATES
    description: >-
      Conditioned-medium-induced macrophage migration.
  - target: Increased Beta-catenin Signaling
    relationship: PERTURBS
    description: >-
      Beta-catenin inhibitor and silencing experiments.
  evidence:
  - reference: PMID:26645994
    reference_title: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: To test the polarity-dependent ability of Pkhd1del4/del4 cholangiocytes to recruit macrophages, we studied the effect of conditioned medium differentially harvested from basolateral and apical sides, on a mouse macrophage cell line (RAW264.7).
    explanation: >-
      The primary paper specifies the non-animal experimental system.
    quote_role: PRIMARY_RESULT
clinical_trials:
- name: NCT04007575
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    IMACA is a completed retrospective observational MRCP diagnostic study with 61 actual participants, comparing
    imaging features with pathology. It is not a drug trial; no registry results are posted.
  notes: >-
    Registry status last verified 2021-11. Status is the registry-reported value, not an inference from the
    study dates.
  evidence:
  - reference: clinicaltrials:NCT04007575
    reference_title: Magnetic Resonance CholangioPancreatography Signs for the Diagnosis of Caroli Disease
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The benefit of this research is to reduce diagnostic errors by highlighting imaging criteria specific to the Caroli disease
    explanation: >-
      Registry summary states the observational study purpose.
- name: NCT01401998
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Hepatorenal fibrocystic disease observational registry including Caroli syndrome; builds clinical/genetic
    databases and biospecimen resources. It is not a therapeutic trial.
  notes: >-
    Registry status last verified 2026-06. Status is the registry-reported value, not an inference from the
    study dates.
  evidence:
  - reference: clinicaltrials:NCT01401998
    reference_title: 'Core A: The Hepato/Renal Fibrocystic Diseases Translational Resource (ARPKD Database Study)'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This study aims to build a registry of a clinical database (medical health information), a mutational database (genetic information) and an educational resource about HRFD to eventually provide information about these diseases to families, physicians and genetic counselors via our existing HIPAA- approved study website.
    explanation: >-
      Registry summary states the observational study purpose.

📚

References & Deep Research

References

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."

PMID:35728731

EASL Clinical Practice Guidelines on the management of cystic liver diseases.

1 finding

The 2022 EASL guideline covers diagnosis and management of Caroli disease and syndrome within the cystic liver disease spectrum.

"These Clinical Practice Guidelines cover the diagnosis and management of hepatic cysts, mucinous cystic neoplasms of the liver, biliary hamartomas, polycystic liver disease, Caroli disease, Caroli syndrome, biliary hamartomas and peribiliary cysts."

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (4)

Debundle two pathophysiology nodes (PR #8116 review item B) · 2026-08-08T17:36:19Z · View source

PR #8116 review follow-up (ai4c-reviewer, 2026-08-08). Item B: split two bundled pathophysiology nodes into atomic ones, following the schema-valid spec the reviewer supplied. Split 1 replaces 'Bile Stasis, Hepatolithiasis and Recurrent Bacterial Cholangitis' with three TISSUE/ESTABLISHED nodes retaining UBERON:0003704 - 'Bile Stasis in the Dilated Segments' (inherits the inbound edge from Segmental Saccular Dilatation; DIRECT edges to Hepatolithiasis and to Recurrent Bacterial Cholangitis), 'Hepatolithiasis' (DIRECT edge to Recurrent Bacterial Cholangitis), and 'Recurrent Bacterial Cholangitis' (takes both pre-existing cholangitis evidence items unchanged and inherits both outbound edges to Chronic Biliary Inflammation and to Progressive Peribiliary Fibrosis). This fixes the gap the reviewer identified: the bundled node carried only cholangitis evidence, so the stasis and stone claims it named were unsourced. Both new nodes now cite PMID:32884228, which states that the destructive inflammatory state leads to recurrent episodes of cholangitis and the development of biliary stones. Split 2 replaces 'Chronic Biliary Inflammation and Cholangiocarcinogenesis' with 'Chronic Biliary Inflammation' (CELLULAR, ESTABLISHED, keeping CL:0002538 and GO:1904056, newly evidenced by the PMID:32884228 decades-of-destruction sentence) and 'Cholangiocarcinoma' (TISSUE, role consequence, PROVISIONAL, keeping the incidence and incidental-detection evidence), so PROVISIONAL now grades only the half whose derivation is actually uncertain. The inflammation-to-carcinoma edge carries its own INDIRECT_UNKNOWN_INTERMEDIATES CausalEdge evidence item graded PARTIAL, quoting the 'is postulated' sentence that justifies PROVISIONAL. mechanism_confidence was deliberately NOT placed on the CausalEdge - the reviewer corrected their own earlier suggestion, as CausalEdge has no such slot. Foreign keys updated: the Antibiotic Therapy for Cholangitis target_mechanisms now targets Recurrent Bacterial Cholangitis, and the caroli_cca_incidence_uncertainty discussion attaches_to now targets pathophysiology#Cholangiocarcinoma. Review item D (no deep-research artifact in research/) is NOT addressed: the reviewer escalated it to a maintainer decision and this run cannot execute a DR provider. Suggestions E-H are non-blocking and left open. Validation: linkml-validate clean; just validate-terms passed; just count-verified-snippets reported 50/50 verified against cached references (up from 46/46, so all four new snippets verified); pytest tests/test_data.py -k 'mechanism or attaches or foreign or pathophys or discussion' 9420 passed. No reference cache file was created or edited by hand - all four new snippets quote PMID_32884228.md, already committed on this branch.

Address PR #8116 review item C-residual: attach GeneReviews claims · 2026-08-08T13:50:59Z · View source

PR Shepherd pass on PR #8116. The reviewer's item C-residual noted that GeneReviews PMID:20301501 was mined only as references[].findings, so no claim in the entry was actually backed by it and the findings sat outside the snippet audit. Added two evidence items citing the already-cached GeneReviews record: (1) on the inheritance block, the explicit autosomal-recessive statement plus the 25% per-conception sib recurrence risk, replacing reliance on the inference from the ARPKD label; (2) a new 'Avoidance of Hepatotoxic and Nephrotoxic Agents' treatment carrying the Agents/circumstances-to-avoid guidance, with an explicit scope caveat that the advice is written for ARPKD-PKHD1 and must not be transferred wholesale to simple sporadic Caroli disease. No target_mechanisms asserted on that treatment, since the source makes no mechanism-specific claim. Validation: just validate (schema OK, 46/46 snippets verified, up from 44/44), just count-verified-snippets (46/46), just validate-terms (passed), targeted pytest subset (5621 passed). Review items B (pathophysiology node bundling) and D (missing deep-research artifact) are NOT addressed and remain open.

Correct CCA onset-age claim on the carcinogenesis node; add GeneReviews references block · 2026-08-07T23:09:51Z · View source

PR #8116 review follow-up (ai4c-reviewer, 2026-08-07). Item A: the 'Chronic Biliary Inflammation and Cholangiocarcinogenesis' pathophysiology node still asserted that cholangiocarcinoma arises 'at a notably younger age', which none of its four evidence items supported and which the PMID:22197937 evidence added elsewhere in the same file contradicts (mean age at CCA diagnosis 60.1 years). The clause is replaced with the corrected framing already applied at the phenotype level: onset is predominantly beyond 40 years, so the excess risk is one of incidence rather than of markedly earlier onset. Item C: added a top-level references block citing PMID:20301501 (GeneReviews, Autosomal Recessive Polycystic Kidney Disease - PKHD1) tagged GeneReviews, with one finding mined per GeneReviews domain - clinical characteristics (names the hepatobiliary presentation as Caroli disease and attributes it to ductal plate remodeling), diagnosis/testing (biallelic PKHD1), management (ascending cholangitis, cholestasis, portal hypertension, LTx/CLKTx), and genetic counseling (autosomal recessive, 25% sib recurrence risk). The cache file was created by just fetch-reference PMID:20301501, never hand-written. Outcome is needs_followup because two review items remain open and were deliberately not attempted here: item B (splitting the two bundled pathophysiology nodes, a structural change beyond a shepherd fix) and item D (no deep-research artifact exists for Caroli in research/, which this run cannot generate). Validation: just validate passed; just count-verified-snippets reported 44/44 verified; all four references findings supporting_text values were confirmed as exact whitespace-normalized substrings of the fetched cache.

Create: Caroli disease (MONDO:0010913) with Caroli syndrome subtype · 2026-08-07T09:17:55Z · View source

New entry created by the automated curation scanner (high_effort tier) in response to issue #6526, which reported that Caroli disease had no dismech entry. NEC preflight. MONDO carries two live sibling terms — MONDO:0010913 (Caroli disease) and MONDO:0018808 (Caroli syndrome) — plus an obsolete MONDO:0000506. `just preflight-dr` is not applicable (no DR report was used; neither MONDO term records an RO:0004003 causal gene, so the automated check would return SKIP). Identity was instead confirmed manually against the MONDO records via OAK: the definition of MONDO:0010913 (Orphanet:53035, OMIM:600643) matches non-obstructive cystic dilatation of the intrahepatic bile ducts, and MONDO:0018808 is defined as that lesion plus congenital hepatic fibrosis. The two are modelled as one entry with two subtypes rather than two entries, since they share one ductal plate malformation mechanism; the rationale is recorded in the entry's notes and mappings blocks. Mechanism graph. Seven-node chain: fibrocystin loss from the cholangiocyte primary cilium (MOLECULAR, root) -> ductal plate malformation of the intrahepatic biliary tree -> segmental saccular dilatation of the large intrahepatic ducts -> bile stasis, hepatolithiasis and recurrent bacterial cholangitis -> progressive peribiliary fibrosis -> presinusoidal portal hypertension (ORGANISM), with a parallel consequence node for chronic biliary inflammation and cholangiocarcinogenesis. Two conformance declarations: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction on the root node, and fibrotic_response#Excessive ECM Deposition on the fibrosis node. Evidence discipline. Eight references, all fetched with just fetch-reference and verified: PMID:33824930 (Lasagni fibrocystic liver disease review — ductal plate / ciliopathy / PKHD1 mechanism), PMID:32884228 (Fahrner systematic review, 561 patients — CCA 6.6%), PMID:34294522 (German 17-centre series, 198 patients — CCA 7.1%), PMID:22197937 (Srinath CHF/ARPKD natural history, 1230 patients), PMID:14598246 (Masyuk PCK rat — tagged MODEL_ORGANISM), PMID:25327281 (Wang clinical classification, 30 patients), PMID:42438734 (the case report named in the issue), PMID:35728731 (EASL clinical practice guidelines; fetched but not ultimately cited, since its abstract carries no quotable disease-specific claim). Deliberate omissions rather than gaps of effort: - No prevalence record. No source in the evidence set states a population rate with a quotable figure; the widely repeated 1-in-1,000,000 estimate is not traceable to a citable abstract here. - No phenotype frequency bands, per docs/frequency-evidence-guidelines.md — the available snippets support the disease-phenotype associations but not quantitative bands. - Three evidence items are marked PARTIAL rather than SUPPORT where the source hedges or is single-patient: the planar-cell-polarity role of fibrocystin (the source says "unclear function ... supposedly involved"), the cholelithiasis phenotype (the source names cholestasis, not stones), and the beta-blocker / variceal-ligation treatments (n=1 case report showing initial benefit then long-term failure). - The cholangiocarcinogenesis node is mechanism_confidence PROVISIONAL: the inflammation-to-carcinoma link is inferred from the epidemiological association, not demonstrated in Caroli tissue. Two KNOWLEDGE_GAP discussions with proposed experiments: the wide (2.7-37.5%) spread in reported cholangiocarcinoma incidence with no identified risk factors, and the absence of any therapy targeting the ciliopathy mechanism. Validation: just validate kb/disorders/Caroli_Disease.yaml passes schema, term and reference validation; 43/43 snippets verified against cached references. Outcome is needs_followup: structured Orphanet provenance (ORPHA:53035 / ORPHA:480520 are not in references_cache and need an Orphadata refresh), a snippet-backed prevalence record, a hepatolithiasis-specific citation, and histopathology / imaging_findings blocks remain for a second pass. These are recorded on the entry's tracked_issues note.

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

Upstream germline defect: biallelic PKHD1 dysfunction reduces or alters fibrocystin.
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.
Developmental lesion: malformed large intrahepatic ducts become segmentally or diffusely ectatic and remain connected to the biliary tree.
Biophysical consequence: ectatic ducts cause sluggish flow and bile stasis, promoting pigment stones, sludge, obstruction, and bacterial colonization.
Clinical consequence: recurrent cholangitis produces pain, fever, jaundice, abscess, and sepsis.
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)
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:

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

(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.
(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.
(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.
(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.
(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.
(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.
(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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Caroli Disease: Comprehensive Disease-Characteristics Report

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1. Disease information

Definition and nomenclature

2. Etiology, risk, and protective factors

Causal factors

Risk factors

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Causal gene and protein

Variant classes and interpretation

Epigenetics

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

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Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Imaging and clinical evaluation

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Differential diagnosis

11. Outcome and prognosis

Cancer risk

Treatment-associated prognosis

12. Treatment and current implementation

Medical and interventional care

Surgery

Advanced and experimental treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

PCK rat

Pkhd1del4/del4 mouse

Mechanistic findings and limitations

Overall assessment

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