Autosomal dominant polycystic liver disease

Mendelian MONDO:0000447 Pathograph 44 Show in embeddings browser autosomal dominant disease liver disorder

Autosomal dominant polycystic liver disease (ADPLD), also called isolated polycystic liver disease, is an inherited disorder characterized by multiple biliary epithelial cysts with absent or limited kidney involvement. Expression is age-dependent and variably penetrant; many individuals remain asymptomatic, while extensive cyst growth causes hepatomegaly and compression symptoms despite preserved liver synthetic function. PRKCSH, SEC63, GANAB, ALG8 and SEC61B connect endoplasmic-reticulum protein biogenesis to reduced functional polycystin-1 dosage. Monoallelic PKHD1 variants can produce an overlapping liver-predominant phenotype through a less resolved mechanism. The reported LRP5 association remains contested. Treatment is guided by symptoms and cyst distribution, with medical volume control, targeted procedures and transplantation reserved for selected symptomatic disease.

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1
Mappings
1
Definitions
1
Inheritance
13
Pathophys.
26
Phenotypes
1
Gaps
44
Pathograph
7
Genes
8
Medical Actions
5
Subtypes
4
Differentials
2
Trials
23
References
1
Deep Research
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Mappings

MONDO
MONDO:0000447 autosomal dominant polycystic liver disease
skos:exactMatch MONDO Orphanet:2924 xref
MONDO:0000447 carries Orphanet:2924 as a disease cross-reference, and ORPHA:2924 is the Orphanet structured record used by this entry.
📘

Definitions

1
Orphanet isolated PCLD definition
Genetic isolated polycystic liver disease characterized by numerous cysts spread throughout the liver, usually described as ADPLD.
OTHER
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"Isolated polycystic liver disease (PCLD) is a genetic disorder characterized by the appearance of numerous cysts spread throughout the liver and that in most cases is described as autosomal dominant polycystic liver disease (ADPCLD)."
Orphanet provides the structured definition for this entry.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Autosomal dominant transmission with age-dependent, incomplete penetrance and variable expression. A heterozygous pathogenic variant has a 50% transmission probability; this is not a 50% probability of severe symptomatic disease. Some monoallelic PKHD1 carriers have liver cysts, distinct from biallelic ARPKD.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"- Autosomal dominant"
Orphanet records autosomal dominant inheritance for isolated polycystic liver disease.
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Both PCLD and ADPKD have an autosomal dominant inheritance pattern and the recurrence risk is 50%."
Transmission risk is distinct from age-dependent clinical severity.
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Subtypes

5
PRKCSH-related polycystic liver disease 1 MONDO:0008265
PRKCSH hgnc:9411 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PRKCSH (hgnc:9411). hgnc:9411 is a gene from the HUGO Gene Nomenclature Committee.
PRKCSH-related ADPLD subtype with numerous liver cysts and possible kidney cysts.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"PRKCSH | PRKCSH beta subunit of glucosidase II | hgnc:9411 | Disease-causing germline mutation(s) in"
Orphanet lists PRKCSH as a disease-causing gene for the ADPLD record.
SEC63-related polycystic liver disease 2 MONDO:0014860
SEC63 hgnc:21082 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SEC63 (hgnc:21082). hgnc:21082 is a gene from the HUGO Gene Nomenclature Committee.
SEC63-related ADPLD subtype with numerous liver cysts and possible kidney cysts.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"SEC63 | SEC63 protein translocation regulator | hgnc:21082 | Disease-causing germline mutation(s) in"
Orphanet lists SEC63 as a disease-causing gene for the ADPLD record.
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Discussions and Knowledge Gaps

1
Does LRP5 independently cause ADPLD after excluding linked GANAB variation?
KNOWLEDGE GAP OPEN adpld_lrp5_validity
Attached to
genetic#Reported LRP5 association
The initial linked family and Wnt assays support an association, but linked noncoding GANAB variants and incomplete functional validation leave causal attribution contested.
Show evidence (1 reference)
PMID:29243290 SUPPORT Other
"the close proximity of LRP5 and GANAB on chromosome 11 precludes the use of linkage or segregation analyses alone to distinguish the disease genes in this region."
Authors question causal attribution in the earlier LRP5 pedigree. Their own GANAB family is distinct; the original LRP5 family was not shown to carry a GANAB mutation.
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Pathophysiology

13
Somatic inactivation in biliary cyst epithelium
Acquired loss of the remaining functional PRKCSH or SEC63 allele can deepen a germline defect in focal cyst epithelium. Detection is gene-, tissue- and assay-dependent; human data do not demonstrate a detected second hit in every cyst or directly establish its time of initiation.
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
PRKCSH hgnc:9411 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRKCSH (hgnc:9411). hgnc:9411 is a gene from the HUGO Gene Nomenclature Committee. SEC63 hgnc:21082 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SEC63 (hgnc:21082). hgnc:21082 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired ER protein biogenesis Loss of remaining gene function disrupts ER protein processing.
Show evidence (2 references)
PMID:21856269 SUPPORT PRIMARY RESULT Human Clinical
"The wild-type allele of PRKCSH was lost (LOH) in 76% of cysts (54/71)."
Laser-microdissected cyst epithelia from eight surgical patients; this is a cyst-level result, not penetrance in carriers.
PMID:23209713 SUPPORT PRIMARY RESULT Human Clinical
"We found LOH in one of the 14 cysts of patient #3, while somatic mutations were conspicuously absent from samples from the other 2 patients (38 cysts)."
Only the patient with 14 cysts carried a convincing truncating allele. The other two shared a variant not enriched in cases; formalin fixation prevented complete somatic sequencing in the truncating-allele patient.
Impaired ER protein biogenesis
PRKCSH and GANAB encode glucosidase II subunits, ALG8 participates in N-glycan precursor synthesis, and SEC63/SEC61B participate in protein translocation. Their loss affects ER protein handling, with gene-specific glycosylation and stress responses.
PRKCSH hgnc:9411 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRKCSH (hgnc:9411). hgnc:9411 is a gene from the HUGO Gene Nomenclature Committee. SEC63 hgnc:21082 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SEC63 (hgnc:21082). hgnc:21082 is a gene from the HUGO Gene Nomenclature Committee. ALG8 hgnc:23161 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG8 (hgnc:23161). hgnc:23161 is a gene from the HUGO Gene Nomenclature Committee. GANAB hgnc:4138 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GANAB (hgnc:4138). hgnc:4138 is a gene from the HUGO Gene Nomenclature Committee. SEC61B hgnc:16993 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SEC61B (hgnc:16993). hgnc:16993 is a gene from the HUGO Gene Nomenclature Committee.
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Impaired polycystin-1 maturation Disrupted ER processing reduces mature polycystin-1 availability.
Show evidence (1 reference)
PMID:28375157 SUPPORT PRIMARY RESULT In Vitro
"We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1"
CRISPR knockouts and rescue in immortalized mouse renal epithelial cells carrying a tagged Pkd1 BAC; not direct experiments in patient cholangiocytes.
Impaired polycystin-1 maturation
PC1 maturation and export are impaired. ALG8 knockout causes hypoglycosylation; GANAB knockout impairs glucose trimming; SEC61B loss markedly reduces PC1 abundance. Cell-model differences should not be treated as quantitative predictors of patient liver severity.
polycystin-1 maturation GO:0051604 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased polycystin-1 maturation, annotated with protein maturation (GO:0051604). GO:0051604 is a biological process from the Gene Ontology.
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Reduced functional polycystin-1 dosage Defective maturation and trafficking diminish effective PC1 activity.
Show evidence (1 reference)
PMID:28375157 SUPPORT PRIMARY RESULT In Vitro
"We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1"
CRISPR knockouts and rescue in immortalized mouse renal epithelial cells carrying a tagged Pkd1 BAC; not direct experiments in patient cholangiocytes.
Reduced functional polycystin-1 dosage
Reduced functional PC1 dosage permits cystogenesis; conditional mouse rescue identifies PC1 as a limiting component. Bile-duct and kidney-tubule thresholds differ, but the complete downstream signaling sequence in human ADPLD is unresolved.
Downstream
Cholangiocyte proliferation PC1 deficiency permits epithelial growth through incompletely resolved signaling.
Hepatic cyst expansion Reduced PC1 activity permits biliary cyst formation and growth.
Show evidence (2 references)
PMID:21685914 SUPPORT PRIMARY RESULT Model Organism
"Pkd1, but not Pkd2, overexpression completely abrogated the ADPLD liver cystic phenotype"
Male conditional Prkcsh mice, examined eight weeks after induction. Kidney rescue later became incomplete, emphasizing tissue, time and dosage dependence.
PMID:28375157 SUPPORT PRIMARY RESULT In Vitro
"We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1"
CRISPR knockouts and rescue in immortalized mouse renal epithelial cells carrying a tagged Pkd1 BAC; not direct experiments in patient cholangiocytes.
PKHD1-associated biliary cyst formation
Some monoallelic PKHD1 carriers develop liver-predominant cysts. Fibrocystin signaling is incompletely resolved and should not be forced into the ER maturation pathway: Pkhd1-null renal cells retained PC1 abundance and ciliary localization. The causal genetic assignment is incompletely penetrant; the intervening cellular mechanism remains uncertain.
PKHD1 hgnc:9016 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PKHD1 (hgnc:9016). hgnc:9016 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Hepatic cyst expansion PKHD1 carrier status can predispose to biliary cysts through unresolved intermediates.
Show evidence (2 references)
PMID:28375157 SUPPORT PRIMARY RESULT Human Clinical
"We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD."
Nine loss-of-function alleles plus one known ARPKD missense allele in the 102-case discovery cohort; not all rare PKHD1 missense variants are established causes.
PMID:28375157 SUPPORT PRIMARY RESULT In Vitro
"PKHD1 acts by a different mechanism than the protein biogenetic pathway impacted by the other PCLD genes."
Two independently derived Pkhd1-null cell lines retained PC1 processing and ciliary localization.
Increased cholangiocyte cAMP signaling
cAMP promotes biliary epithelial proliferation and fluid secretion. Somatostatin receptors offer a way to reduce this signaling; trial efficacy does not establish every upstream molecular step.
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
Downstream
Cholangiocyte proliferation cAMP signaling promotes cyst-lining epithelial growth.
Cyst epithelial fluid secretion cAMP-dependent transport promotes fluid accumulation.
Show evidence (1 reference)
PMID:41328663 SUPPORT REVIEW SYNTHESIS Other
"SSAs inhibit cAMP, reducing fluid secretion and cell proliferation."
Current position statement synthesizes the pharmacologic pathway.
Cholangiocyte proliferation
Expansion of cyst-lining biliary epithelial cells contributes to growing hepatic cyst walls.
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
epithelial cell proliferation GO:0050673 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased epithelial cell proliferation (GO:0050673). GO:0050673 is a biological process from the Gene Ontology.
Downstream
Hepatic cyst expansion Epithelial proliferation expands the cyst wall.
Show evidence (1 reference)
PMID:41328663 SUPPORT REVIEW SYNTHESIS Other
"SSAs inhibit cAMP, reducing fluid secretion and cell proliferation."
Mechanistic synthesis distinguishes epithelial proliferation from luminal secretion.
Cyst epithelial fluid secretion
cAMP-dependent anion and water secretion expands the lumen of biliary epithelial cysts.
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
Downstream
Hepatic cyst expansion Fluid accumulation enlarges the cyst lumen.
Show evidence (1 reference)
PMID:41328663 SUPPORT REVIEW SYNTHESIS Other
"Biliary epithelia regulate cAMP‐dependent Cl and HCO3 secretion, facilitating fluid accumulation."
Position statement connects biliary epithelial transport to cyst-fluid accumulation.
Hepatic cyst expansion
Progressive enlargement of noncommunicating biliary epithelial cysts increases liver volume. The relative contribution of developmental remnants and adult-onset cyst initiation can vary.
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Polycystic liver disease Multiple hepatic cysts define the phenotype.
Hepatic mass effect Increasing cyst volume enlarges the liver and compresses adjacent structures.
Hepatic cyst hemorrhage Existing hepatic cysts provide the substrate for this secondary complication; cyst enlargement alone is not sufficient, and precipitating events vary.
Hepatic cyst infection Existing hepatic cysts provide the substrate for this secondary complication; cyst enlargement alone is not sufficient, and precipitating events vary.
Hepatic cyst rupture Existing hepatic cysts provide the substrate for this secondary complication; cyst enlargement alone is not sufficient, and precipitating events vary.
Show evidence (3 references)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"PLD is a non-communicating biliary tree disorder and should be differentiated from other neoplastic, infectious and traumatic conditions"
Review distinguishes disconnected cysts from communicating duct abnormalities.
PMID:35487607 SUPPORT REVIEW SYNTHESIS Other
"Though isolated PCLD and PCLD due to ADPKD are genetically distinct, they follow a similar clinical course of hepatomegaly from multiple cysts with preserved liver function."
The review supports the core clinical course of hepatomegaly with preserved liver function.
PMID:28375157 SUPPORT BACKGROUND Other
"Liver cysts in both PCLD and ADPKD are lined with biliary epithelium."
Introductory histologic synthesis in the gene-discovery paper supports the biliary epithelial origin.
Hepatic mass effect
Large cyst burden produces hepatomegaly, capsular tension and compression of adjacent organs. Synthetic liver function can remain preserved despite severe symptoms.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hepatomegaly Progressive hepatic cyst expansion enlarges the liver.
Abdominal distention Enlarged cystic liver volume produces abdominal distention.
Early satiety Compression from marked liver enlargement causes early satiety.
Abdominal pain Voluminous hepatic cysts and compression cause abdominal pain.
Dyspnea Marked hepatomegaly can mechanically impair breathing.
Gastroesophageal reflux Upper gastrointestinal compression can produce reflux symptoms.
Back pain Mechanical back pain can result from massive liver enlargement.
Hepatic vascular compression Expanding cysts compress vessels.
Biliary compression Strategic cysts compress bile ducts.
Reduced nutritional intake Gastric compression and early satiety reduce intake.
Show evidence (2 references)
PMID:35487607 SUPPORT REVIEW SYNTHESIS Other
"Though isolated PCLD and PCLD due to ADPKD are genetically distinct, they follow a similar clinical course of hepatomegaly from multiple cysts with preserved liver function."
The review supports the core clinical course of hepatomegaly with preserved liver function.
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ."
The review supports mass-effect symptoms from voluminous cysts.
Hepatic vascular compression
Cysts can compress hepatic veins, the portal circulation or the inferior vena cava. Venous obstruction can produce portal hypertension, ascites and peripheral edema without primary cirrhosis.
Downstream
Portal hypertension Hepatic venous or portal obstruction increases portal pressure.
Ascites Venous obstruction can promote ascites.
Pedal edema Vena-caval or venous compression impedes lower-extremity drainage.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"In advanced stages there are 2 processes that may lead up to portal hypertension. First, there is reduction of hepatic vein outflow. Secondly, portal vein inflow may be compressed in advanced disease due to the volume effect of cysts."
Clinical synthesis supports compression mechanisms in advanced PLD.
Biliary compression
Strategically located cysts can obstruct bile ducts, producing jaundice or cholestatic abnormalities; this is an uncommon complication rather than universal loss of synthetic function.
Downstream
Jaundice Biliary obstruction can cause jaundice.
Hyperbilirubinemia Impaired bile drainage can elevate bilirubin.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"An uncommon cause of jaundice is obstruction of the intrahepatic or extrahepatic bile ducts by hepatic cysts"
Review specifically supports the obstructive route to jaundice.
Reduced nutritional intake
Gastric compression and early satiety limit food intake in severe disease, causing malnutrition and loss of muscle mass. Liver weight can obscure body-weight loss.
Downstream
Malnutrition Insufficient intake causes malnutrition.
Skeletal muscle atrophy Prolonged nutritional compromise contributes to muscle wasting.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Patients reduce their meal size because of early satiety and malnutrition eventually leads to muscle mass loss and sarcopenia."
EASL describes the nutritional consequence of severe mass effect.
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Pathograph

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

26
Blood 1
Gastrointestinal hemorrhage OCCASIONAL HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0002239 | Gastrointestinal hemorrhage | Occasional (29-5%)"
Orphanet lists gastrointestinal hemorrhage as occasional.
Cardiovascular 3
Dilatation of the cerebral artery OCCASIONAL HP:0004944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilatation of the cerebral artery (HP:0004944). HP:0004944 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers. ADPKD aneurysm screening recommendations are not automatically applicable to isolated ADPLD.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0004944 | Dilatation of the cerebral artery | Occasional (29-5%)"
Orphanet lists cerebral artery dilatation as occasional.
Abnormal heart valve morphology OCCASIONAL HP:0001654 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart valve morphology (HP:0001654). HP:0001654 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0001654 | Abnormal heart valve morphology | Occasional (29-5%)"
Orphanet lists abnormal heart valve morphology as occasional.
Portal hypertension HP:0001409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Portal hypertension (HP:0001409). HP:0001409 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"These patients develop portal hypertension and ascites and/or hepatic hydrothorax."
EASL describes a complication of advanced PLD rather than a universal finding.
Digestive 9
Polycystic liver disease VERY_FREQUENT HP:0006557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polycystic liver disease (HP:0006557). HP:0006557 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0006557 | Polycystic liver disease | Very frequent (99-80%)"
Orphanet lists polycystic liver disease as very frequent.
PMID:36246085 SUPPORT Human Clinical
"Polycystic liver disease (PLD) manifests as numerous fluid-filled cysts scattered throughout the liver parenchyma."
Human cohort framing supports numerous liver cysts as the core phenotype.
Hepatomegaly VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0002240 | Hepatomegaly | Very frequent (99-80%)"
Orphanet lists hepatomegaly as very frequent.
PMID:35487607 SUPPORT REVIEW SYNTHESIS Other
"they follow a similar clinical course of hepatomegaly from multiple cysts with preserved liver function."
The review directly links PCLD to hepatomegaly from multiple cysts.
Abdominal distention VERY_FREQUENT HP:0003270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal distention (HP:0003270). HP:0003270 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0003270 | Abdominal distention | Very frequent (99-80%)"
Orphanet lists abdominal distention as very frequent.
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ."
The review names abdominal distension among major complaints.
Early satiety FREQUENT HP:0033842 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Early satiety (HP:0033842). HP:0033842 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0033842 | Early satiety | Frequent (79-30%)"
Orphanet lists early satiety as frequent.
PMID:27016902 SUPPORT Human Clinical
"Indications for surgery were abdominal distention, abdominal pain, early satiety, supine dyspnea, fatigue, uterine pro-lapse, hepatic venous outflow obstruction with ascites, obstruction of the inferior vena cava and dialysis hypotension, bile duct obstruction, and infected cysts."
The surgical cohort includes early satiety among symptomatic PLD indications for surgery.
Gastroesophageal reflux OCCASIONAL HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0002020 | Gastroesophageal reflux | Occasional (29-5%)"
Orphanet lists gastroesophageal reflux as occasional.
PMID:27016902 SUPPORT BACKGROUND Human Clinical
"Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea, early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction, portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression."
Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured ADPLD-specific frequency or new mechanistic experiment.
Jaundice OCCASIONAL HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0000952 | Jaundice | Occasional (29-5%)"
Orphanet lists jaundice as occasional.
PMID:27016902 SUPPORT BACKGROUND Human Clinical
"Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea, early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction, portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression."
Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured ADPLD-specific frequency or new mechanistic experiment.
Abnormality of the pancreas OCCASIONAL HP:0001732 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the pancreas (HP:0001732). HP:0001732 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0001732 | Abnormality of the pancreas | Occasional (29-5%)"
Orphanet lists pancreatic abnormalities as occasional.
Ascites HP:0001541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ascites (HP:0001541). HP:0001541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"These patients develop portal hypertension and ascites and/or hepatic hydrothorax."
EASL describes a complication of advanced PLD rather than a universal finding.
Malnutrition HP:0004395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malnutrition (HP:0004395). HP:0004395 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Patients reduce their meal size because of early satiety and malnutrition eventually leads to muscle mass loss and sarcopenia."
EASL describes a complication of advanced PLD rather than a universal finding.
Genitourinary 1
Multiple renal cysts FREQUENT HP:0005562 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple renal cysts (HP:0005562). HP:0005562 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers. Renal involvement varies by gene and age; an ADPKD prognosis cannot be inferred from a few renal cysts.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0005562 | Multiple renal cysts | Frequent (79-30%)"
Orphanet lists multiple renal cysts as frequent in this ADPLD record.
PMID:29038287 SUPPORT REVIEW SYNTHESIS Other
"autosomal dominant polycystic liver diseases (ADPLD), which result in significant PLD with minimal PKD."
The genetics review supports limited kidney cyst involvement in ADPLD.
Limbs 1
Pedal edema OCCASIONAL HP:0010741 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pedal edema (HP:0010741). HP:0010741 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0010741 | Pedal edema | Occasional (29-5%)"
Orphanet lists pedal edema as occasional.
Metabolism 3
Elevated alkaline phosphatase OCCASIONAL Elevated circulating alkaline phosphatase concentration HP:0003155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated alkaline phosphatase, annotated with Elevated circulating alkaline phosphatase concentration (HP:0003155). HP:0003155 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0003155 | Elevated circulating alkaline phosphatase concentration | Occasional (29-5%)"
Orphanet lists elevated alkaline phosphatase as occasional.
Elevated gamma-glutamyltransferase OCCASIONAL Elevated gamma-glutamyltransferase level HP:0030948 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated gamma-glutamyltransferase, annotated with Elevated gamma-glutamyltransferase level (HP:0030948). HP:0030948 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0030948 | Elevated gamma-glutamyltransferase level | Occasional (29-5%)"
Orphanet lists elevated gamma-glutamyltransferase as occasional.
Hyperbilirubinemia OCCASIONAL Increased total bilirubin HP:0003573 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased total bilirubin (HP:0003573). HP:0003573 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0003573 | Increased total bilirubin | Occasional (29-5%)"
Orphanet lists increased total bilirubin as occasional.
Musculoskeletal 1
Skeletal muscle atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Patients reduce their meal size because of early satiety and malnutrition eventually leads to muscle mass loss and sarcopenia."
EASL describes a complication of advanced PLD rather than a universal finding.
Respiratory 2
Dyspnea OCCASIONAL HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0002094 | Dyspnea | Occasional (29-5%)"
Orphanet lists dyspnea as occasional.
PMID:27016902 SUPPORT BACKGROUND Human Clinical
"Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea, early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction, portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression."
Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured ADPLD-specific frequency or new mechanistic experiment.
Respiratory insufficiency OCCASIONAL HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"HP:0002093 | Respiratory insufficiency | Occasional (29-5%)"
Orphanet lists respiratory insufficiency as occasional.
Constitutional 2
Abdominal pain OCCASIONAL HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers. The reviews describe pain as a major complaint among symptomatic patients; that clinical prominence does not provide a conflicting numerical frequency for all carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0002027 | Abdominal pain | Occasional (29-5%)"
Orphanet lists abdominal pain as occasional.
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ."
The review names abdominal pain among major complaints.
Back pain OCCASIONAL HP:0003418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Back pain (HP:0003418). HP:0003418 is a phenotype from the Human Phenotype Ontology.
Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for unselected variant carriers.
Show evidence (2 references)
ORPHA:2924 SUPPORT Other
"HP:0003418 | Back pain | Occasional (29-5%)"
Orphanet lists back pain as occasional.
PMID:27016902 SUPPORT BACKGROUND Human Clinical
"Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea, early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction, portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression."
Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured ADPLD-specific frequency or new mechanistic experiment.
Other 3
Hepatic cyst hemorrhage
Needs a specific HPO term. OLS HP searches for hepatic cyst hemorrhage, hepatic cyst infection, hepatic cyst rupture, liver hemorrhage, hepatic hemorrhage, liver infection, liver abscess and cyst rupture found no equivalent term. Liver abscess and unusual liver infection have different definitions and are not substituted for infection of a pre-existing cyst.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Intrahepatic cyst bleeding typically presents as acute pain in the upper right-side of the abdomen."
The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
Hepatic cyst infection
Needs a specific HPO term. OLS HP searches for hepatic cyst hemorrhage, hepatic cyst infection, hepatic cyst rupture, liver hemorrhage, hepatic hemorrhage, liver infection, liver abscess and cyst rupture found no equivalent term. Liver abscess and unusual liver infection have different definitions and are not substituted for infection of a pre-existing cyst.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Cyst infections are a serious complication because of its indolent course, demanding treatment and high risk of recurrence."
The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
Hepatic cyst rupture
Needs a specific HPO term. OLS HP searches for hepatic cyst hemorrhage, hepatic cyst infection, hepatic cyst rupture, liver hemorrhage, hepatic hemorrhage, liver infection, liver abscess and cyst rupture found no equivalent term. Liver abscess and unusual liver infection have different definitions and are not substituted for infection of a pre-existing cyst.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Cyst rupture is an exceptional rare complication and presents with acute onset of pain."
The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
🧬

Genetic Associations

7
Heterozygous PRKCSH pathogenic variants (Causative)
Gene: PRKCSH hgnc:9411 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRKCSH (hgnc:9411). hgnc:9411 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (3 references)
ORPHA:2924 SUPPORT Other
"PRKCSH | PRKCSH beta subunit of glucosidase II | hgnc:9411 | Disease-causing germline mutation(s) in"
Orphanet lists PRKCSH as a disease-causing gene.
PMID:38097330 SUPPORT REVIEW SYNTHESIS Other
"The two major genes are PRKCSH and SEC63"
The genetics review identifies PRKCSH as a major ADPLD gene.
PMID:21856269 SUPPORT PRIMARY RESULT Human Clinical
"The wild-type allele of PRKCSH was lost (LOH) in 76% of cysts (54/71)."
Laser-microdissected cyst epithelia from eight surgical patients; this is a cyst-level result, not penetrance in carriers.
Heterozygous SEC63 pathogenic variants (Causative)
Gene: SEC63 hgnc:21082 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SEC63 (hgnc:21082). hgnc:21082 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (3 references)
ORPHA:2924 SUPPORT Other
"SEC63 | SEC63 protein translocation regulator | hgnc:21082 | Disease-causing germline mutation(s) in"
Orphanet lists SEC63 as a disease-causing gene.
PMID:38097330 SUPPORT REVIEW SYNTHESIS Other
"The two major genes are PRKCSH and SEC63"
The genetics review identifies SEC63 as a major ADPLD gene.
PMID:23209713 SUPPORT PRIMARY RESULT Human Clinical
"We found LOH in one of the 14 cysts of patient #3, while somatic mutations were conspicuously absent from samples from the other 2 patients (38 cysts)."
Only the patient with 14 cysts carried a convincing truncating allele. The other two shared a variant not enriched in cases; formalin fixation prevented complete somatic sequencing in the truncating-allele patient.
Heterozygous ALG8 pathogenic variants (Causative)
Gene: ALG8 hgnc:23161 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALG8 (hgnc:23161). hgnc:23161 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (3 references)
ORPHA:2924 SUPPORT Other
"ALG8 | ALG8 alpha-1,3-glucosyltransferase | hgnc:23161 | Disease-causing germline mutation(s) in"
Orphanet lists ALG8 as a disease-causing gene.
PMID:29038287 SUPPORT REVIEW SYNTHESIS Other
"ADPLD (PRKCSH, SEC63, LRP5, ALG8, and SEC61B)"
The genetics review includes ALG8 among reported ADPLD genes.
PMID:28375157 SUPPORT PRIMARY RESULT Human Clinical
"identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B."
Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts and functional assays contribute different levels of support.
Reported LRP5 association (Reported association with contested causal attribution)
Gene: LRP5 hgnc:6697 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LRP5 (hgnc:6697). hgnc:6697 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (4 references)
ORPHA:2924 SUPPORT Other
"LRP5 | LDL receptor related protein 5 | hgnc:6697 | Disease-causing germline mutation(s) in"
Orphanet lists LRP5 as a disease-causing gene.
PMID:29038287 SUPPORT REVIEW SYNTHESIS Other
"ADPLD (PRKCSH, SEC63, LRP5, ALG8, and SEC61B)"
The genetics review includes LRP5 among reported ADPLD genes.
PMID:24706814 SUPPORT PRIMARY RESULT In Vitro
"Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation."
Original study reports altered Wnt signaling for the liver-associated variants; this differs from high-bone-mass LRP5 gain of function.
+ 1 more reference
Heterozygous GANAB pathogenic variants (Causative)
Gene: GANAB hgnc:4138 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GANAB (hgnc:4138). hgnc:4138 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (2 references)
PMID:28375157 SUPPORT PRIMARY RESULT Human Clinical
"identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B."
Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts and functional assays contribute different levels of support.
PMID:29243290 SUPPORT PRIMARY RESULT In Vitro
"The RT-PCR product from the family T90 mutant minigene instead showed 100% skipping of the 101 bp exon 24"
GANAB NM_198335.3:c.2791+4_2791+12delAGTGACCAA was tested in HEK cells and healthy-donor primary human cholangiocytes using constructs. Exon skipping predicts a frameshift; this is not patient RNA or evidence for a separate enhancer target.
Heterozygous SEC61B pathogenic variants (Causative)
Gene: SEC61B hgnc:16993 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SEC61B (hgnc:16993). hgnc:16993 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:28375157 SUPPORT PRIMARY RESULT Human Clinical
"identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B."
Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts and functional assays contribute different levels of support.
Heterozygous PKHD1 pathogenic variants (Causative)
Gene: PKHD1 hgnc:9016 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PKHD1 (hgnc:9016). hgnc:9016 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:28375157 SUPPORT PRIMARY RESULT Human Clinical
"We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD."
Nine loss-of-function alleles plus one known ARPKD missense allele in the 102-case discovery cohort; not all rare PKHD1 missense variants are established causes.
🗃️

External Assertions

1
Orphanet isolated polycystic liver disease record
Orphanet structured disease record ORPHA:2924
Orphanet's ORPHA:2924 structured record defines isolated polycystic liver disease, lists autosomal dominant inheritance and adult onset, provides the European point-prevalence class, asserts disease-causing gene associations for ALG8, LRP5, PRKCSH, and SEC63, and supplies the HPO phenotype-frequency table used in this curation.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"Isolated polycystic liver disease (PCLD) is a genetic disorder characterized by the appearance of numerous cysts spread throughout the liver and that in most cases is described as autosomal dominant polycystic liver disease (ADPCLD)."
Orphanet defines the disease scope as genetic isolated PCLD, usually described as ADPCLD.
💊

Medical Actions

8
Somatostatin analogue therapy
Action: Somatostatin analogue therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Somatostatin analogue therapy, annotated with Somatostatin Analog Therapy (NCIT:C15449). NCIT:C15449 is a clinical intervention from the NCI Thesaurus. Ontology label: Somatostatin Analog Therapy NCIT:C15449
Agent: Somatostatin Receptor Agonist NCIT:C62799 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Somatostatin Receptor Agonist (NCIT:C62799). NCIT:C62799 is a therapeutic agent from the NCI Thesaurus. Octreotide NCIT:C711 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Octreotide (NCIT:C711). NCIT:C711 is a therapeutic agent from the NCI Thesaurus. Lanreotide NCIT:C1523 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Lanreotide (NCIT:C1523). NCIT:C1523 is a therapeutic agent from the NCI Thesaurus.
Platform: Peptide
Long-acting octreotide or lanreotide can modestly reduce or stabilize liver volume in symptomatic diffuse PLD. These uses remain off-label as described in the 2026 ERN statement. Assess symptoms and consistent volumetry over 6–12 months; response can include symptom relief with volume stabilization. Benefit can persist during ongoing treatment for several years, while withdrawal can cause rebound. Monitor gastrointestinal intolerance, glucose disturbance, gallstones, injection reactions and cyst infection. Advanced kidney disease requires individualized dosing and caution; avoid during pregnancy or breastfeeding. Pasireotide has more glucose toxicity and is not first-line. Volume reduction does not establish prevention of transplantation or renal functional decline.
Mechanism Target:
INHIBITS Increased cholangiocyte cAMP signaling — Somatostatin signaling lowers cAMP-dependent secretion and growth.
INHIBITS Hepatic cyst expansion — Medical therapy can reduce or stabilize cyst-associated liver volume.
Show evidence (6 references)
PMID:41328663 SUPPORT REVIEW SYNTHESIS Other
"Patients with liver volume‐related symptoms who have non‐localised disease should be considered for treatment."
ERN 2026 consensus supports symptom- and distribution-based selection, not routine treatment of incidental asymptomatic cysts.
PMID:20431041 SUPPORT PRIMARY RESULT Human Clinical
"Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048)."
One-year 42-patient randomized trial: 34 ADPKD and eight ADPLD. The overall volume effect is not an independently powered ADPLD subgroup estimate. Two SF-36 subdomains improved within the treated group; broad quality-of-life benefit was not uniform.
PMID:19646443 SUPPORT PRIMARY RESULT Human Clinical
"The mean liver volume decreased 2.9%, from 4606 mL"
Six-month randomized trial of 54 mixed ADPKD/ADPLD participants versus a 1.6% volume increase with placebo; genotype stratification was post hoc.
+ 3 more references
Aspiration sclerotherapy
Action: Aspiration sclerotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Aspiration sclerotherapy, annotated with Sclerotherapy (NCIT:C62732). NCIT:C62732 is a clinical intervention from the NCI Thesaurus. Ontology label: Sclerotherapy NCIT:C62732
A dominant large or strategically located accessible cyst causing symptoms may be treated by image-guided aspiration with sclerosis. This is a targeted approach rather than a treatment for all diffuse small cysts; recurrence of symptoms is more frequent in PLD than in a solitary simple cyst.
Mechanism Target:
INHIBITS Hepatic mass effect — Targeted cyst decompression can relieve compression symptoms.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"When a large or strategically located cyst is the main cause of symptoms, percutaneous aspiration sclerotherapy can also be performed in the context of PLD."
Guideline selection is based on the symptomatic dominant cyst.
Cyst fenestration or selected hepatic resection
Action: Cyst fenestration or selected hepatic resectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cyst fenestration or selected hepatic resection, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Fenestration is considered for accessible superficial large cysts; segmental resection can help severe disease clustered in selected segments with sufficient spared parenchyma and patent vasculature. These procedures carry morbidity, recurrence and possible difficulty at later transplantation. In the 186-patient combined resection/fenestration series, 170 had ADPKD and only 16 ADPLD; major complications occurred in 21% and 90-day mortality was 2.7%. Its durable median 61% volume reduction comes from selected patients at a single expert center, not a randomized comparison with transplantation.
Mechanism Target:
INHIBITS Hepatic mass effect — Reducing cyst burden can relieve mechanical symptoms.
Show evidence (2 references)
PMID:27016902 SUPPORT PRIMARY RESULT Human Clinical
"Sustained long-term reductions in LV after PHCF can be achieved in selected patients with severe, highly symptomatic PLD."
Retrospective single-center series, predominantly ADPKD; selection and missing follow-up imaging limit generalization.
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Since surgical resection in PLD is associated with high morbidity, especially in the presence of vascular abnormalities and biliary dilatation"
Guideline cautions against treating resection as a universally appropriate option.
Liver transplantation
Action: Liver transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. Ontology label: Liver Transplantation NCIT:C15271
Platform: Surgery
Refer selected patients with massive symptomatic PLD, severe malnutrition, refractory vascular complications or recurrent complications when other approaches fail or are unsuitable. Preserved synthetic function can make conventional MELD underestimate burden, requiring local exception pathways. Combined liver-kidney transplantation is considered only for substantial independent renal disease, not automatically for isolated ADPLD.
Mechanism Target:
INHIBITS Hepatic mass effect — Removing the cystic liver eliminates the source of compression.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Liver transplantation is the only curative treatment for PLD and only the most severe cases with massive PLD are eligible."
EASL limits transplantation to selected severe disease and discusses allocation despite preserved liver function.
Estrogen exposure counseling
Action: Estrogen exposure counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Estrogen exposure counseling, annotated with Counseling (NCIT:C61547). NCIT:C61547 is a clinical intervention from the NCI Thesaurus. Ontology label: Counseling NCIT:C61547
Review estrogen-containing contraception and hormone replacement; EASL recommends stopping exogenous estrogen in female patients with PLD. Choose alternatives through individualized reproductive counseling. Evidence for pregnancy as an independent progression factor is inconsistent, and patients should not be counseled against pregnancy solely because of PLD.
Show evidence (2 references)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Stopping exogenous oestrogen administration is recommended in female patients with PLD"
EASL recommendation based on observational and experimental evidence; prevention benefit from withdrawal has not been proven in a definitive trial.
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Patients with PLD should not be counselled against pregnancy"
The recommendation distinguishes exogenous estrogen use from pregnancy counseling.
Nutritional and exercise rehabilitation
Action: Nutritional and exercise rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional and exercise rehabilitation, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
For severe PLD with early satiety, malnutrition or sarcopenia, provide dietitian-supervised nutrition and physical rehabilitation. Small frequent meals can help intake. Avoid interpreting liver-related body weight as preserved muscle mass; no specific diet is established to prevent cyst formation.
Mechanism Target:
INHIBITS Reduced nutritional intake — Individualized nutrition can mitigate inadequate intake and its consequences.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Patients with PLD and sarcopenia should receive intensive nutrition and exercise rehabilitation"
Guideline supports multidisciplinary nutritional and functional care.
Genetic and reproductive counseling
Action: Genetic and reproductive counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic and reproductive counseling, annotated with Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Explain variable expression, the 50% transmission risk for a heterozygous pathogenic allele, limits of negative testing and uncertainty from VUS. Offer preconception counseling and discuss reproductive testing when a familial variant is known. Do not convert a candidate LRP5 variant into a definitive diagnosis without reassessment.
Show evidence (1 reference)
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Patients with PLD should receive preconception counselling concerning the risk of passing on PLD to the newborn"
EASL recommends preconception counseling.
Pain and complication management
Action: Pain and complication managementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pain and complication management, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Evaluate new severe pain for hemorrhage, infection, rupture or obstruction rather than attributing it automatically to stable liver size. Provide individualized analgesia and targeted management of confirmed complications; avoid unnecessary cyst intervention for mild asymptomatic disease.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Supportive management with analgesics is the first-line treatment in patients with acute or chronic abdominal pain and tenderness."
Clinical review supports symptom care alongside evaluation for acute complications.
🔬

Diagnosis

4
Abdominal ultrasonography
Ultrasound establishes cyst distribution in liver and kidneys. EASL uses more than ten hepatic cysts as a general PLD criterion; family-based criteria may recognize younger at-risk relatives with fewer cysts. Liver cysts alone do not distinguish ADPLD from liver-predominant ADPKD. Cyst morphology and communication with the biliary tree guide alternative diagnoses.
ultrasonography procedure NCIT:C19337 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:23296249 SUPPORT REVIEW SYNTHESIS Other
"Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver and to differentiate between ADPKD and PCLD."
This review directly supports ultrasonography for diagnosis and differential separation.
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Ultrasonography is the first instrument to assess liver phenotype."
This review identifies ultrasonography as the first imaging instrument for liver phenotype assessment.
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Current diagnosis of PLD is made in the presence of >10 hepatic cysts."
General guideline criterion; clinical family context remains important.
CT or MRI liver volume assessment
CT or MRI defines cyst distribution, vascular compression, residual parenchyma and height-adjusted liver volume for treatment planning. Volume and symptom burden are separate measures. Age-adjusted progression estimates are promising but the 80-patient tertiary-center derivation cohort was retrospective, often relied on single imaging, included VUS in some analyses and requires external validation.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Results: Total liver and kidney volumes can be measured and correlated with clinical endpoints.
Show evidence (2 references)
PMID:36246085 SUPPORT Human Clinical
"Identified genotypes were correlated with total liver and kidney volume (assessed by CT or MRI), organ function, co-morbidities, and clinical endpoints."
The cohort used CT or MRI liver-volume assessment for genotype-phenotype and outcome correlation.
PMID:36246085 SUPPORT PRIMARY RESULT Human Clinical
"Additionally, most patients had single imaging only but no longitudinal imaging data, impeding intra-individual liver growth assessment."
Full-text limitation: estimated growth from age and volume is not directly measured longitudinal growth.
Molecular genetic testing
Use genetic counseling and an appropriate cystic kidney/liver panel when the phenotype, family history or reproductive question warrants clarification. Include deletion/duplication assessment and consider splice-region or other variants missed by routine coding analysis. A negative panel does not exclude ADPLD, and a VUS does not confirm it. Genetic testing is not routine screening for asymptomatic relatives solely to find liver cysts.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (4 references)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics."
The review supports molecular diagnostics when imaging or screening is ambiguous.
PMID:38097330 SUPPORT REVIEW SYNTHESIS Other
"employing a next-generation sequencing panel containing all known PKD and ciliopathy genes is recommended for clinical testing."
The genetics review supports broad NGS-panel clinical testing because of gene and phenotype overlap.
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf SUPPORT REVIEW SYNTHESIS Other
"Genetic testing should not be used to screen for PLD"
EASL distinguishes screening from diagnostic or reproductive use.
+ 1 more reference
PLD symptom and nutritional assessment
Assess PLD-Q or POLCA scores alongside imaging to attribute symptoms and monitor response. Evaluate intake, functional muscle loss and sarcopenia; a heavy cystic liver can mask weight loss. The 2026 suggested PROM and volume thresholds are consensus aids, not validated predictors of individual drug response.
Show evidence (1 reference)
PMID:41328663 SUPPORT REVIEW SYNTHESIS Other
"However, so far there is no robust cut‐off level, that predicts response to SSA therapy in both scoring systems."
Full-text caveat limits numerical PLD-Q/POLCA threshold interpretation.
📈

Progression

2
Onset
Age: Adult
Adult clinical presentation is typical; this catalog age does not mean that every carrier develops symptomatic disease in adulthood.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"- Age of onset: Adult"
Orphanet records adult age of onset.
Clinical course
Disease expression is variable, ranging from asymptomatic cyst burden to severe symptomatic hepatomegaly requiring hospitalization, surgery, or transplant assessment.
Show evidence (1 reference)
PMID:36246085 SUPPORT Human Clinical
"Polycystic liver disease (PLD) is a highly variable condition that can be asymptomatic or severe."
This cohort study supports the variable clinical course.
📊

Prevalence

1
Europe
Point Prevalence 1.0–9.0 per 100,000 1–9 per 100,000
Orphanet reports a European point-prevalence class of 1-9 per 100,000. This is a catalog estimate for clinically recognized disease, not the frequency of incidental liver cysts or all incompletely penetrant variant carriers.
Show evidence (1 reference)
ORPHA:2924 SUPPORT Other
"| 1-9 / 100 000 | Europe | Point prevalence | EXPERT |"
Orphadata provides the European point-prevalence class.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Autosomal dominant polycystic liver disease:

ADPKD with liver-predominant disease
Overlapping Features Substantial bilateral renal cysts, kidney enlargement or impaired renal function suggest ADPKD. GANAB and ALG8 can span the kidney/liver spectrum, so liver morphology alone is insufficient.
Show evidence (1 reference)
PMID:29038287 SUPPORT REVIEW SYNTHESIS Other
"ADPLD is defined as dominantly inherited disease with significant PLD without significant PKD."
Review defines the clinical distinction while recognizing genic overlap.
Caroli disease or syndrome and ARPKD
Overlapping Features Communicating intrahepatic duct ectasia, recurrent cholangitis and congenital hepatic fibrosis favor Caroli syndrome or ARPKD rather than isolated noncommunicating hepatic cysts.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"In CS large and small intrahepatic bile duct ecstasies are accompanied with CHF."
Review distinguishes communicating duct disease with congenital hepatic fibrosis.
Simple hepatic cysts and biliary hamartomas
Overlapping Features A few incidental cysts or small von Meyenburg complexes do not by themselves establish inherited ADPLD; age, family history, morphology and kidney findings matter.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"VMC are frequently an incidental finding at radiological imaging, surgery or autopsy studies."
Review differentiates incidental biliary hamartomas from severe inherited polycystic disease.
Cystic neoplasm or infection
Overlapping Features Complex walls, nodules, septations, enhancement or acute systemic features require evaluation for another cystic lesion or a superimposed complication rather than assuming uncomplicated ADPLD.
Show evidence (1 reference)
PMID:24886261 SUPPORT REVIEW SYNTHESIS Other
"PLD is a non-communicating biliary tree disorder and should be differentiated from other neoplastic, infectious and traumatic conditions"
The differential includes distinct diseases; listing them does not classify ADPLD as infectious.
🔬

Clinical Trials

2
NCT00426153 COMPLETED
Registry phase 2/3 trial of octreotide LAR in severe PLD. The published first-year randomized comparison enrolled 42 participants, including eight with ADPLD, assigned 28 to octreotide and 14 to placebo. Liver volume was the primary endpoint; renal endpoints excluded ADPLD and do not establish kidney protection.
Target Phenotypes: Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
clinicaltrials:NCT00426153 SUPPORT Other
"A total of 42 patients will be recruited -14 who will receive placebo and 28 the study drug."
Registry purpose statement; current status and phase were independently verified through the live registry.
PMID:20431041 SUPPORT PRIMARY RESULT Human Clinical
"Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048)."
One-year 42-patient randomized trial: 34 ADPKD and eight ADPLD. The overall volume effect is not an independently powered ADPLD subgroup estimate. Two SF-36 subdomains improved within the treated group; broad quality-of-life benefit was not uniform.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2900957/ SUPPORT PRIMARY RESULT Human Clinical
"The dose was reduced to 30 mg in seven and 20 mg in four patients receiving octreotide, mostly because of diarrhea/loose stools, especially in the first 2 weeks after an injection"
Full-text tolerability results limit the abstract statement that treatment was well tolerated; one participant also had persistent steatorrhea and weight loss.
NCT05281328 ACTIVE_NOT_RECRUITING
POSITANO phase 2/3 trial compares weekly or fortnightly CAM2029 octreotide depot with placebo in symptomatic PLD. The 53-week randomized period is complete and registry results were posted June 2026; the open-label extension remains active, with estimated study completion in August 2027. Seventy-one participants were randomized, and the posted primary volume analysis includes 67 with baseline MRI. Registry-reported mean changes were -0.7% for combined CAM2029 arms and +3.9% for placebo, with estimated relative difference -4.3% (95% CI -8.4 to -0.1; P=0.0443). These mixed-etiology registry results do not establish an ADPLD-specific effect or a licensed indication.
Target Phenotypes: Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
clinicaltrials:NCT05281328 SUPPORT Other
"The purpose of the trial is to compare the effectiveness and safety of 2 treatment regimens of CAM2029 (given weekly or every 2 weeks) to placebo in participants with symptomatic PLD, either isolated as in autosomal dominant PLD (ADPLD) or associated with autosomal dominant polycystic kidney..."
Registry summary defines the population and randomized comparison.
url:https://clinicaltrials.gov/api/v2/studies/NCT05281328 SUPPORT PRIMARY RESULT Human Clinical
"The baseline MRI scan was missing for 4 participants (1 in each CAM2029 separate group and 2 in the placebo group)."
Posted primary-results population statement; 71 randomized and 67 in the displayed volume denominators. The live registry includes both results and continuing extension status.
{ }

Source YAML

click to show 
name: Autosomal dominant polycystic liver disease
creation_date: '2026-05-09T06:38:39Z'
category: Mendelian
description: >-
  Autosomal dominant polycystic liver disease (ADPLD), also called isolated polycystic liver
  disease, is an inherited disorder characterized by multiple biliary epithelial cysts with
  absent or limited kidney involvement. Expression is age-dependent and variably penetrant;
  many individuals remain asymptomatic, while extensive cyst growth causes hepatomegaly and
  compression symptoms despite preserved liver synthetic function. PRKCSH, SEC63, GANAB, ALG8
  and SEC61B connect endoplasmic-reticulum protein biogenesis to reduced functional polycystin-1
  dosage. Monoallelic PKHD1 variants can produce an overlapping liver-predominant phenotype
  through a less resolved mechanism. The reported LRP5 association remains contested. Treatment
  is guided by symptoms and cyst distribution, with medical volume control, targeted procedures
  and transplantation reserved for selected symptomatic disease.
synonyms:
- ADPLD
- ADPCLD
- Isolated polycystic liver disease
- PCLD
- Polycystic liver disease
disease_term:
  preferred_term: autosomal dominant polycystic liver disease
  term:
    id: MONDO:0000447
    label: autosomal dominant polycystic liver disease
parents:
- autosomal dominant disease
- liver disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000447
      label: autosomal dominant polycystic liver disease
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO Orphanet:2924 xref
    mapping_justification: >-
      MONDO:0000447 carries Orphanet:2924 as a disease cross-reference, and ORPHA:2924 is the
      Orphanet structured record used by this entry.
external_assertions:
- name: Orphanet isolated polycystic liver disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:2924
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2924
  description: >-
    Orphanet's ORPHA:2924 structured record defines isolated polycystic liver disease, lists
    autosomal dominant inheritance and adult onset, provides the European point-prevalence class,
    asserts disease-causing gene associations for ALG8, LRP5, PRKCSH, and SEC63, and supplies
    the HPO phenotype-frequency table used in this curation.
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Isolated polycystic liver disease (PCLD) is a genetic disorder characterized by the appearance
      of numerous cysts spread throughout the liver and that in most cases is described as autosomal
      dominant polycystic liver disease (ADPCLD).
    explanation: Orphanet defines the disease scope as genetic isolated PCLD, usually described as ADPCLD.
definitions:
- name: Orphanet isolated PCLD definition
  definition_type: OTHER
  description: >-
    Genetic isolated polycystic liver disease characterized by numerous cysts spread throughout
    the liver, usually described as ADPLD.
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Isolated polycystic liver disease (PCLD) is a genetic disorder characterized by the appearance
      of numerous cysts spread throughout the liver and that in most cases is described as autosomal
      dominant polycystic liver disease (ADPCLD).
    explanation: Orphanet provides the structured definition for this entry.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Autosomal dominant transmission with age-dependent, incomplete penetrance and variable expression.
    A heterozygous pathogenic variant has a 50% transmission probability; this is not a 50%
    probability of severe symptomatic disease. Some monoallelic PKHD1 carriers have liver cysts,
    distinct from biallelic ARPKD.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '- Autosomal dominant'
    explanation: Orphanet records autosomal dominant inheritance for isolated polycystic liver disease.
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Both PCLD and ADPKD have an autosomal dominant inheritance pattern and the recurrence risk is 50%.
    explanation: Transmission risk is distinct from age-dependent clinical severity.
    quote_role: REVIEW_SYNTHESIS
prevalence:
- population: Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 9.0
  notes: >-
    Orphanet reports a European point-prevalence class of 1-9 per 100,000. This is a catalog
    estimate for clinically recognized disease, not the frequency of incidental liver cysts
    or all incompletely penetrant variant carriers.
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '| 1-9 / 100 000 | Europe | Point prevalence | EXPERT |'
    explanation: Orphadata provides the European point-prevalence class.
progression:
- phase: Onset
  age_range: Adult
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '- Age of onset: Adult'
    explanation: Orphanet records adult age of onset.
  notes: >-
    Adult clinical presentation is typical; this catalog age does not mean that every carrier
    develops symptomatic disease in adulthood.
- phase: Clinical course
  notes: >-
    Disease expression is variable, ranging from asymptomatic cyst burden to severe symptomatic
    hepatomegaly requiring hospitalization, surgery, or transplant assessment.
  evidence:
  - reference: PMID:36246085
    reference_title: Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Polycystic liver disease (PLD) is a highly variable condition that can be asymptomatic or severe.
    explanation: This cohort study supports the variable clinical course.
has_subtypes:
- name: PCLD1
  display_name: PRKCSH-related polycystic liver disease 1
  subtype_term:
    preferred_term: polycystic liver disease 1
    term:
      id: MONDO:0008265
      label: polycystic liver disease 1
  description: PRKCSH-related ADPLD subtype with numerous liver cysts and possible kidney cysts.
  genes:
  - preferred_term: PRKCSH
    term:
      id: hgnc:9411
      label: PRKCSH
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: PRKCSH | PRKCSH beta subunit of glucosidase II | hgnc:9411 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists PRKCSH as a disease-causing gene for the ADPLD record.
- name: PCLD2
  display_name: SEC63-related polycystic liver disease 2
  subtype_term:
    preferred_term: polycystic liver disease 2
    term:
      id: MONDO:0014860
      label: polycystic liver disease 2
  description: SEC63-related ADPLD subtype with numerous liver cysts and possible kidney cysts.
  genes:
  - preferred_term: SEC63
    term:
      id: hgnc:21082
      label: SEC63
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SEC63 | SEC63 protein translocation regulator | hgnc:21082 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists SEC63 as a disease-causing gene for the ADPLD record.
- name: ALG8-related ADPLD
  description: >-
    Monoallelic loss-of-function variants produce variably penetrant kidney/liver cystic disease,
    sometimes severe liver-predominant disease. Biallelic ALG8 disease is a congenital disorder
    of glycosylation and is a different phenotype.
  genes:
  - preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ALG8 | ALG8 alpha-1,3-glucosyltransferase | hgnc:23161 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists ALG8 as a disease-causing gene for the ADPLD record.
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.
    explanation: >-
      Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts
      and functional assays contribute different levels of support.
    quote_role: PRIMARY_RESULT
  subtype_term:
    preferred_term: polycystic liver disease 3 with or without kidney cysts
    term:
      id: MONDO:0054743
      label: polycystic liver disease 3 with or without kidney cysts
- name: LRP5-related ADPLD
  description: >-
    Historical catalog subtype with disputed causal attribution; the ontology binding records
    the named subtype and does not resolve the GANAB-linkage concern.
  genes:
  - preferred_term: LRP5
    term:
      id: hgnc:6697
      label: LRP5
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: LRP5 | LDL receptor related protein 5 | hgnc:6697 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists LRP5 as a disease-causing gene for the ADPLD record.
  - reference: PMID:29243290
    reference_title: A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the close proximity of LRP5 and GANAB on chromosome 11 precludes the use of linkage or
      segregation analyses alone to distinguish the disease genes in this region.
    explanation: >-
      Authors question causal attribution in the earlier LRP5 pedigree. Their own GANAB family
      is distinct; the original LRP5 family was not shown to carry a GANAB mutation.
  subtype_term:
    preferred_term: polycystic liver disease 4 with or without kidney cysts
    term:
      id: MONDO:0044327
      label: polycystic liver disease 4 with or without kidney cysts
- name: SEC61B-related ADPLD
  subtype_term:
    preferred_term: SEC61B-related polycystic liver disease
    term:
      id: MONDO:0550003
      label: SEC61B-related polycystic liver disease
  description: >-
    Rare loss-of-function and start-loss variants were identified in two PCLD probands; cell
    knockouts and rescue support impaired polycystin-1 biogenesis. The small discovery series
    does not define universal severity or penetrance.
  genes:
  - preferred_term: SEC61B
    term:
      id: hgnc:16993
      label: SEC61B
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.
    explanation: >-
      Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts
      and functional assays contribute different levels of support.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Somatic inactivation in biliary cyst epithelium
  description: >-
    Acquired loss of the remaining functional PRKCSH or SEC63 allele can deepen a germline defect
    in focal cyst epithelium. Detection is gene-, tissue- and assay-dependent; human data do
    not demonstrate a detected second hit in every cyst or directly establish its time of initiation.
  genes:
  - preferred_term: PRKCSH
    term:
      id: hgnc:9411
      label: PRKCSH
  - preferred_term: SEC63
    term:
      id: hgnc:21082
      label: SEC63
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  downstream:
  - target: Impaired ER protein biogenesis
    description: Loss of remaining gene function disrupts ER protein processing.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:21856269
    reference_title: >-
      Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant
      polycystic liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The wild-type allele of PRKCSH was lost (LOH) in 76% of cysts (54/71).
    explanation: >-
      Laser-microdissected cyst epithelia from eight surgical patients; this is a cyst-level
      result, not penetrance in carriers.
    quote_role: PRIMARY_RESULT
  - reference: PMID:23209713
    reference_title: Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found LOH in one of the 14 cysts of patient #3, while somatic mutations were conspicuously absent from samples from the other 2 patients (38 cysts)."
    explanation: >-
      Only the patient with 14 cysts carried a convincing truncating allele. The other two shared
      a variant not enriched in cases; formalin fixation prevented complete somatic sequencing
      in the truncating-allele patient.
    quote_role: PRIMARY_RESULT
- name: Impaired ER protein biogenesis
  description: >-
    PRKCSH and GANAB encode glucosidase II subunits, ALG8 participates in N-glycan precursor
    synthesis, and SEC63/SEC61B participate in protein translocation. Their loss affects ER
    protein handling, with gene-specific glycosylation and stress responses.
  genes:
  - preferred_term: PRKCSH
    term:
      id: hgnc:9411
      label: PRKCSH
  - preferred_term: SEC63
    term:
      id: hgnc:21082
      label: SEC63
  - preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  - preferred_term: GANAB
    term:
      id: hgnc:4138
      label: GANAB
  - preferred_term: SEC61B
    term:
      id: hgnc:16993
      label: SEC61B
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  downstream:
  - target: Impaired polycystin-1 maturation
    description: Disrupted ER processing reduces mature polycystin-1 availability.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28375157
      reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We inactivated these candidate genes in cell line models to show that loss of function
        of each results in defective maturation and trafficking of polycystin-1
      explanation: >-
        CRISPR knockouts and rescue in immortalized mouse renal epithelial cells carrying a
        tagged Pkd1 BAC; not direct experiments in patient cholangiocytes.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We inactivated these candidate genes in cell line models to show that loss of function
      of each results in defective maturation and trafficking of polycystin-1
    explanation: >-
      CRISPR knockouts and rescue in immortalized mouse renal epithelial cells carrying a tagged
      Pkd1 BAC; not direct experiments in patient cholangiocytes.
    quote_role: PRIMARY_RESULT
- name: Impaired polycystin-1 maturation
  description: >-
    PC1 maturation and export are impaired. ALG8 knockout causes hypoglycosylation; GANAB knockout
    impairs glucose trimming; SEC61B loss markedly reduces PC1 abundance. Cell-model differences
    should not be treated as quantitative predictors of patient liver severity.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  biological_processes:
  - preferred_term: polycystin-1 maturation
    term:
      id: GO:0051604
      label: protein maturation
    modifier: DECREASED
  downstream:
  - target: Reduced functional polycystin-1 dosage
    description: Defective maturation and trafficking diminish effective PC1 activity.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We inactivated these candidate genes in cell line models to show that loss of function
      of each results in defective maturation and trafficking of polycystin-1
    explanation: >-
      CRISPR knockouts and rescue in immortalized mouse renal epithelial cells carrying a tagged
      Pkd1 BAC; not direct experiments in patient cholangiocytes.
    quote_role: PRIMARY_RESULT
- name: Reduced functional polycystin-1 dosage
  description: >-
    Reduced functional PC1 dosage permits cystogenesis; conditional mouse rescue identifies
    PC1 as a limiting component. Bile-duct and kidney-tubule thresholds differ, but the complete
    downstream signaling sequence in human ADPLD is unresolved.
  downstream:
  - target: Cholangiocyte proliferation
    description: PC1 deficiency permits epithelial growth through incompletely resolved signaling.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hepatic cyst expansion
    description: Reduced PC1 activity permits biliary cyst formation and growth.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21685914
      reference_title: >-
        A genetic interaction network of five genes for human polycystic kidney and liver diseases
        defines polycystin-1 as the central determinant of cyst formation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Pkd1, but not Pkd2, overexpression completely abrogated the ADPLD liver cystic phenotype
      explanation: >-
        Male conditional Prkcsh mice, examined eight weeks after induction. Kidney rescue later
        became incomplete, emphasizing tissue, time and dosage dependence.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:21685914
    reference_title: >-
      A genetic interaction network of five genes for human polycystic kidney and liver diseases
      defines polycystin-1 as the central determinant of cyst formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Pkd1, but not Pkd2, overexpression completely abrogated the ADPLD liver cystic phenotype
    explanation: >-
      Male conditional Prkcsh mice, examined eight weeks after induction. Kidney rescue later
      became incomplete, emphasizing tissue, time and dosage dependence.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We inactivated these candidate genes in cell line models to show that loss of function
      of each results in defective maturation and trafficking of polycystin-1
    explanation: >-
      CRISPR knockouts and rescue in immortalized mouse renal epithelial cells carrying a tagged
      Pkd1 BAC; not direct experiments in patient cholangiocytes.
    quote_role: PRIMARY_RESULT
- name: PKHD1-associated biliary cyst formation
  description: >-
    Some monoallelic PKHD1 carriers develop liver-predominant cysts. Fibrocystin signaling is incompletely
    resolved and should not be forced into the ER maturation pathway: Pkhd1-null renal cells retained PC1 abundance
    and ciliary localization. The causal genetic assignment is incompletely penetrant; the intervening cellular
    mechanism remains uncertain.
  genes:
  - preferred_term: PKHD1
    term:
      id: hgnc:9016
      label: PKHD1
  downstream:
  - target: Hepatic cyst expansion
    description: PKHD1 carrier status can predispose to biliary cysts through unresolved intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal
      recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can
      present with clinical PCLD.
    explanation: >-
      Nine loss-of-function alleles plus one known ARPKD missense allele in the 102-case discovery
      cohort; not all rare PKHD1 missense variants are established causes.
    quote_role: PRIMARY_RESULT
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PKHD1 acts by a different mechanism than the protein biogenetic pathway impacted by the other PCLD genes.
    explanation: Two independently derived Pkhd1-null cell lines retained PC1 processing and ciliary localization.
    quote_role: PRIMARY_RESULT
- name: Increased cholangiocyte cAMP signaling
  description: >-
    cAMP promotes biliary epithelial proliferation and fluid secretion. Somatostatin receptors
    offer a way to reduce this signaling; trial efficacy does not establish every upstream molecular
    step.
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  downstream:
  - target: Cholangiocyte proliferation
    description: cAMP signaling promotes cyst-lining epithelial growth.
    causal_link_type: DIRECT
  - target: Cyst epithelial fluid secretion
    description: cAMP-dependent transport promotes fluid accumulation.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41328663
    reference_title: >-
      Medical Management of Polycystic Liver Disease: A Position Statement From the European
      Reference Network on Hepatological Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SSAs inhibit cAMP, reducing fluid secretion and cell proliferation.
    explanation: Current position statement synthesizes the pharmacologic pathway.
    quote_role: REVIEW_SYNTHESIS
- name: Cholangiocyte proliferation
  description: Expansion of cyst-lining biliary epithelial cells contributes to growing hepatic cyst walls.
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  biological_processes:
  - preferred_term: epithelial cell proliferation
    term:
      id: GO:0050673
      label: epithelial cell proliferation
    modifier: INCREASED
  downstream:
  - target: Hepatic cyst expansion
    description: Epithelial proliferation expands the cyst wall.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41328663
    reference_title: >-
      Medical Management of Polycystic Liver Disease: A Position Statement From the European
      Reference Network on Hepatological Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SSAs inhibit cAMP, reducing fluid secretion and cell proliferation.
    explanation: Mechanistic synthesis distinguishes epithelial proliferation from luminal secretion.
    quote_role: REVIEW_SYNTHESIS
- name: Cyst epithelial fluid secretion
  description: cAMP-dependent anion and water secretion expands the lumen of biliary epithelial cysts.
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  downstream:
  - target: Hepatic cyst expansion
    description: Fluid accumulation enlarges the cyst lumen.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41328663
    reference_title: >-
      Medical Management of Polycystic Liver Disease: A Position Statement From the European
      Reference Network on Hepatological Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Biliary epithelia regulate cAMP‐dependent Cl and HCO3 secretion, facilitating fluid accumulation.
    explanation: Position statement connects biliary epithelial transport to cyst-fluid accumulation.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatic cyst expansion
  description: >-
    Progressive enlargement of noncommunicating biliary epithelial cysts increases liver volume.
    The relative contribution of developmental remnants and adult-onset cyst initiation can
    vary.
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Polycystic liver disease
    description: Multiple hepatic cysts define the phenotype.
    causal_link_type: DIRECT
  - target: Hepatic mass effect
    description: Increasing cyst volume enlarges the liver and compresses adjacent structures.
    causal_link_type: DIRECT
  - target: Hepatic cyst hemorrhage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Existing hepatic cysts provide the substrate for this secondary complication; cyst enlargement alone is not sufficient, and precipitating events vary.
    evidence:
    - reference: PMID:24886261
      reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Intrahepatic cyst bleeding typically presents as acute pain in the upper right-side of the abdomen.
      explanation: The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
  - target: Hepatic cyst infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Existing hepatic cysts provide the substrate for this secondary complication; cyst enlargement alone is not sufficient, and precipitating events vary.
    evidence:
    - reference: PMID:24886261
      reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Cyst infections are a serious complication because of its indolent course, demanding treatment and high risk of recurrence.
      explanation: The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
  - target: Hepatic cyst rupture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Existing hepatic cysts provide the substrate for this secondary complication; cyst enlargement alone is not sufficient, and precipitating events vary.
    evidence:
    - reference: PMID:24886261
      reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Cyst rupture is an exceptional rare complication and presents with acute onset of pain.
      explanation: The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PLD is a non-communicating biliary tree disorder and should be differentiated from other
      neoplastic, infectious and traumatic conditions
    explanation: Review distinguishes disconnected cysts from communicating duct abnormalities.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:35487607
    reference_title: Polycystic Kidney/Liver Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Though isolated PCLD and PCLD due to ADPKD are genetically distinct, they follow a similar
      clinical course of hepatomegaly from multiple cysts with preserved liver function.
    explanation: The review supports the core clinical course of hepatomegaly with preserved liver function.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: Liver cysts in both PCLD and ADPKD are lined with biliary epithelium.
    explanation: Introductory histologic synthesis in the gene-discovery paper supports the biliary epithelial origin.
- name: Hepatic mass effect
  description: >-
    Large cyst burden produces hepatomegaly, capsular tension and compression of adjacent organs.
    Synthetic liver function can remain preserved despite severe symptoms.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Hepatomegaly
    causal_link_type: DIRECT
    description: Progressive hepatic cyst expansion enlarges the liver.
  - target: Abdominal distention
    causal_link_type: DIRECT
    description: Enlarged cystic liver volume produces abdominal distention.
  - target: Early satiety
    causal_link_type: DIRECT
    description: Compression from marked liver enlargement causes early satiety.
  - target: Abdominal pain
    causal_link_type: DIRECT
    description: Voluminous hepatic cysts and compression cause abdominal pain.
  - target: Dyspnea
    causal_link_type: DIRECT
    description: Marked hepatomegaly can mechanically impair breathing.
  - target: Gastroesophageal reflux
    causal_link_type: DIRECT
    description: Upper gastrointestinal compression can produce reflux symptoms.
  - target: Back pain
    causal_link_type: DIRECT
    description: Mechanical back pain can result from massive liver enlargement.
  - target: Hepatic vascular compression
    description: Expanding cysts compress vessels.
    causal_link_type: DIRECT
  - target: Biliary compression
    description: Strategic cysts compress bile ducts.
    causal_link_type: DIRECT
  - target: Reduced nutritional intake
    description: Gastric compression and early satiety reduce intake.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35487607
    reference_title: Polycystic Kidney/Liver Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Though isolated PCLD and PCLD due to ADPKD are genetically distinct, they follow a similar
      clinical course of hepatomegaly from multiple cysts with preserved liver function.
    explanation: The review supports the core clinical course of hepatomegaly with preserved liver function.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Major complaints include abdominal pain, abdominal distension and atypical symptoms because
      of voluminous cysts resulting in compression of adjacent tissue or failure of the affected
      organ.
    explanation: The review supports mass-effect symptoms from voluminous cysts.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatic vascular compression
  description: >-
    Cysts can compress hepatic veins, the portal circulation or the inferior vena cava. Venous
    obstruction can produce portal hypertension, ascites and peripheral edema without primary
    cirrhosis.
  downstream:
  - target: Portal hypertension
    description: Hepatic venous or portal obstruction increases portal pressure.
    causal_link_type: DIRECT
  - target: Ascites
    description: Venous obstruction can promote ascites.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pedal edema
    description: Vena-caval or venous compression impedes lower-extremity drainage.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In advanced stages there are 2 processes that may lead up to portal hypertension. First,
      there is reduction of hepatic vein outflow. Secondly, portal vein inflow may be compressed
      in advanced disease due to the volume effect of cysts.
    explanation: Clinical synthesis supports compression mechanisms in advanced PLD.
    quote_role: REVIEW_SYNTHESIS
- name: Biliary compression
  description: >-
    Strategically located cysts can obstruct bile ducts, producing jaundice or cholestatic abnormalities;
    this is an uncommon complication rather than universal loss of synthetic function.
  downstream:
  - target: Jaundice
    description: Biliary obstruction can cause jaundice.
    causal_link_type: DIRECT
  - target: Hyperbilirubinemia
    description: Impaired bile drainage can elevate bilirubin.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: An uncommon cause of jaundice is obstruction of the intrahepatic or extrahepatic bile ducts by hepatic cysts
    explanation: Review specifically supports the obstructive route to jaundice.
    quote_role: REVIEW_SYNTHESIS
- name: Reduced nutritional intake
  description: >-
    Gastric compression and early satiety limit food intake in severe disease, causing malnutrition
    and loss of muscle mass. Liver weight can obscure body-weight loss.
  downstream:
  - target: Malnutrition
    description: Insufficient intake causes malnutrition.
    causal_link_type: DIRECT
  - target: Skeletal muscle atrophy
    description: Prolonged nutritional compromise contributes to muscle wasting.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  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: OTHER
    snippet: >-
      Patients reduce their meal size because of early satiety and malnutrition eventually leads
      to muscle mass loss and sarcopenia.
    explanation: EASL describes the nutritional consequence of severe mass effect.
    quote_role: REVIEW_SYNTHESIS
genetic:
- name: Heterozygous PRKCSH pathogenic variants
  gene_term:
    preferred_term: PRKCSH
    term:
      id: hgnc:9411
      label: PRKCSH
  association: Causative
  relationship_type: CAUSATIVE
  features: >-
    Loss-of-function alleles, including nonsense, frameshift and splice variants, impair the
    glucosidase II beta subunit. Somatic loss of the remaining allele has been demonstrated
    in human cyst epithelium; severity and age of expression vary.
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: PRKCSH | PRKCSH beta subunit of glucosidase II | hgnc:9411 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists PRKCSH as a disease-causing gene.
  - reference: PMID:38097330
    reference_title: Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The two major genes are PRKCSH and SEC63
    explanation: The genetics review identifies PRKCSH as a major ADPLD gene.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21856269
    reference_title: >-
      Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant
      polycystic liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The wild-type allele of PRKCSH was lost (LOH) in 76% of cysts (54/71).
    explanation: >-
      Laser-microdissected cyst epithelia from eight surgical patients; this is a cyst-level
      result, not penetrance in carriers.
    quote_role: PRIMARY_RESULT
  variant_origin: GERMLINE
- name: Heterozygous SEC63 pathogenic variants
  gene_term:
    preferred_term: SEC63
    term:
      id: hgnc:21082
      label: SEC63
  association: Causative
  relationship_type: CAUSATIVE
  features: >-
    Loss-of-function variants impair an ER protein-translocation cofactor. Individual in-frame
    or missense variants need independent classification: the historical c.1703_1705delAAG allele
    was not enriched over controls in a re-evaluation and should not be treated as pathogenic
    from an old report alone.
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SEC63 | SEC63 protein translocation regulator | hgnc:21082 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists SEC63 as a disease-causing gene.
  - reference: PMID:38097330
    reference_title: Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The two major genes are PRKCSH and SEC63
    explanation: The genetics review identifies SEC63 as a major ADPLD gene.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:23209713
    reference_title: Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found LOH in one of the 14 cysts of patient #3, while somatic mutations were conspicuously absent from samples from the other 2 patients (38 cysts)."
    explanation: >-
      Only the patient with 14 cysts carried a convincing truncating allele. The other two shared
      a variant not enriched in cases; formalin fixation prevented complete somatic sequencing
      in the truncating-allele patient.
    quote_role: PRIMARY_RESULT
  variant_origin: GERMLINE
- name: Heterozygous ALG8 pathogenic variants
  gene_term:
    preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  association: Causative
  relationship_type: CAUSATIVE
  features: >-
    Monoallelic loss-of-function variants produce variably penetrant kidney/liver cystic disease,
    sometimes severe liver-predominant disease. Biallelic ALG8 disease is a congenital disorder
    of glycosylation and is a different phenotype.
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ALG8 | ALG8 alpha-1,3-glucosyltransferase | hgnc:23161 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists ALG8 as a disease-causing gene.
  - reference: PMID:29038287
    reference_title: Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ADPLD (PRKCSH, SEC63, LRP5, ALG8, and SEC61B)
    explanation: The genetics review includes ALG8 among reported ADPLD genes.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.
    explanation: >-
      Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts
      and functional assays contribute different levels of support.
    quote_role: PRIMARY_RESULT
  variant_origin: GERMLINE
- name: Reported LRP5 association
  gene_term:
    preferred_term: LRP5
    term:
      id: hgnc:6697
      label: LRP5
  association: Reported association with contested causal attribution
  relationship_type: DISPUTED
  features: >-
    Initial linkage, rare missense variants and in-vitro Wnt assays support an association,
    but later work noted that nearby GANAB lies within the same linked interval. Re-evaluation
    of coding and noncoding GANAB sequence in the original family was requested. This does not
    prove that the original family has a GANAB variant or that LRP5 is definitively refuted.
    Bone-disease LRP5 gain-of-function mechanisms must not be transferred to this claim.
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: LRP5 | LDL receptor related protein 5 | hgnc:6697 | Disease-causing germline mutation(s) in
    explanation: Orphanet lists LRP5 as a disease-causing gene.
  - reference: PMID:29038287
    reference_title: Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ADPLD (PRKCSH, SEC63, LRP5, ALG8, and SEC61B)
    explanation: The genetics review includes LRP5 among reported ADPLD genes.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24706814
    reference_title: Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation.
    explanation: >-
      Original study reports altered Wnt signaling for the liver-associated variants; this differs
      from high-bone-mass LRP5 gain of function.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29243290
    reference_title: A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the close proximity of LRP5 and GANAB on chromosome 11 precludes the use of linkage or
      segregation analyses alone to distinguish the disease genes in this region.
    explanation: >-
      Authors question causal attribution in the earlier LRP5 pedigree. Their own GANAB family
      is distinct; the original LRP5 family was not shown to carry a GANAB mutation.
  variant_origin: GERMLINE
- name: Heterozygous GANAB pathogenic variants
  gene_term:
    preferred_term: GANAB
    term:
      id: hgnc:4138
      label: GANAB
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.
    explanation: >-
      Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts
      and functional assays contribute different levels of support.
    quote_role: PRIMARY_RESULT
  - reference: PMID:29243290
    reference_title: A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The RT-PCR product from the family T90 mutant minigene instead showed 100% skipping of the 101 bp exon 24
    explanation: >-
      GANAB NM_198335.3:c.2791+4_2791+12delAGTGACCAA was tested in HEK cells and healthy-donor
      primary human cholangiocytes using constructs. Exon skipping predicts a frameshift; this
      is not patient RNA or evidence for a separate enhancer target.
    quote_role: PRIMARY_RESULT
  variant_origin: GERMLINE
  features: >-
    Loss-of-function variants affect glucosidase II alpha and can produce liver-predominant
    disease or mild cystic kidney disease. A splice-region deletion outside canonical splice
    dinucleotides segregated in five affected siblings and caused exon skipping in minigene
    assays; a negative coding-only analysis can miss such alleles.
- name: Heterozygous SEC61B pathogenic variants
  gene_term:
    preferred_term: SEC61B
    term:
      id: hgnc:16993
      label: SEC61B
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B.
    explanation: >-
      Discovery cohort of 102 PRKCSH/SEC63-unexplained probands; gene burden, independent cohorts
      and functional assays contribute different levels of support.
    quote_role: PRIMARY_RESULT
  variant_origin: GERMLINE
  features: >-
    Rare loss-of-function and start-loss variants were identified in two PCLD probands; cell
    knockouts and rescue support impaired polycystin-1 biogenesis. The small discovery series
    does not define universal severity or penetrance.
- name: Heterozygous PKHD1 pathogenic variants
  gene_term:
    preferred_term: PKHD1
    term:
      id: hgnc:9016
      label: PKHD1
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant inheritance
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal
      recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can
      present with clinical PCLD.
    explanation: >-
      Nine loss-of-function alleles plus one known ARPKD missense allele in the 102-case discovery
      cohort; not all rare PKHD1 missense variants are established causes.
    quote_role: PRIMARY_RESULT
  variant_origin: GERMLINE
  features: >-
    Monoallelic pathogenic PKHD1 variants are enriched in liver-predominant cystic disease,
    often with small cysts and limited renal involvement. Penetrance is incomplete. This is
    distinct from biallelic ARPKD and its congenital hepatic fibrosis; the mechanism does not
    appear to be the same PC1 maturation defect as the ER genes.
phenotypes:
- category: Hepatic
  name: Polycystic liver disease
  frequency: VERY_FREQUENT
  description: Numerous liver cysts are the defining manifestation.
  phenotype_term:
    preferred_term: Polycystic liver disease
    term:
      id: HP:0006557
      label: Polycystic liver disease
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0006557 | Polycystic liver disease | Very frequent (99-80%)
    explanation: Orphanet lists polycystic liver disease as very frequent.
  - reference: PMID:36246085
    reference_title: Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Polycystic liver disease (PLD) manifests as numerous fluid-filled cysts scattered throughout the liver parenchyma.
    explanation: Human cohort framing supports numerous liver cysts as the core phenotype.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Hepatic
  name: Hepatomegaly
  frequency: VERY_FREQUENT
  description: Multiple cysts enlarge the liver.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0002240 | Hepatomegaly | Very frequent (99-80%)
    explanation: Orphanet lists hepatomegaly as very frequent.
  - reference: PMID:35487607
    reference_title: Polycystic Kidney/Liver Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: they follow a similar clinical course of hepatomegaly from multiple cysts with preserved liver function.
    explanation: The review directly links PCLD to hepatomegaly from multiple cysts.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Gastrointestinal
  name: Abdominal distention
  frequency: VERY_FREQUENT
  description: Enlarged polycystic liver volume causes abdominal distention.
  phenotype_term:
    preferred_term: Abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0003270 | Abdominal distention | Very frequent (99-80%)
    explanation: Orphanet lists abdominal distention as very frequent.
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Major complaints include abdominal pain, abdominal distension and atypical symptoms because
      of voluminous cysts resulting in compression of adjacent tissue or failure of the affected
      organ.
    explanation: The review names abdominal distension among major complaints.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Renal
  name: Multiple renal cysts
  frequency: FREQUENT
  description: Kidney cysts can occur in ADPLD, though kidney involvement is limited compared with ADPKD.
  phenotype_term:
    preferred_term: Multiple renal cysts
    term:
      id: HP:0005562
      label: Multiple renal cysts
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0005562 | Multiple renal cysts | Frequent (79-30%)
    explanation: Orphanet lists multiple renal cysts as frequent in this ADPLD record.
  - reference: PMID:29038287
    reference_title: Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: autosomal dominant polycystic liver diseases (ADPLD), which result in significant PLD with minimal PKD.
    explanation: The genetics review supports limited kidney cyst involvement in ADPLD.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers. Renal involvement varies by gene and age; an ADPKD
    prognosis cannot be inferred from a few renal cysts.
- category: Gastrointestinal
  name: Early satiety
  frequency: FREQUENT
  description: Liver mass effect can cause early fullness with meals.
  phenotype_term:
    preferred_term: Early satiety
    term:
      id: HP:0033842
      label: Early satiety
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0033842 | Early satiety | Frequent (79-30%)
    explanation: Orphanet lists early satiety as frequent.
  - reference: PMID:27016902
    reference_title: >-
      Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst
      Fenestration for Massive Polycystic Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Indications for surgery were abdominal distention, abdominal pain, early satiety, supine
      dyspnea, fatigue, uterine pro-lapse, hepatic venous outflow obstruction with ascites,
      obstruction of the inferior vena cava and dialysis hypotension, bile duct obstruction,
      and infected cysts.
    explanation: The surgical cohort includes early satiety among symptomatic PLD indications for surgery.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Gastrointestinal
  name: Abdominal pain
  frequency: OCCASIONAL
  description: Cystic liver enlargement and compression can cause abdominal pain.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0002027 | Abdominal pain | Occasional (29-5%)
    explanation: Orphanet lists abdominal pain as occasional.
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Major complaints include abdominal pain, abdominal distension and atypical symptoms because
      of voluminous cysts resulting in compression of adjacent tissue or failure of the affected
      organ.
    explanation: The review names abdominal pain among major complaints.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified estimate for
    unselected variant carriers. The reviews describe pain as a major complaint among symptomatic patients;
    that clinical prominence does not provide a conflicting numerical frequency for all carriers.
- category: Respiratory
  name: Dyspnea
  frequency: OCCASIONAL
  description: Massive hepatomegaly can mechanically impair breathing, especially supine.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0002094 | Dyspnea | Occasional (29-5%)
    explanation: Orphanet lists dyspnea as occasional.
  - reference: PMID:27016902
    reference_title: >-
      Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst
      Fenestration for Massive Polycystic Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea,
      early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction,
      portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression.
    explanation: >-
      Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured
      ADPLD-specific frequency or new mechanistic experiment.
    quote_role: BACKGROUND
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Respiratory
  name: Respiratory insufficiency
  frequency: OCCASIONAL
  description: >-
    Reported in the Orphanet disease catalog; the cited catalog does not establish a specific
    causal mechanism or a screening indication.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0002093 | Respiratory insufficiency | Occasional (29-5%)
    explanation: Orphanet lists respiratory insufficiency as occasional.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  frequency: OCCASIONAL
  description: Liver enlargement can compress adjacent upper gastrointestinal structures.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0002020 | Gastroesophageal reflux | Occasional (29-5%)
    explanation: Orphanet lists gastroesophageal reflux as occasional.
  - reference: PMID:27016902
    reference_title: >-
      Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst
      Fenestration for Massive Polycystic Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea,
      early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction,
      portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression.
    explanation: >-
      Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured
      ADPLD-specific frequency or new mechanistic experiment.
    quote_role: BACKGROUND
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Musculoskeletal
  name: Back pain
  frequency: OCCASIONAL
  description: Mechanical back pain can result from massive liver enlargement.
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0003418 | Back pain | Occasional (29-5%)
    explanation: Orphanet lists back pain as occasional.
  - reference: PMID:27016902
    reference_title: >-
      Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst
      Fenestration for Massive Polycystic Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea,
      early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction,
      portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression.
    explanation: >-
      Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured
      ADPLD-specific frequency or new mechanistic experiment.
    quote_role: BACKGROUND
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Hepatic
  name: Jaundice
  frequency: OCCASIONAL
  description: Bile duct compression can rarely cause jaundice.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000952 | Jaundice | Occasional (29-5%)
    explanation: Orphanet lists jaundice as occasional.
  - reference: PMID:27016902
    reference_title: >-
      Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst
      Fenestration for Massive Polycystic Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic enlargement causes liver enlargement, which can be marked and result in dyspnea,
      early satiety, gastroesophageal reflux, mechanical back pain, hepatic venous outflow obstruction,
      portal vein and inferior vena cava compression, and, rarely, jaundice from bile duct compression.
    explanation: >-
      Introductory clinical synthesis in a predominantly ADPKD surgical cohort; not a measured
      ADPLD-specific frequency or new mechanistic experiment.
    quote_role: BACKGROUND
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Hepatic
  name: Elevated alkaline phosphatase
  frequency: OCCASIONAL
  description: Cholestatic enzyme elevation can occur in a subset of patients.
  phenotype_term:
    preferred_term: Elevated alkaline phosphatase
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0003155 | Elevated circulating alkaline phosphatase concentration | Occasional (29-5%)
    explanation: Orphanet lists elevated alkaline phosphatase as occasional.
  reports_on:
  - target: Hepatic cyst expansion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: This laboratory finding can accompany PLD but is not a validated measure of cyst growth or mass-effect severity.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Hepatic
  name: Elevated gamma-glutamyltransferase
  frequency: OCCASIONAL
  description: GGT elevation can occur in a subset of patients.
  phenotype_term:
    preferred_term: Elevated gamma-glutamyltransferase
    term:
      id: HP:0030948
      label: Elevated gamma-glutamyltransferase level
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0030948 | Elevated gamma-glutamyltransferase level | Occasional (29-5%)
    explanation: Orphanet lists elevated gamma-glutamyltransferase as occasional.
  reports_on:
  - target: Hepatic cyst expansion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: This laboratory finding can accompany PLD but is not a validated measure of cyst growth or mass-effect severity.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Hepatic
  name: Hyperbilirubinemia
  frequency: OCCASIONAL
  description: Increased total bilirubin can occur in a subset of patients.
  phenotype_term:
    preferred_term: Increased total bilirubin
    term:
      id: HP:0003573
      label: Increased total bilirubin
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0003573 | Increased total bilirubin | Occasional (29-5%)
    explanation: Orphanet lists increased total bilirubin as occasional.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Gastrointestinal
  name: Gastrointestinal hemorrhage
  frequency: OCCASIONAL
  description: >-
    Reported in the Orphanet disease catalog; the cited catalog does not establish a specific
    causal mechanism or a screening indication.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0002239 | Gastrointestinal hemorrhage | Occasional (29-5%)
    explanation: Orphanet lists gastrointestinal hemorrhage as occasional.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Cardiovascular
  name: Pedal edema
  frequency: OCCASIONAL
  description: Venous compression and advanced mass effect can cause lower-extremity edema.
  phenotype_term:
    preferred_term: Pedal edema
    term:
      id: HP:0010741
      label: Pedal edema
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0010741 | Pedal edema | Occasional (29-5%)
    explanation: Orphanet lists pedal edema as occasional.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Vascular
  name: Dilatation of the cerebral artery
  frequency: OCCASIONAL
  description: >-
    Reported in the Orphanet disease catalog; the cited catalog does not establish a specific
    causal mechanism or a screening indication.
  phenotype_term:
    preferred_term: Dilatation of the cerebral artery
    term:
      id: HP:0004944
      label: Dilatation of the cerebral artery
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0004944 | Dilatation of the cerebral artery | Occasional (29-5%)
    explanation: Orphanet lists cerebral artery dilatation as occasional.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers. ADPKD aneurysm screening recommendations are not
    automatically applicable to isolated ADPLD.
- category: Cardiovascular
  name: Abnormal heart valve morphology
  frequency: OCCASIONAL
  description: >-
    Reported in the Orphanet disease catalog; the cited catalog does not establish a specific
    causal mechanism or a screening indication.
  phenotype_term:
    preferred_term: Abnormal heart valve morphology
    term:
      id: HP:0001654
      label: Abnormal heart valve morphology
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0001654 | Abnormal heart valve morphology | Occasional (29-5%)
    explanation: Orphanet lists abnormal heart valve morphology as occasional.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- category: Gastrointestinal
  name: Abnormality of the pancreas
  frequency: OCCASIONAL
  description: >-
    Reported in the Orphanet disease catalog; the cited catalog does not establish a specific
    causal mechanism or a screening indication.
  phenotype_term:
    preferred_term: Abnormality of the pancreas
    term:
      id: HP:0001732
      label: Abnormality of the pancreas
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: ORPHA:2924
    reference_title: Isolated polycystic liver disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0001732 | Abnormality of the pancreas | Occasional (29-5%)
    explanation: Orphanet lists pancreatic abnormalities as occasional.
  notes: >-
    Frequency is inherited from the Orphanet catalog and is not a prospective, age-stratified
    estimate for unselected variant carriers.
- name: Portal hypertension
  category: Hepatic
  description: Complication of severe symptomatic PLD; no population-wide frequency is inferred.
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  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: OTHER
    snippet: These patients develop portal hypertension and ascites and/or hepatic hydrothorax.
    explanation: EASL describes a complication of advanced PLD rather than a universal finding.
    quote_role: REVIEW_SYNTHESIS
- name: Ascites
  category: Hepatic
  description: Complication of severe symptomatic PLD; no population-wide frequency is inferred.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  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: OTHER
    snippet: These patients develop portal hypertension and ascites and/or hepatic hydrothorax.
    explanation: EASL describes a complication of advanced PLD rather than a universal finding.
    quote_role: REVIEW_SYNTHESIS
- name: Malnutrition
  category: Gastrointestinal
  description: Complication of severe symptomatic PLD; no population-wide frequency is inferred.
  phenotype_term:
    preferred_term: Malnutrition
    term:
      id: HP:0004395
      label: Malnutrition
  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: OTHER
    snippet: >-
      Patients reduce their meal size because of early satiety and malnutrition eventually leads
      to muscle mass loss and sarcopenia.
    explanation: EASL describes a complication of advanced PLD rather than a universal finding.
    quote_role: REVIEW_SYNTHESIS
- name: Skeletal muscle atrophy
  category: Musculoskeletal
  description: Complication of severe symptomatic PLD; no population-wide frequency is inferred.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  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: OTHER
    snippet: >-
      Patients reduce their meal size because of early satiety and malnutrition eventually leads
      to muscle mass loss and sarcopenia.
    explanation: EASL describes a complication of advanced PLD rather than a universal finding.
    quote_role: REVIEW_SYNTHESIS
- name: Hepatic cyst hemorrhage
  category: Hepatic
  description: Bleeding into a hepatic cyst may cause sudden right upper abdominal pain. This is a complication of existing cysts, with no ADPLD-specific frequency established here.
  phenotype_term:
    preferred_term: Hepatic cyst hemorrhage
  notes: Needs a specific HPO term. OLS HP searches for hepatic cyst hemorrhage, hepatic cyst infection, hepatic cyst rupture, liver hemorrhage, hepatic hemorrhage, liver infection, liver abscess and cyst rupture found no equivalent term. Liver abscess and unusual liver infection have different definitions and are not substituted for infection of a pre-existing cyst.
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Intrahepatic cyst bleeding typically presents as acute pain in the upper right-side of the abdomen.
    explanation: The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
- name: Hepatic cyst infection
  category: Hepatic
  description: Secondary infection of an existing hepatic cyst can cause pain, fever and systemic inflammation. It may recur and requires assessment and targeted management; it is a complication of genetic ADPLD.
  phenotype_term:
    preferred_term: Hepatic cyst infection
  notes: Needs a specific HPO term. OLS HP searches for hepatic cyst hemorrhage, hepatic cyst infection, hepatic cyst rupture, liver hemorrhage, hepatic hemorrhage, liver infection, liver abscess and cyst rupture found no equivalent term. Liver abscess and unusual liver infection have different definitions and are not substituted for infection of a pre-existing cyst.
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Cyst infections are a serious complication because of its indolent course, demanding treatment and high risk of recurrence.
    explanation: The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
- name: Hepatic cyst rupture
  category: Hepatic
  description: Rare rupture of a hepatic cyst can cause acute pain and peritoneal fluid leakage; bleeding can occasionally cause hemodynamic compromise.
  phenotype_term:
    preferred_term: Hepatic cyst rupture
  notes: Needs a specific HPO term. OLS HP searches for hepatic cyst hemorrhage, hepatic cyst infection, hepatic cyst rupture, liver hemorrhage, hepatic hemorrhage, liver infection, liver abscess and cyst rupture found no equivalent term. Liver abscess and unusual liver infection have different definitions and are not substituted for infection of a pre-existing cyst.
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Cyst rupture is an exceptional rare complication and presents with acute onset of pain.
    explanation: The review discusses this complication in PCLD and ADPKD; no mixed-cohort frequency is assigned to isolated ADPLD.
diagnosis:
- name: Abdominal ultrasonography
  description: >-
    Ultrasound establishes cyst distribution in liver and kidneys. EASL uses more than ten hepatic
    cysts as a general PLD criterion; family-based criteria may recognize younger at-risk relatives
    with fewer cysts. Liver cysts alone do not distinguish ADPLD from liver-predominant ADPKD.
    Cyst morphology and communication with the biliary tree guide alternative diagnoses.
  diagnosis_term:
    preferred_term: ultrasonography procedure
    term:
      id: NCIT:C19337
      label: Diagnostic Ultrasound
  evidence:
  - reference: PMID:23296249
    reference_title: Diagnosis and management of polycystic liver disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ultrasonography is very useful for achieving a correct diagnosis of a polycystic liver
      and to differentiate between ADPKD and PCLD.
    explanation: This review directly supports ultrasonography for diagnosis and differential separation.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Ultrasonography is the first instrument to assess liver phenotype.
    explanation: This review identifies ultrasonography as the first imaging instrument for liver phenotype assessment.
    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: OTHER
    snippet: Current diagnosis of PLD is made in the presence of >10 hepatic cysts.
    explanation: General guideline criterion; clinical family context remains important.
    quote_role: REVIEW_SYNTHESIS
- name: CT or MRI liver volume assessment
  description: >-
    CT or MRI defines cyst distribution, vascular compression, residual parenchyma and height-adjusted
    liver volume for treatment planning. Volume and symptom burden are separate measures. Age-adjusted
    progression estimates are promising but the 80-patient tertiary-center derivation cohort
    was retrospective, often relied on single imaging, included VUS in some analyses and requires
    external validation.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Total liver and kidney volumes can be measured and correlated with clinical endpoints.
  evidence:
  - reference: PMID:36246085
    reference_title: Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identified genotypes were correlated with total liver and kidney volume (assessed by CT
      or MRI), organ function, co-morbidities, and clinical endpoints.
    explanation: The cohort used CT or MRI liver-volume assessment for genotype-phenotype and outcome correlation.
  - reference: PMID:36246085
    reference_title: Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, most patients had single imaging only but no longitudinal imaging data,
      impeding intra-individual liver growth assessment.
    explanation: 'Full-text limitation: estimated growth from age and volume is not directly measured longitudinal growth.'
    quote_role: PRIMARY_RESULT
- name: Molecular genetic testing
  description: >-
    Use genetic counseling and an appropriate cystic kidney/liver panel when the phenotype,
    family history or reproductive question warrants clarification. Include deletion/duplication
    assessment and consider splice-region or other variants missed by routine coding analysis.
    A negative panel does not exclude ADPLD, and a VUS does not confirm it. Genetic testing
    is not routine screening for asymptomatic relatives solely to find liver cysts.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics.
    explanation: The review supports molecular diagnostics when imaging or screening is ambiguous.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38097330
    reference_title: Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      employing a next-generation sequencing panel containing all known PKD and ciliopathy genes
      is recommended for clinical testing.
    explanation: The genetics review supports broad NGS-panel clinical testing because of gene and phenotype overlap.
    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: OTHER
    snippet: Genetic testing should not be used to screen for PLD
    explanation: EASL distinguishes screening from diagnostic or reproductive use.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:29243290
    reference_title: A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family T90 variant was initially filtered out by our standard whole exome sequence
      analysis pipeline due to its intronic annotation.
    explanation: Full text demonstrates a specific coding-filter blind spot, not universal failure of exome sequencing.
    quote_role: PRIMARY_RESULT
- name: PLD symptom and nutritional assessment
  description: >-
    Assess PLD-Q or POLCA scores alongside imaging to attribute symptoms and monitor response.
    Evaluate intake, functional muscle loss and sarcopenia; a heavy cystic liver can mask weight
    loss. The 2026 suggested PROM and volume thresholds are consensus aids, not validated predictors
    of individual drug response.
  evidence:
  - reference: PMID:41328663
    reference_title: >-
      Medical Management of Polycystic Liver Disease: A Position Statement From the European
      Reference Network on Hepatological Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: However, so far there is no robust cut‐off level, that predicts response to SSA therapy in both scoring systems.
    explanation: Full-text caveat limits numerical PLD-Q/POLCA threshold interpretation.
    quote_role: REVIEW_SYNTHESIS
treatments:
- name: Somatostatin analogue therapy
  description: >-
    Long-acting octreotide or lanreotide can modestly reduce or stabilize liver volume in symptomatic
    diffuse PLD. These uses remain off-label as described in the 2026 ERN statement. Assess
    symptoms and consistent volumetry over 6–12 months; response can include symptom relief
    with volume stabilization. Benefit can persist during ongoing treatment for several years,
    while withdrawal can cause rebound. Monitor gastrointestinal intolerance, glucose disturbance,
    gallstones, injection reactions and cyst infection. Advanced kidney disease requires individualized
    dosing and caution; avoid during pregnancy or breastfeeding. Pasireotide has more glucose
    toxicity and is not first-line. Volume reduction does not establish prevention of transplantation
    or renal functional decline.
  treatment_term:
    preferred_term: Somatostatin analogue therapy
    term:
      id: NCIT:C15449
      label: Somatostatin Analog Therapy
    therapeutic_agent:
    - preferred_term: Somatostatin Receptor Agonist
      term:
        id: NCIT:C62799
        label: Somatostatin Receptor Agonist
    - preferred_term: Octreotide
      term:
        id: NCIT:C711
        label: Octreotide
    - preferred_term: Lanreotide
      term:
        id: NCIT:C1523
        label: Lanreotide
  evidence:
  - reference: PMID:41328663
    reference_title: >-
      Medical Management of Polycystic Liver Disease: A Position Statement From the European
      Reference Network on Hepatological Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Patients with liver volume‐related symptoms who have non‐localised disease should be considered for treatment.
    explanation: >-
      ERN 2026 consensus supports symptom- and distribution-based selection, not routine treatment
      of incidental asymptomatic cysts.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20431041
    reference_title: Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically
      unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048).
    explanation: >-
      One-year 42-patient randomized trial: 34 ADPKD and eight ADPLD. The overall volume effect
      is not an independently powered ADPLD subgroup estimate. Two SF-36 subdomains improved
      within the treated group; broad quality-of-life benefit was not uniform.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19646443
    reference_title: 'Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The mean liver volume decreased 2.9%, from 4606 mL
    explanation: >-
      Six-month randomized trial of 54 mixed ADPKD/ADPLD participants versus a 1.6% volume increase
      with placebo; genotype stratification was post hoc.
    quote_role: PRIMARY_RESULT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2900957/
    reference_title: >-
      Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic
      Kidney and Liver Disease - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The dose was reduced to 30 mg in seven and 20 mg in four patients receiving octreotide,
      mostly because of diarrhea/loose stools, especially in the first 2 weeks after an injection
    explanation: >-
      Full-text tolerability results limit the abstract statement that treatment was well tolerated;
      one participant also had persistent steatorrhea and weight loss.
    quote_role: PRIMARY_RESULT
  - reference: PMID:41328663
    reference_title: >-
      Medical Management of Polycystic Liver Disease: A Position Statement From the European
      Reference Network on Hepatological Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: There is currently no robust evidence suggesting that SSA mitigates progression to liver‐related endpoints in PLD.
    explanation: >-
      The clinical goal is symptom relief, with liver volume as a response measure; hard-outcome
      benefit remains unproved.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41328663
    reference_title: >-
      Medical Management of Polycystic Liver Disease: A Position Statement From the European
      Reference Network on Hepatological Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Early discontinuation can lead to rebound in both liver volume and disease‐related symptom
      burden within 3–4 months after withdrawal.
    explanation: >-
      Durability depends on ongoing treatment and natural history; the older blanket short-lived
      description is insufficient.
    quote_role: REVIEW_SYNTHESIS
  target_mechanisms:
  - target: Increased cholangiocyte cAMP signaling
    treatment_effect: INHIBITS
    description: Somatostatin signaling lowers cAMP-dependent secretion and growth.
  - target: Hepatic cyst expansion
    treatment_effect: INHIBITS
    description: Medical therapy can reduce or stabilize cyst-associated liver volume.
  therapeutic_modality: PEPTIDE
- name: Aspiration sclerotherapy
  description: >-
    A dominant large or strategically located accessible cyst causing symptoms may be treated
    by image-guided aspiration with sclerosis. This is a targeted approach rather than a treatment
    for all diffuse small cysts; recurrence of symptoms is more frequent in PLD than in a solitary
    simple cyst.
  treatment_term:
    preferred_term: Aspiration sclerotherapy
    term:
      id: NCIT:C62732
      label: Sclerotherapy
  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: OTHER
    snippet: >-
      When a large or strategically located cyst is the main cause of symptoms, percutaneous
      aspiration sclerotherapy can also be performed in the context of PLD.
    explanation: Guideline selection is based on the symptomatic dominant cyst.
    quote_role: REVIEW_SYNTHESIS
  target_mechanisms:
  - target: Hepatic mass effect
    treatment_effect: INHIBITS
    description: Targeted cyst decompression can relieve compression symptoms.
- name: Cyst fenestration or selected hepatic resection
  description: >-
    Fenestration is considered for accessible superficial large cysts; segmental resection can
    help severe disease clustered in selected segments with sufficient spared parenchyma and
    patent vasculature. These procedures carry morbidity, recurrence and possible difficulty
    at later transplantation. In the 186-patient combined resection/fenestration series, 170
    had ADPKD and only 16 ADPLD; major complications occurred in 21% and 90-day mortality was
    2.7%. Its durable median 61% volume reduction comes from selected patients at a single expert
    center, not a randomized comparison with transplantation.
  treatment_term:
    preferred_term: Cyst fenestration or selected hepatic resection
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:27016902
    reference_title: >-
      Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst
      Fenestration for Massive Polycystic Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sustained long-term reductions in LV after PHCF can be achieved in selected patients with
      severe, highly symptomatic PLD.
    explanation: >-
      Retrospective single-center series, predominantly ADPKD; selection and missing follow-up
      imaging limit generalization.
    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: OTHER
    snippet: >-
      Since surgical resection in PLD is associated with high morbidity, especially in the presence
      of vascular abnormalities and biliary dilatation
    explanation: Guideline cautions against treating resection as a universally appropriate option.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Hepatic mass effect
    treatment_effect: INHIBITS
    description: Reducing cyst burden can relieve mechanical symptoms.
- name: Liver transplantation
  description: >-
    Refer selected patients with massive symptomatic PLD, severe malnutrition, refractory vascular
    complications or recurrent complications when other approaches fail or are unsuitable. Preserved
    synthetic function can make conventional MELD underestimate burden, requiring local exception
    pathways. Combined liver-kidney transplantation is considered only for substantial independent
    renal disease, not automatically for isolated ADPLD.
  treatment_term:
    preferred_term: Liver transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  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: OTHER
    snippet: >-
      Liver transplantation is the only curative treatment for PLD and only the most severe
      cases with massive PLD are eligible.
    explanation: EASL limits transplantation to selected severe disease and discusses allocation despite preserved liver function.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Hepatic mass effect
    treatment_effect: INHIBITS
    description: Removing the cystic liver eliminates the source of compression.
- name: Estrogen exposure counseling
  description: >-
    Review estrogen-containing contraception and hormone replacement; EASL recommends stopping
    exogenous estrogen in female patients with PLD. Choose alternatives through individualized
    reproductive counseling. Evidence for pregnancy as an independent progression factor is
    inconsistent, and patients should not be counseled against pregnancy solely because of PLD.
  treatment_term:
    preferred_term: Estrogen exposure counseling
    term:
      id: NCIT:C61547
      label: Counseling
  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: OTHER
    snippet: Stopping exogenous oestrogen administration is recommended in female patients with PLD
    explanation: >-
      EASL recommendation based on observational and experimental evidence; prevention benefit
      from withdrawal has not been proven in a definitive trial.
    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: OTHER
    snippet: Patients with PLD should not be counselled against pregnancy
    explanation: The recommendation distinguishes exogenous estrogen use from pregnancy counseling.
    quote_role: REVIEW_SYNTHESIS
- name: Nutritional and exercise rehabilitation
  description: >-
    For severe PLD with early satiety, malnutrition or sarcopenia, provide dietitian-supervised
    nutrition and physical rehabilitation. Small frequent meals can help intake. Avoid interpreting
    liver-related body weight as preserved muscle mass; no specific diet is established to prevent
    cyst formation.
  treatment_term:
    preferred_term: Nutritional and exercise rehabilitation
    term:
      id: NCIT:C15747
      label: Supportive Care
  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: OTHER
    snippet: Patients with PLD and sarcopenia should receive intensive nutrition and exercise rehabilitation
    explanation: Guideline supports multidisciplinary nutritional and functional care.
    quote_role: REVIEW_SYNTHESIS
  target_mechanisms:
  - target: Reduced nutritional intake
    treatment_effect: INHIBITS
    description: Individualized nutrition can mitigate inadequate intake and its consequences.
- name: Genetic and reproductive counseling
  description: >-
    Explain variable expression, the 50% transmission risk for a heterozygous pathogenic allele,
    limits of negative testing and uncertainty from VUS. Offer preconception counseling and
    discuss reproductive testing when a familial variant is known. Do not convert a candidate
    LRP5 variant into a definitive diagnosis without reassessment.
  treatment_term:
    preferred_term: Genetic and reproductive counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  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: OTHER
    snippet: Patients with PLD should receive preconception counselling concerning the risk of passing on PLD to the newborn
    explanation: EASL recommends preconception counseling.
    quote_role: REVIEW_SYNTHESIS
- name: Pain and complication management
  description: >-
    Evaluate new severe pain for hemorrhage, infection, rupture or obstruction rather than attributing
    it automatically to stable liver size. Provide individualized analgesia and targeted management
    of confirmed complications; avoid unnecessary cyst intervention for mild asymptomatic disease.
  treatment_term:
    preferred_term: Pain and complication management
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Supportive management with analgesics is the first-line treatment in patients with acute
      or chronic abdominal pain and tenderness.
    explanation: Clinical review supports symptom care alongside evaluation for acute complications.
    quote_role: REVIEW_SYNTHESIS
references:
- reference: ORPHA:2924
  title: Isolated polycystic liver disease
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:23296249
  title: Diagnosis and management of polycystic liver disease.
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:24886261
  title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:26877954
  title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:27016902
  title: >-
    Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst
    Fenestration for Massive Polycystic Liver Disease.
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:22974902
  title: 'Liver transplantation for massive hepatomegaly due to polycystic liver disease: an extreme case.'
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:29038287
  title: Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:35487607
  title: Polycystic Kidney/Liver Disease.
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:36246085
  title: Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:38097330
  title: Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.
  found_in:
  - Autosomal_Dominant_Polycystic_Liver_Disease-deep-research-fallback.md
  findings: []
- reference: PMID:29243290
  title: A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
- reference: PMID:28375157
  title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
- reference: PMID:24706814
  title: Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.
- reference: PMID:21685914
  title: >-
    A genetic interaction network of five genes for human polycystic kidney and liver diseases
    defines polycystin-1 as the central determinant of cyst formation.
- reference: PMID:21856269
  title: >-
    Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant
    polycystic liver disease.
- reference: PMID:23209713
  title: Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease.
- reference: PMID:20431041
  title: Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
- reference: PMID:19646443
  title: 'Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.'
- reference: PMID:41328663
  title: >-
    Medical Management of Polycystic Liver Disease: A Position Statement From the European Reference
    Network on Hepatological Diseases.
- reference: url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
  title: https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
  findings:
  - statement: EASL Clinical Practice Guidelines on the management of cystic liver diseases (Journal of Hepatology, 2022; DOI:10.1016/j.jhep.2022.06.002; PMID:35728731). Full guideline PDF from the Sociedade Brasileira de Gastroenterologia mirror. The title field preserves the generated cache metadata.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2900957/
  title: >-
    Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic
    Kidney and Liver Disease - PMC
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05281328
  title: https://clinicaltrials.gov/api/v2/studies/NCT05281328
  findings:
  - statement: ClinicalTrials.gov v2 structured record for POSITANO (NCT05281328), including posted results and extension status, retrieved September 2026.
- reference: PMID:28862642
  title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
  findings:
  - statement: >-
      Corrigendum to PMID:28375157 corrects Pkd1 RT-PCR primer sequences; it does not retract
      the genetic or cell-rescue conclusions.
discussions:
- discussion_id: adpld_lrp5_validity
  kind: KNOWLEDGE_GAP
  prompt: Does LRP5 independently cause ADPLD after excluding linked GANAB variation?
  attaches_to:
  - genetic#Reported LRP5 association
  rationale: >-
    The initial linked family and Wnt assays support an association, but linked noncoding GANAB
    variants and incomplete functional validation leave causal attribution contested.
  status: OPEN
  evidence:
  - reference: PMID:29243290
    reference_title: A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the close proximity of LRP5 and GANAB on chromosome 11 precludes the use of linkage or
      segregation analyses alone to distinguish the disease genes in this region.
    explanation: >-
      Authors question causal attribution in the earlier LRP5 pedigree. Their own GANAB family
      is distinct; the original LRP5 family was not shown to carry a GANAB mutation.
notes: >-
  Reviewed the manual source-curation fallback report; it is not a completed external provider
  report. Most catalog frequencies lack age and ascertainment denominators. ADPLD must be distinguished
  from ADPKD before transferring renal prognosis or vascular-screening advice. Limited renal
  cysts can occur without progressive polycystic kidney disease. Some catalog associations remain
  unconnected because their mechanism is not established. LRP5 remains represented as disputed
  rather than erased or treated as definitively refuted. Mouse PC1 rescue and cell knockout
  evidence are not human therapeutic efficacy; proteasome inhibition is experimental and is
  not a clinical treatment recommendation.
clinical_trials:
- name: NCT00426153
  status: COMPLETED
  description: >-
    Registry phase 2/3 trial of octreotide LAR in severe PLD. The published first-year randomized
    comparison enrolled 42 participants, including eight with ADPLD, assigned 28 to octreotide
    and 14 to placebo. Liver volume was the primary endpoint; renal endpoints excluded ADPLD
    and do not establish kidney protection.
  target_phenotypes:
  - preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: clinicaltrials:NCT00426153
    reference_title: >-
      Pilot Study Of Long-Acting Octreotide (Octreotide LAR® Depot) In The Treatment Of Patients
      With Severe Polycystic Liver Disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A total of 42 patients will be recruited -14 who will receive placebo and 28 the study drug.
    explanation: Registry purpose statement; current status and phase were independently verified through the live registry.
  - reference: PMID:20431041
    reference_title: Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically
      unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048).
    explanation: >-
      One-year 42-patient randomized trial: 34 ADPKD and eight ADPLD. The overall volume effect
      is not an independently powered ADPLD subgroup estimate. Two SF-36 subdomains improved
      within the treated group; broad quality-of-life benefit was not uniform.
    quote_role: PRIMARY_RESULT
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2900957/
    reference_title: >-
      Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic
      Kidney and Liver Disease - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The dose was reduced to 30 mg in seven and 20 mg in four patients receiving octreotide,
      mostly because of diarrhea/loose stools, especially in the first 2 weeks after an injection
    explanation: >-
      Full-text tolerability results limit the abstract statement that treatment was well tolerated;
      one participant also had persistent steatorrhea and weight loss.
    quote_role: PRIMARY_RESULT
- name: NCT05281328
  status: ACTIVE_NOT_RECRUITING
  description: >-
    POSITANO phase 2/3 trial compares weekly or fortnightly CAM2029 octreotide depot with placebo
    in symptomatic PLD. The 53-week randomized period is complete and registry results were
    posted June 2026; the open-label extension remains active, with estimated study completion
    in August 2027. Seventy-one participants were randomized, and the posted primary volume
    analysis includes 67 with baseline MRI. Registry-reported mean changes were -0.7% for combined
    CAM2029 arms and +3.9% for placebo, with estimated relative difference -4.3% (95% CI -8.4
    to -0.1; P=0.0443). These mixed-etiology registry results do not establish an ADPLD-specific
    effect or a licensed indication.
  target_phenotypes:
  - preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: clinicaltrials:NCT05281328
    reference_title: >-
      A Randomized, Placebo-controlled, Double-blind, Multi-center Trial to Assess Efficacy
      and Safety of Octreotide Subcutaneous Depot (CAM2029) in Patients With Symptomatic Polycystic
      Liver Disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of the trial is to compare the effectiveness and safety of 2 treatment regimens
      of CAM2029 (given weekly or every 2 weeks) to placebo in participants with symptomatic
      PLD, either isolated as in autosomal dominant PLD (ADPLD) or associated with autosomal
      dominant polycystic kidney disease (ADPKD).
    explanation: Registry summary defines the population and randomized comparison.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT05281328
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT05281328
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The baseline MRI scan was missing for 4 participants (1 in each CAM2029 separate group and 2 in the placebo group).
    explanation: >-
      Posted primary-results population statement; 71 randomized and 67 in the displayed volume
      denominators. The live registry includes both results and continuing extension status.
    quote_role: PRIMARY_RESULT
differential_diagnoses:
- name: ADPKD with liver-predominant disease
  description: >-
    Substantial bilateral renal cysts, kidney enlargement or impaired renal function suggest
    ADPKD. GANAB and ALG8 can span the kidney/liver spectrum, so liver morphology alone is insufficient.
  evidence:
  - reference: PMID:29038287
    reference_title: Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ADPLD is defined as dominantly inherited disease with significant PLD without significant PKD.
    explanation: Review defines the clinical distinction while recognizing genic overlap.
    quote_role: REVIEW_SYNTHESIS
- name: Caroli disease or syndrome and ARPKD
  description: >-
    Communicating intrahepatic duct ectasia, recurrent cholangitis and congenital hepatic fibrosis
    favor Caroli syndrome or ARPKD rather than isolated noncommunicating hepatic cysts.
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In CS large and small intrahepatic bile duct ecstasies are accompanied with CHF.
    explanation: Review distinguishes communicating duct disease with congenital hepatic fibrosis.
    quote_role: REVIEW_SYNTHESIS
- name: Simple hepatic cysts and biliary hamartomas
  description: >-
    A few incidental cysts or small von Meyenburg complexes do not by themselves establish inherited
    ADPLD; age, family history, morphology and kidney findings matter.
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: VMC are frequently an incidental finding at radiological imaging, surgery or autopsy studies.
    explanation: Review differentiates incidental biliary hamartomas from severe inherited polycystic disease.
    quote_role: REVIEW_SYNTHESIS
- name: Cystic neoplasm or infection
  description: >-
    Complex walls, nodules, septations, enhancement or acute systemic features require evaluation
    for another cystic lesion or a superimposed complication rather than assuming uncomplicated
    ADPLD.
  evidence:
  - reference: PMID:24886261
    reference_title: 'Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PLD is a non-communicating biliary tree disorder and should be differentiated from other
      neoplastic, infectious and traumatic conditions
    explanation: The differential includes distinct diseases; listing them does not classify ADPLD as infectious.
    quote_role: REVIEW_SYNTHESIS
📚

References & Deep Research

References

23
ORPHA:2924
Isolated polycystic liver disease
No top-level findings curated for this source.
PMID:23296249
Diagnosis and management of polycystic liver disease.
No top-level findings curated for this source.
PMID:24886261
Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management.
No top-level findings curated for this source.
PMID:26877954
Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
No top-level findings curated for this source.
PMID:27016902
Outcomes and Durability of Hepatic Reduction after Combined Partial Hepatectomy and Cyst Fenestration for Massive Polycystic Liver Disease.
No top-level findings curated for this source.
PMID:22974902
Liver transplantation for massive hepatomegaly due to polycystic liver disease: an extreme case.
No top-level findings curated for this source.
PMID:29038287
Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
No top-level findings curated for this source.
PMID:35487607
Polycystic Kidney/Liver Disease.
No top-level findings curated for this source.
PMID:36246085
Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
No top-level findings curated for this source.
PMID:38097330
Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes.
No top-level findings curated for this source.
PMID:29243290
A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
No top-level findings curated for this source.
PMID:28375157
Isolated polycystic liver disease genes define effectors of polycystin-1 function.
No top-level findings curated for this source.
PMID:24706814
Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.
No top-level findings curated for this source.
PMID:21685914
A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.
No top-level findings curated for this source.
PMID:21856269
Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant polycystic liver disease.
No top-level findings curated for this source.
PMID:23209713
Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease.
No top-level findings curated for this source.
PMID:20431041
Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.
No top-level findings curated for this source.
PMID:19646443
Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial.
No top-level findings curated for this source.
PMID:41328663
Medical Management of Polycystic Liver Disease: A Position Statement From the European Reference Network on Hepatological Diseases.
No top-level findings curated for this source.
url:https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
https://socgastro.org.br/novo/wp-content/uploads/2025/01/PIIS0168827822003476.pdf
1 finding
EASL Clinical Practice Guidelines on the management of cystic liver diseases (Journal of Hepatology, 2022; DOI:10.1016/j.jhep.2022.06.002; PMID:35728731). Full guideline PDF from the Sociedade Brasileira de Gastroenterologia mirror. The title field preserves the generated cache metadata.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2900957/
Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic Kidney and Liver Disease - PMC
No top-level findings curated for this source.
url:https://clinicaltrials.gov/api/v2/studies/NCT05281328
https://clinicaltrials.gov/api/v2/studies/NCT05281328
1 finding
ClinicalTrials.gov v2 structured record for POSITANO (NCT05281328), including posted results and extension status, retrieved September 2026.
PMID:28862642
Isolated polycystic liver disease genes define effectors of polycystin-1 function.
1 finding
Corrigendum to PMID:28375157 corrects Pkd1 RT-PCR primer sequences; it does not retract the genetic or cell-rescue conclusions.

Deep Research

1

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.

Autosomal Dominant Polycystic Liver Disease Deep Research Fallback ▸

Autosomal Dominant Polycystic Liver Disease Deep Research Fallback

Provider Attempts

  • falcon: timeout --foreground 120s just research-disorder falcon Autosomal_Dominant_Polycystic_Liver_Disease produced no usable content and was terminated with signal 15.
  • openai: timeout --foreground 120s just research-disorder openai Autosomal_Dominant_Polycystic_Liver_Disease produced no usable content and was terminated with signal 15.

Because the preferred deep-research providers did not return usable content in bounded attempts, this fallback records the literature scope used for curation. All YAML evidence was taken from generated Orphanet and PubMed reference caches, not from hand-created reference text.

Literature Scope

Autosomal dominant polycystic liver disease corresponds to MONDO:0000447 and Orphanet ORPHA:2924. The Orphanet record for isolated polycystic liver disease defines the condition as genetic PCLD with numerous cysts throughout the liver, usually described as ADPCLD. It records adult onset, autosomal dominant inheritance, a European point-prevalence band of 1-9 per 100,000, HPO phenotype-frequency rows, and disease-causing gene assertions for ALG8, LRP5, PRKCSH, and SEC63.

Human clinical reviews and cohorts were used to anchor the phenotype, diagnosis, and management sections. PLD reviews define PCLD as distinct from ADPKD-associated PLD but clinically similar in producing hepatomegaly from multiple cysts with preserved liver function. They support ultrasonography as the first imaging instrument, CT or MRI liver-volume assessment for severity and risk stratification, molecular diagnostics when imaging or screening is ambiguous, and management that ranges from conservative care to somatostatin analogs, cyst-directed procedures, and liver transplantation.

The mechanistic pathophysiology is centered on the best-supported PRKCSH and SEC63 branch. The principal mechanism review links PRKCSH and SEC63 to endoplasmic-reticulum protein biogenesis and quality control, inefficient polycystin maturation, and PC1 dosage as a rate-limiting component of cystic disease in model systems. Human clinical and surgical sources then support the downstream cholangiocyte-derived epithelial cysts, hepatic enlargement, and mass-effect symptom burden.

Curation Decisions

  • Used MONDO:0000447 as the disease term because it carries the Orphanet:2924 cross-reference and matches the ADPLD/PCLD scope.
  • Included all ORPHA very frequent and frequent HPO phenotypes: polycystic liver disease, hepatomegaly, abdominal distention, multiple renal cysts, and early satiety.
  • Added selected ORPHA occasional phenotypes with coherent clinical relevance to mass-effect, hepatobiliary, vascular, cardiac, or pancreatic involvement. Feeding difficulties in infancy and the broad respiratory-system parent row were not included because this entry is adult-onset and already includes the more specific dyspnea and respiratory insufficiency rows.
  • Modeled subtypes for PRKCSH/PCLD1 and SEC63/PCLD2 with MONDO term bindings, and included ALG8-related and LRP5-related ADPLD as Orphanet-supported gene-defined subtypes without forcing unavailable local MONDO subtype terms.
  • Represented somatostatin analog therapy with generic pharmacotherapy plus an NCIT somatostatin receptor agonist therapeutic-agent binding, and kept cyst-directed surgery and liver transplantation as separate treatment entries.