Intrahepatic cholestasis

Summary

Intrahepatic cholestasis (MONDO:0019072) is a disease with 3 cohort genes and 3 clinical trials. Top therapeutic interventions include ursodiol.

At a glance

• Cohort genes: 3
• ClinVar variants: 2
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intrahepatic cholestasis
Mondo ID	MONDO:0019072
MeSH	D002780
DOID	DOID:1852
SNOMED CT	235888006
UMLS	C0008372
MedGen	3042
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › biliary tract disorder › bile duct disorder › cholestasis › intrahepatic cholestasis

Related subtypes (4): extrahepatic cholestasis, obstructive jaundice, biliary atresia, parenteral nutrition-associated cholestasis

Subtypes (2): familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374098	NM_003742.4(ABCB11):c.3148C>T (p.Arg1050Cys)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
2445978	NM_000443.4(ABCB4):c.1449CAC[1] (p.Thr485del)	ABCB4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
LSR	Moderate	Autosomal recessive	intrahepatic cholestasis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCB11	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB11	Orphanet:79304	Progressive familial intrahepatic cholestasis type 2
ABCB11	Orphanet:99961	Benign recurrent intrahepatic cholestasis type 2
ABCB4	Orphanet:69663	Low phospholipid-associated cholelithiasis
ABCB4	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB4	Orphanet:79305	Progressive familial intrahepatic cholestasis type 3

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LSR	HGNC:29572	ENSG00000105699	Q86X29	Lipolysis-stimulated lipoprotein receptor	gencc
ABCB11	HGNC:42	ENSG00000073734	O95342	Bile salt export pump	clinvar
ABCB4	HGNC:45	ENSG00000005471	P21439	Phosphatidylcholine translocator ABCB4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LSR	Lipolysis-stimulated lipoprotein receptor	Probable role in the clearance of triglyceride-rich lipoprotein from blood.
ABCB11	Bile salt export pump	Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeosta…
ABCB4	Phosphatidylcholine translocator ABCB4	Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	2	51.9×	1e-03
Antibody/Immunoglobulin	1	9.7×	0.099

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LSR	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, LISCH7
ABCB11	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
ABCB4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	3
body of pancreas	1
mucosa of transverse colon	1
liver	1
thymus	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LSR	234	ubiquitous	marker	mucosa of transverse colon, right lobe of liver, body of pancreas
ABCB11	125	tissue_specific	marker	right lobe of liver, liver, thymus
ABCB4	188	broad	marker	right lobe of liver, secondary oocyte, oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCB11	2,407
ABCB4	2,333
LSR	1,346

Intra-cohort edges

A	B	Sources
ABCB11	ABCB4	biogrid_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCB11	O95342	8
ABCB4	P21439	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LSR	Q86X29	57.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ABC transporter disorders	2	292.8×	3e-04	ABCB11, ABCB4
Defective ABCB11 causes PFIC2 and BRIC2	1	3806.7×	0.001	ABCB11
Defective ABCB4 causes PFIC3, ICP3 and GBD1	1	3806.7×	0.001	ABCB4
Disorders of transmembrane transporters	2	92.8×	0.001	ABCB11, ABCB4
VLDL clearance	1	634.4×	0.006	LSR
Metabolism of lipids	2	21.0×	0.010	ABCB11, ABCB4
Recycling of bile acids and salts	1	200.3×	0.011	ABCB11
LDL clearance	1	181.3×	0.011	LSR
Bile acid and bile salt metabolism	1	165.5×	0.011	ABCB11
Plasma lipoprotein clearance	1	158.6×	0.011	LSR
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	152.3×	0.011	ABCB11
Transport of small molecules	2	16.8×	0.011	LSR, ABCB4
Synthesis of bile acids and bile salts	1	135.9×	0.011	ABCB11
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.019	LSR
Disease	2	8.7×	0.022	ABCB11, ABCB4
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.024	ABCB4
Metabolism of steroids	1	45.9×	0.024	ABCB11
Metabolism	2	7.7×	0.024	ABCB11, ABCB4
ABC-family protein mediated transport	1	40.5×	0.026	ABCB4
PPARA activates gene expression	1	31.5×	0.031	ABCB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid homeostasis	2	224.7×	8e-04	ABCB11, ABCB4
canalicular bile acid transport	1	5617.3×	0.001	ABCB11
positive regulation of bile acid secretion	1	5617.3×	0.001	ABCB11
transmembrane transport	2	112.3×	0.001	ABCB11, ABCB4
response to fenofibrate	1	2808.7×	0.002	ABCB4
tricellular tight junction assembly	1	2808.7×	0.002	LSR
xenobiotic export from cell	1	1872.4×	0.002	ABCB11
protein localization to tricellular tight junction	1	1872.4×	0.002	LSR
obsolete regulation of bile acid metabolic process	1	1872.4×	0.002	ABCB11
positive regulation of phospholipid translocation	1	1404.3×	0.002	ABCB4
cellular response to bile acid	1	1404.3×	0.002	ABCB4
bile acid secretion	1	1123.5×	0.002	ABCB4
regulation of fatty acid beta-oxidation	1	936.2×	0.003	ABCB11
positive regulation of cholesterol transport	1	802.5×	0.003	ABCB4
positive regulation of phospholipid transport	1	802.5×	0.003	ABCB4
establishment of blood-brain barrier	1	468.1×	0.004	LSR
epithelial structure maintenance	1	401.2×	0.005	LSR
bile acid metabolic process	1	330.4×	0.005	ABCB11
phospholipid homeostasis	1	330.4×	0.005	ABCB11
xenobiotic transmembrane transport	1	312.1×	0.005	ABCB11
bile acid and bile salt transport	1	216.1×	0.006	ABCB11
bile acid biosynthetic process	1	208.1×	0.006	ABCB11
phospholipid translocation	1	208.1×	0.006	ABCB4
maintenance of blood-brain barrier	1	160.5×	0.008	LSR
establishment of skin barrier	1	151.8×	0.008	LSR
liver development	1	73.9×	0.016	LSR
fatty acid metabolic process	1	64.6×	0.018	ABCB11
cholesterol homeostasis	1	52.0×	0.021	ABCB11
xenobiotic metabolic process	1	49.7×	0.021	ABCB11
lipid metabolic process	1	30.5×	0.033	ABCB4

Therapeutics

Drugs indicated for this disease

1 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Odevixibat	Approved (phase 4)
Ademetionine	Phase 3 (in late-stage trials)
Ursodiol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Linerixibat.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ABCB11	TELMISARTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCB11	327	4
ABCB4	1	2
LSR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ABCB11	85	Binding:37, ADMET:31, Functional:13, Toxicity:4
ABCB4	4	ADMET:3, Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABCB11
B	Phased (≥1) drug, not yet approved	1	ABCB4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	LSR
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LSR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01576458	PHASE3	COMPLETED	Ursodeoxycholic Acid in the Treatment of Intrahepatic Cholestasis of Pregnancy
NCT06781242	Not specified	RECRUITING	Genotype-phenotype Relationship Between Cryptogenic Cholestasis and Familial Intrahepatic Cholestasis
NCT01381939	Not specified	COMPLETED	Induction of Labor in Intrahepatic Cholestasis of Pregnancy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
URSODIOL	4	2
CHEMBL5409583	0	1